Natural Alternative to Antihypertensive Drugs

High Blood Pressure Exercise Program

Natural Blood Pressure is a comprehensive program that helps people lower, control the high blood pressure in the most effective way. By plain explanation as well as instruction, Christian Goodman (Blue Heron), the creator of Natural Blood Pressure will drop your blood pressure to normal in less than a week. The principle behind Blue Heron Health News blood pressure program is what the author calls the focused break. This is a special breathing technique that enables blood vessels to relax, stimulating the cardiovascular system. If you have high blood pressure, then this blood pressure program is worth a try. It is either that, or continue to take medication and suffer the effects of high blood pressure. With an 8-week, full money back guarantee, you have nothing to lose but your high blood pressure! Read more...

High Blood Pressure Exercise Program Summary


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Urotensin Expression in Hypertension and Heart Failure

Contracting human coronary, mammary, and radial arteries in responding tissue however, some samples fail to respond to urotensin but are reactive toward ET-1 (69). These results demonstrate binding of urotensin to the urotensin receptor in the human vasculature. Urotensin gene expression is abundant in the human kidney and atrium and throughout the vasculature (70). Urine levels of urotensin are significantly higher in hypertensive compared with normotensive individuals and suggest that the kidney may produce urotensin in hypertension. A role for urotensin in essential hypertension has been confirmed in a study by Cheung et al. (71), which showed that plasma levels of urotensin are significantly higher in hypertensive patients compared with normotensive subjects and correlate with systolic BP.

Treatment Of Arterial Hypertension

Natriuretic peptides are increased in patients with LV hypertrophy, above-normal LV mass index, and LV diastolic dysfunction. Therefore, measurements of natriuretic peptides in hypertensive patients would not permit an accurate differentiation between the pathophysiological mechanisms known to cause elevations of natriuretic peptides in arterial hypertension (24). Despite these limitations, Kato et al. (25) have reported that both ANP and BNP were significantly increased in patients with essential and malignant hypertension when compared to normotensive controls. These levels significantly declined after the patients received adequate antihypertensive treatment. It has also been shown that regression of LV mass is paralleled by a significant decline in plasma BNP levels in hypertensive patients. An interesting study by Minami et al. (26) in obese hypertensive patients shows that a dietary intervention using a standard diet of 2000 kcal d followed by a hypocaloric diet of 850 kcal d...

Definition Classification and Diagnosis of Hypertension

Hypertension is a disorder of the cardiovascular system characterized by elevated arterial blood pressure. The blood pressure in the arteries is dependent on the energy of cardiac contractions, elasticity, and contractile state of arterial walls, as well as on the volume and viscosity of the blood. It fluctuates with every heartbeat. The maximal pressure occurs near the end of the stroke output and is termed systolic. The minimal pressure occurs late in ventricular diastole and is termed diastolic. Individuals with a systolic blood pressure at or under 120mmHg and diastolic pressure at or under 80 mmHg are considered normotensive. The term 'prehypertensive' is used for individuals with a systolic pressure under 140, but above 120 mmHg and diastolic pressure under 90, but above 80 mmHg. Patients with 140-159 mmHg systolic and over 90 mmHg diastolic have phase I hypertension, while patients with systolic pressure over 160 mmHg and diastolic pressure over 100 mmHg have phase II...

Pathophysiology Biochemistry and Genetics of Hypertension

The pathophysiology of essential hypertension has been extensively studied over the last 50 years. Peripheral vascular resistance is usually increased in hypertensive individuals. Normally, the autonomic nervous system, kidneys, adrenal cortex, local hormones, and cytokines regulate vascular resistance. Failure of the normal regulation of vascular resistance leads to hypertension. The failure can theoretically occur in any part of the regulatory system. Initially, overactivity of the sympathetic nervous system plays a major role in the development and maintenance of hypertension. The excessive activation of the renin-angiotensin system (RAS) or enhanced sensitivity to its primary effector, Ang II, contributes to the development and maintenance of hypertension. The fact that inhibitors of the formation of Ang II or its antagonists at the receptor level are highly useful antihypertensive drugs supports the likely involvement of RAS in the pathogenesis of hypertension. Since calcium ions...

Mineralocoticoid Hypertension

In 1942 Selye described experimental mineralocorticoid hypertension in rats produced by desoxycorticosterone acetate (DOCA) and salt. It is a low-renin salt-dependent model, which has been widely used in the evaluation of antihypertensive drugs. Recently this model has been shown to be useful in the evaluation of endothelin antagonists. The endothelin system was found to be involved in the pathogenesis of low-renin hypertension16 and endothelin antagonists lower arterial pressure in DOCA-salt hypertensive rats. Iglarz et al17 reported that rosiglitazone, an activator of peroxisome proliferator-activated receptor g (PPARg), prevents the development of hypertension in DOCA-salt rats.

Spontaneous Hypertension

The first strain of rats with inheritable hypertension was bred in New Zealand by Smirk and Hall and is known as New Zealand hypertensive rats. Most of the currently available SHRs are derived from the strain developed in Japan by Okamoto and Aoki. The substrains of Okamoto-Aoki rats have undergone changes and differ in various aspects from the original strain. Okamoto-Aoki SHRs have been cross-bred with strains with other inheritable abnormalities, including hyperlipemia and obesity. The stroke-prone SHRs (SPSHRs) die from a type of stroke that resembles a rare The importance of salt intake in the pathogenesis of hypertension has been explored using Dahl salt-sensitive (DSS) and Dahl salt-resistant (DSR) rats. It has been reported that optimal dietary potassium chloride (2.6 ) can prevent hypertension and protect cerebral and renal vasculature in DSS rats fed a 1 sodium chloride-containing diet for 8 months.19 Lighthall eta .20 detected three new salt-sensitive genes in the kidneys...

Treatment of Hypertension

The current JNC VII guidelines recommend that antihypertensive therapy should start with a thiazide diuretic or a b-adrenoceptor antagonist as the first choice and newer drugs should only be added in special circumstances.1 Some investigators disagree, however, with the JNC recommendations and feel that drugs inhibiting RAS - ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) - should be the first-line drugs in the treatment of hypertension, since they provide benefits beyond blood pressure reduction. Extended-release formulations of calcium antagonists are also often used as first-line therapy.

Drug Resistant Hypertension

Many cases of drug-resistant hypertension are in reality unrecognized failures of compliance. There are, however, patients who do not respond to any of the available drugs or their combinations. The most common cause of drug-resistant hypertension is atheroscleroric renal artery disease. These patients may respond to minoxidil, a highly effective vasodilator. Its side effects include tachycardia and hair growth, as well as sodium and water retention. Because of its side effects, it is rarely used clinically. The mechanism of its antihypertensive action involves activation of vascular KATP channels. There is a need for a safer KArP channel activator for the treatment of drug-resistant hypertension.

Hypertension in Hemodialysis Patients

Hypertension occurs in 90 of patients starting hemodialysis and persists in 70-90 of hemodialysis patients in the US 57 . In the large, multicenter Hemodialysis (HEMO) Study more than 70 of patients were hypertensive by JNC VI guidelines, and almost 75 required antihypertensive medications 58 . This is contrary to the situation in the late 1960s, when strict control of true dry body weight was practiced and the majority of patients did not require antihypertensive agents 59 . There is a consensus that most patients on dialysis have volume-dependent hypertension. Only a small proportion of patients have vasoconstrictive hypertension requiring bilateral nephrectomy in the past 59 or blood The possibility of controlling blood pressure in a reno-prival state by drastic reduction in dietary salt intake was first shown by Kempner 60, 61 in the 1940s. It was subsequently shown that the beneficial effect of the 'rice diet' on hypertension was related to the lowering of plasma volume and...

High Blood Pressure and Kidney Failure

Hypertension (high blood pressure) is a common feature of renal failure. It appears in most patients at some point as the disease progresses. The reasons for hypertension in almost all patients with chronic kidney disease (in addition to those whose hypertension is their primary disorder) are complex, but have to do with hormones produced by normal kidneys that regulate blood pressure, especially hormones that control sodium balance. In susceptible people, retention of sodium increases blood pressure, and hormones that increase the sodium content of the body tend to be produced in increased amounts. Other hormones may play a role in hypertension as well, including parathyroid hormone and insulin, both of which tend to rise in patients with hypertension. The body tends to pro duce decreased amounts of substances normally released by the kidneys that lower blood pressure. For these many reasons, high blood pressure is a very common feature of kidney failure. Occasionally people have...


Natriuretic peptides appear to play an important role in preventing the development of arterial and pulmonary hypertension. Overexpression ofthe genes encoding ANP and BNP results in raised circulating concentrations of these peptides and substantially decreased arterial BP (173,174). Moreover, overexpression of ANP protects against the development of pulmonary hypertension in animals exposed to chronic hypoxia. Conversely, ANP gene KO mice are prone to develop salt-sensitive arterial hypertension and pulmonary hypertension with accompanying right ventricular hypertrophy (175). The ability of ANP to defend against salt-induced arterial hypertension may reflect a combination of the natriuretic, diuretic, vasorelaxant, and sympathoinhibitory properties of this pep-tide. The NPR-A gene KO mice phenotype is also characterized by arterial hypertension, which appears to be independent of sodium loading (176). Genetic disruption of NPR-A is also associated with a marked cardiac hypertrophy...

Diet Hypertension

The major dietary risk factors for hypertension and stroke are as follows 4 Overweight. Obesity is commonly associated with high blood pressure. Overweight hypertensive persons who lose weight often experience a significant reduction in blood pressure.21 intake of essential PUFAs can increase risk of high blood pressure (see Fig. 5.9). 4 Salt. Although for most people sodium in the diet plays only a minor role in determining blood pressure, some individuals are very sensitive to sodium in the diet. Individuals with a family history of hypertension or who are older than 55 years are most likely to be sodium sensitive.22 In about one-third of cases of hypertension, blood pressure can be significantly lowered by limiting sodium intake, most of which comes from salt added to processed foods, such as bread, cheese, canned soups and salty snacks. 4 Potassium. High sodium intake is a much stronger risk factor when combined with low potassium intake.5 People with low intakes of potassium are...

Defining intermediate endpoints or surrogates

The second point implicit in the Prentice criterion is that the IE S is chosen in a way that depends on the interventions under comparison. For example, cholesterol reduction may serve as an IE S for CAD in a trial of a cholesterol-lowering drug, but it is unlikely to be useful in a study of antihypertensive drugs. In addition, once validated, cholesterol may be a valid IE S for trials of other cholesterol-lowering agents, but not for an E I acting via a different pathway. Universal IE Ss which apply for all E Is are very rare. This point is directly related to the position of the IE S on the disease pathway. Cholesterol changes may serve as an IE S for CAD provided that the treatments under study do not differentially affect CAD via pathways that bypass the cholesterol-lowering effect - if they have a side effect of raising blood pressure, for example.

The Merger Between Merck Co Inc and Sharp Dohme

I should like to stress, however, that the first post-merger product was the discovery by the Sharp and Dohme arm of the diuretic chlorothiazide, a major breakthrough. The compound was synthesized by one of Dr James Sprague's chemists, Dr Novello. The biology was headed by Karl Beyer, MD, PhD, a renowned pharmacologist. Chlorothiazide was truly a breakthrough diuretic. Its marketing potential was greatly underestimated for two reasons chlorothiazide was the first diuretic which, unlike the prior mercurials, was a drug, not a poison, and, secondly, it proved to be not only a safe diuretic but, importantly, also a very effective antihypertensive.

Compounds possessing two symbiotic biological activities

We tried a different approach to discover compounds with two symbiotic biological activities. Instead of screening for leads possessing two desired symbiotic properties, we sought to discover them by design. Since the structural requirements for beta adrenergic blockade are reasonably simple, we started with vasodilators and we tried to incorporate b2 adrenergic blockade by design. In fact, in a 1979 publication, the Medicinal Chemistry and Pharmacology Department at West Point, PA reported the design and synthesis of an antihypertensive beta adrenergic blocking agent that also acted as a vasodilator. We thought that the vasodilating property of this compound was an intrinsic property of the pharmacologic profile and that the vasodilating component was not due to b2 adrenergic agonism.44 This molecule was therefore thought to represent an example of the ''symbiotic approach to drug design.'' Later on we concluded, however, that in fact the vasodilating properties of the compounds in...

Glomerular permeability

There is a clear diurnal variation in albumin excretion which disappears as blood pressure increases 9 . It has also been shown that the proportion of patients with so-called microalbuminuria increases with increased blood pressure - being 12-15 in patients with borderline hypertension to more than 50 in patients with severe hypertension 10 . Albumin excretion can be used to detect hypertension, although there are no comparative data to suggest that it is a more reliable indicator than the measurement of blood pressure itself. Albumin excretion also correlates with changes in blood pressure in patients treated with antihypertensive agents 11 . Indeed, this test can be used to compare the efficacy of different antihypertensive agents 11, 12 and it may prove to be useful in both the detection and monitoring of hypertension (Table 5.3). Detection of hypertension Evolution of hypertension Monitoring of hypertensive therapy Prediction of outcome Increased albumin excretion in patients with...

Methyldopa progenitors

A second significant assignment related to one of Merck's most important products at that time, methyldopa the antihypertensive discovered by Drs Pfister and Stein. Methyldopa had one significant liability its oral bioavailability varied from patient to patient. Our task was, therefore, to discover an oral prodrug with high and predictable bioavailability. Given the medical importance of this antihypertensive medicine, I made an unusual decision I put every organic chemist in the department on the problem and launched a crash program. As I had expected, the well-disciplined West Point medicinal chemists responded beautifully. The project, which was termed ''ester progenitors of methyldopa'' was the subject of a 19 7846 publication by Walfred S. Saari and his collaborators. The program led to the discovery that the pivaloyloxyethyl and the succinimidoethyl esters of methyldopa were more potent antihypertensive agents than methyldopa after oral administration in the SH rat. All esters...

Breakthrough at the Squibb Institute of Medical Research

The first acute challenge to face Basic Research after the reorganization was the breakthrough discovery of captopril, the first potent, orally bioavailable, competitive inhibitor of the angiotensin-converting enzyme by Drs Ondetti and Cushman and their collaborators at the Squibb Institute of Medical Research in Princeton, NJ, in 19 7 7.55 The discovery of an inhibitor for this carboxydipeptidase represented the first successful blockade of the renin-angiotensin system, thus all but validating also renin as a target for enzyme inhibitor design. Captopril proved to be an important new medicine for the treatment of hypertension. The angiotensin-converting enzyme is a zinc-containing exopeptidase. In the design of captopril, Drs Ondetti, Cushman, and their collaborators, built on the presumed similarities of this enzyme and carboxypeptidase A. As pointed out by Dr Cushman et al.56 angiotensin-converting enzyme may play a role in blood pressure regulation both because it 'converts' the...

The structural basis for renal disease

In type 1 diabetes, structural lesions are not present at the time of diagnosis of nephropathy, although nephromegaly and glomerulomegaly may be quite common 11, 23, 24 These phenomena are, however, not signs of diabetic renal disease but may be predictive of late structural lesions and clinical nephropathy 23 . In type 1 diabetes, the structural changes, e.g. increase in basement membrane thickness and mesangial expansion, develop a few years after the onset of diabetes, and progress is thereafter related to glycaemic control and blood pressure 16 . Another risk factor is obviously duration of diabetes or exposure time to risk factors. Initially, the changes are only seen by morphometry, but, later on, clear-cut changes are found as initially described by Kimmelstiel and Wilson 25 . Regression of a lesion may or may not be seen with glycaemic normalization and stabilization with antihypertensive treatment 14 . Earlier in the history of diabe-tology, it was suggested that changes...

Improved Second Generation Converting Enzyme Inhibitors

After my retirement from Merck, when consulting for various biotechnology companies and also for big Pharma, I would encounter situations where a breakthrough had been achieved either by those companies themselves, or by their competitors. When I urged them to act on these events more expeditiously, I was sometimes told that switching manpower would be bad for the morale of the scientists being transferred. I do not believe that this assessment is generally valid, because the company's interests may demand such action and also because medicinal chemists prefer to be on a 'hot project' rather than a lukewarm one. Both of these considerations guided the decision at Merck to increase manpower dramatically on the angiotensin-converting enzyme inhibitor program. Patchett's success paid off handsomely for many hypertensive patients and, in the process, also for Merck & Co., Inc.

Estimation of GFR and renal function

It is characteristic for diabetic patients with normo- or microalbuminuria for the GFR to be increased above normal, the so-called hyperfiltration phenomenon 1, 49-51, 63 although this is not so pronounced in type 2 diabetes. Hyperfiltration may be predictive of late nephropathy 50, 51 , as nephromegaly is also 23 . Therefore, in early diabetic renal disease, it can be expected that serum creatinine or other similar serum or plasma markers may be decreased, reflecting the glomerular hyperfiltration. With overt nephropathy, GFR starts to decrease, correlated to blood pressure level and HbA1c 1, 64 . Without any intervention, GFR typically decreases around 10 ml min year in type 1 diabetes and to a similar extent in type 2 diabetes in poorly controlled individuals 65 . However, this rate of decline can clearly be reduced by antihypertensive treatment and improved glycaemic control - the rate can be most clearly reduced in type 1 diabetes 1, 64 .

Who Benefits from Guidelines

Industry heavily underwrites guideline creation, at least in nephrology. Amgen is the principle sponsor of the NKF-K DOQI guidelines, and as Coyne points out (op. cit.), with potential financial benefits from guidelines for anemia and bone management. There are many other examples. The entire guideline process is tilted towards increasing use of pharmaceuticals since most clinical trials are sponsored drug studies (funded by industry). It is easy to see how guidelines recommending ever-lower blood pressure, cholesterol and glycosylated hemoglobin targets could fuel a major expansion of drug prescribing in these areas.

A new mechanism to lower plasma cholesterol levels in humans the discovery of ezetimibe at Schering

It is of interest to note that combining antihypertensive medicines that lower blood pressure via diverse mechanisms represents a widely accepted regimen. Indeed, a combination of two or more different modes of action are required in some patients to achieve adequate control of blood pressure. The fixed combination ezetimibe simvastatin is another example that shows that combining drugs that approach a medical problem via two different biochemical pharmacologic mechanisms can be beneficial. The concept is not new and is used extensively also in the treatment of cancer, asthma, and congestive heart failure.

Use in Prevention and Therapy

Calcium can reduce blood pressure in hypertensive patients, particularly those who are salt sensitive or who have low plasma levels of renin (the kidney pressor hormone) (Fig. 3.10).1,8,9 Risk of hypertensive disorders of pregnancy (pree-clampsia) may be reduced by ample intake of calcium10. daily supplement of 1500 mg of calcium given to women with hypertension for 4 years produced significant and sustained lowering of systolic blood pressure. In the supplemented group mean systolic press-urefell by 13 mm Hg inthe unsupplemented group it increased by 7 mm Hg.

Regional Differences and Variability in Left Ventricular Wall Motion

In our understanding of the mechanical performance of the heart as a pump we mostly rely on the famous studies of Otto Frank1 and Ernest Starling2 whose observations have been widely accepted for a century. Thus, the clinical therapeutic regimens contain volume substitution (preload), antihypertensive therapy (afterload), bradycardic agent (heart rate) and positive inotropic agent (contractility) drug administration. All these maneuvers involve the heart as a whole. In most of our patients, however, just parts of the ventricle are injured by insufficient energy supply. Therefore, if we treat the ventricle as a whole we may ask whether all the parts of the ventricle act in unison. When we look at heart preparations for morphological analyses (Fig. 5.1) it becomes obvious from the global as well as local anisotropy that there must be an inhomogeneity in myocardial contraction i) across the ventricular wall, ii) from site to site from apex to the base, and, moreover, iii) at any site...

By Zinc ProtoporphyrinIX and Other ho Inhibitors

It may be argued that the change in vascular contractility after the application of HO inducers represents the effect of over-produced endogenous CO. It is still physiologically relevant but does not reflect what can happen under basal conditions. Application of HO inhibitors will help to determine the vascular effect of endogenous CO under basal or resting conditions. The most often used HO inhibitors belong to the family of metalloporphyrins, including ZnPPIX, SnPPIX, cobalt protoporphyrin IX (CoPPIX), and chromium mesoporphyrin (CrMP).61 Intraperitoneal injection of HO inhibitors such as ZnPPIX increased blood pressure and peripheral resistance in normal SD rats.62 The application of HO inhibitors also abolished the antihypertensive effect of HO inducers in vivo53'55 and the vasorelaxant effect of HO inducers in vitro.7,58,59

Mechanisms Indications and Side Effects

Angiotensin converting enzyme inhibitors Block conversion of angiotensin I to II in lungs and vascular endothelium, reduced peripheral vascular resistance (PVR), lower blood pressure indications hypertension side effects reduced bradykinin breakdown in lungs, causing angioedema and cough. Management of toxicity Epinephrine, Hj-blockers, steroids. Angiotensin receptor blockers Decrease formation of angiotensin II at vascular receptor sites indications hypertension side effects few, bradykinin metabolism unaffected, no angio-edema and cough so common with ACE inhibitor therapy. All Produce vascular smooth muscle relaxation with peripheral vasodilation and triggering of baroreceptor-mediated tachycardia main uses hypertension.

Pheochromocytoma and Weight Loss

Pheochromocytoma is a tumour that produces cat-echolamines and is usually derived from adrenomedullary chromaffin cells. When it arises from extra-adrenal chromaffin cells, the tumours are called extra-adrenal PCC or paragangliomas. Similar clinical manifestations may occur in other related tumours that secrete catecholamines, such as chemodectomas and ganglioneuromas 26, 31 . The rarity of PCCs (fewer than 1 of hypertensive patients) should not reduce the importance of these tumours. In fact, when diagnosed and treated, PCC is curable, while when misdiagnosed it can be fatal. Most PCC (90 ) are benign. Occasionally PH is inherited as an autosomal dominant trait and may be part of a multiple The clinical manifestations of PCC are due to the effects of the catecholamines that are stored and released in an uncontrolled way and in large amounts by the tumours 32, 33 . They include (1) sustained hypertension resistant to conventional treatment, (2) hypertensive crisis with malignant...

The Multiple Actions of Carvedilol Antioxidant Properties

However, following detailed medical and commercial analyses, the company decided not to aggressively pursue the indications of angina and hypertension for a number of reasons (1) there was little medical need for another drug to treat these disorders, (2) there were, at the time, no known properties of carvedilol to differentiate the drug from others in the class, (3) generic beta blockers were already available and in wide use, and (4) due to the high promotional expenditure that would be required to penetrate these well-satisfied markets, the commercial return would be low. So in the mid- to late-1980s, the carvedilol program at SmithKline Beecham hit a roadblock, and sat on the verge of termination all for good and logical medical and commercial reasons. A different potential explanation for the extraordinary cardioprotective effects of carvedilol in models of cardiac ischemia and infarction surfaced in the literature. At that time, Weglicki and colleagues suggested that the...

Clinical Trial Issues

From an efficacy perspective, clinical trials of ocular hypotensive agents can be relatively short with well-defined endpoints of IOP reduction following once or twice daily dosing. However, recruitment of glaucoma and ocular hypertensive patients and the provision of the NCE in the correct formulation with reasonable shelf-life and stability are formidable challenges fraught with logistics issues and, ultimately, patient compliance.

Black Cohosh Cimicifuga racemosa

Black cohosh is a plant native to North America. Its root is used for menstrual and premenstrual symptoms. It may have an estrogenic effect (8). It has also been used as a sedative and in the treatment of epilepsy and chorea. A report documents one person experiencing a seizure when taking this herb, but the subject was also using evening primrose oil, a possible proconvulsant (1). Black cohosh is generally well tolerated at usual doses, producing occasional gastrointestinal side effects. This herb is contraindi-cated during pregnancy due to an increased incidence of spontaneous abortion. It also amplifies the effects of antihypertensive medications, possibly resulting in low blood pressure (8).

Definition of Metabolic Syndrome

MetS is a commonly occurring cluster of clinical phenotypes that are individually and collectively strongly related to cardiovascular disease.2 MetS is characterized by disturbed carbohydrate and insulin metabolism, and is clinically defined by threshold values applied to indices of central obesity, dysglycemia, dyslipidemia, and or elevated blood pressure, which must be present concurrently in any one of a variety of combinations.2'3 The cardinal feature of MetS is abdominal obesity, as quantified most directly by increased waist circumference.4,5 Biochemically, MetS is characterized by insulin resistance - hyperinsulinemia - and by dyslipidemia - most typically raised triglycerides and or reduced HDL cholesterol. Additionally, a range of biochemical abnormalities have been secondarily associated, including increased serum concentrations of apolipoprotein B, fibrinogen, free fatty acids, C-reactive protein (CRP), tumor necrosis factor (TNF)-a, interleukin-6, and plasminogen activator...

Benefits of Glycemic Control

The Epidemiology of Diabetes Interventions and Complications (EDIC) study is examining the long-term effects of conventional versus intensive diabetes treatment received during the DCCTon the subsequent development and progression of microvascular, neuropathic, and cardiovascular complications. The previous intensive and conservative treatment arms are combined and have a mean HbA1C of 8 . Results from EDIC indicate that individuals with T1DM have a metabolic memory, where the benefits of a period of good glucose control continue even after HbA1C levels have risen.51 Specifically, DCCT subjects who received intensive therapy have shown a 57 reduction in cardiovascular endpoints (myocardial infarctions and strokes)52 and similar benefits with regards to the development of nephropathy,53 hypertension, and retinopathy. The UKPDS, conducted from 1977 to 1997 in 23 centers throughout England, Northern Ireland, and Scotland, verified that optimal glycemic control has similar benefits in...

Studies in MS and Other Conditions

Meditation has been investigated in a number of other medical conditions. It may improve psoriasis (a skin condition), reduce blood pressure, and improve heart function in people with heart disease. Meditation also has produced some beneficial results in various forms of addiction.

Mechanisms of Renal Dysfunction

Studies have demonstrated significant renal hemodynamic changes in hypertension and diabetes, e.g., decreased renal blood flow, increased renal vascular resistance, elevated glomerular hydrostatic pressure, and proteinuria. The exact mechanisms for renal dysfunction require further investigation and are thought to involve many factors such as activation of the renin-angiotensin system (RAS), enhanced sympathetic activity, and impaired nitric oxide signaling. All these factors lead to endothelial dysfunction and the progression of end-stage renal disease (Figure 3). Hypertension and renal dysfunction Figure 3 Mechanisms of obesity-induced hypertension. regulatory mechanisms plays a significant role in the pathogenesis and prognosis of hypertension and cardiovascular diseases. The sympathetic nervous system activity increases with age, independent of disease state.18 Elevated sympathetic activity correlates with hypertension, insulin resistance, and risk of coronary heart diseases.19...

Management of Renal Dysfunction

Management of hypertension in patients with kidney disease or diabetes is challenging, generally requiring 2-3 years of therapy to achieve the recommended blood pressure level. Studies have shown that some antihypertensive drugs can lower blood pressure without improving endothelial dysfunction and renal damage. For example, the traditional use of diuretics and a- and b-adrenoceptor blockers can lower blood pressure with no direct effect on endothelial dysfunction.53 ACE inhibitors, AT receptor blockers, and calcium channel blockers are the most effectively used treatment for hypertension as they lower blood pressure and improve endothelial dysfunction in hypertensive patients (Figure 6). Aside from the classic treatment of hypertension, an emerging approach to renal dysfunction is the treatment of the components that trigger endothelial dysfunction, e.g., NO bioavailability and oxidative stress. For example, oral treatment with L-arginine, the precursor of NO, reduces blood pressure...

Unmet Medical Need

Renal disease may lead to dysfunction of the vascular endothelium that results in enhanced formation of vasoconstrictor peptides such as ET-1 and thromboxane, decreased formation of vasodilators such as EETs, NO, and prostacyclin, and increased formation of superoxide and inflammatory cytokines. These endothelial abnormalities impair pressure natriuresis and increase blood pressure. Although current antihypertensive drugs effectively reduce blood pressure by promoting the excretion of sodium and water and shift the pressure-natriuresis relationship back to normal, these drugs fail to correct all the pathophysiological changes that occur as a result of hypertension and endothelial dysfunction such a structural changes in renal vasculature, impaired renal autoregulation, tubular atrophy, interstitial fibrosis, and renal hypertrophy. Thus, future studies should focus on new drugs that can be used with current antihypertensive drugs to reduce blood pressure and correct the...

Emerging Approaches to Treat Renal Dysfunction

As mentioned before, treatment of renal dysfunction has focused on improving endothelial and renal function in the context of the treatment of hypertension and obesity. For example, increasing NO and EET levels and decreasing oxidative stress and ET-1 effects are emerging approaches to improve endothelial dysfunction and lower blood pressure in obesity and hypertension. Antioxidants act by reducing the superoxide that is elevated in hypertension and obesity. The reduction in superoxide levels may enhance NO bioavailability. For example, long-term treatment with the SOD mimetic tempol lowers arterial

Endothelin Receptor Antagonists

The ET receptor antagonist, bosentan (Figure 10) is approved for the treatment of pulmonary hypertension in humans supporting the role of ET in the pathogenesis of this type of hypertension. ETA receptor blockade reduces blood pressure and improves endothelial dysfunction in high-endothelin models of hypertension. For example, ETA receptor blockade attenuated hypertension, oxidative stress, and NADPH oxidase activity during chronic aldosterone-induced hypertension.83 ETA receptor blockade also prolongs survival and reduces proteinuria, but has little effect on the progression of hypertension in salt-loaded stroke-prone spontaneously hypertensive rats. ET may also have a role in obesity and its associated hypertension. Increased vascular production of ET-1 in hypertensive patients with increased body mass may be a potential mechanism for endothelial dysfunction. ETA receptor-dependent vasoconstrictor tone increased in obese hypertensive patients and blockade of the ETA receptor induced...

Retinal Vascular Occlusion

This is more common in hypertensive patients compared with normotensives. The most frequent occurrence is the central retinal vein occlusion (CRVO), although branch retinal vein occlusions can occur at arteriovenous crossings. The fundus appearance in CRVO is dramatic with numerous scattered haemorrhages and swelling of the optic disc, and the patient experiences sudden blurring of vision in one eye (Figure 21.12). This can be compared with occlusion of the central retinal artery, which is less common and in which the prognosis is uniformly worse. Here, the fundus appears pale and the arteries are narrowed. There is a cherry-red spot at the macula. In older patients, the already narrowed vessels tend to show less dramatic changes. Hypertonicity of the vessel walls is not seen but arteriovenous nipping remains an important sign and haemorrhages might be present in more severe cases. The cotton-wool spots of hypertension reflect ischaemic damage to the nerve fibre layer caused by...

Coronary Heart Disease

It is clear from these data that CHD is a significant contributor to morbidity and mortality and, therefore, the therapeutic management of these diseases is an important factor in efforts to reduce the global burden of cardiovascular disease. Angina pectoris represents a cardiovascular economic disorder where the demand exceeds the capacity of the coronary vasculature to supply oxygen. Chemical modification of this imbalance can be accomplished using a variety of agents that decrease the oxygen demand (e.g., -adrenoceptor blockers), reduce the resistance against which the heart must work (e.g., antihypertensive medications), or improve oxygen delivery (e.g., coronary vasodilators, nitroglycerin, organic nitrates). Some of the agents perform both functions of reducing demand and increasing supply. Perhaps the greatest advances in the management of CHD have been made in the surgical arena. The use of new diagnostic tools has led to increased success in identifying and characterizing CHD...

Congestive Heart Failure

CHF occurs when the heart is unable to fulfill its primary mission of pumping blood. The severity of heart failure ranges from mild to moderate forms which are treatable, to severe acute heart failure which usually requires more dramatic types of management, including cardiac transplantation. In most instances, heart failure develops after other antecedent cardiovascular diseases including hypertension (nearly 75 of all CHF cases) and MI or other forms of coronary heart disease. In 2002, there were 550 000 new cases of CHF in the USA with more than 50000 deaths attributed to the disorder.1 The total number of individuals with CHF was nearly 5 million with an economic burden of nearly 28 million or 7 of the economic burden of all cardiovascular diseases. The incidence of CHF is greater in African American males and females and in diabetic women (especially those with elevated body mass index (BMI) or reduced renal function) but increases dramatically with age, regardless of gender or...

BAdrenoceptor Antagonists bBlockers

The first -adrenoceptor antagonist, dichloroisoproterenol, was described by I. Slater in 1957. The first clinically useful b-adrenoceptor antagonists, pronethalol and propranolol (Table 2), were discovered and developed by the British pharmacologist Sir James Black. Their usefulness in the treatment of hypertension was first demonstrated in patients by Prichard. Pronethalol was found to be carcinogenic in mice,25 while propranolol was marketed and is still used in the clinic. The discovery of subtypes of b-adrenoceptors, b1 and b2, facilitated the development of additional antagonists with various affinities for the two receptor subtypes. Propranolol is nonselective it has similar affinity for br and b2-adrenoceptors. Blockade of b2-adrenoceptors is likely to cause bronchial constriction, so that propranolol should not be used in patients with bronchial asthma. Propranolol enters the central nervous system and can produce vivid dreams as one of its side effects. Another nonselective...

Adrenoceptor Antagonists

A-Adrenoceptors are subdivided into two major classes, ai and a2, each of which has three subclasses. Antagonists of a adrenoceptors, e.g., quinazolines (prazosin, doxazosin, and terazosin), are antihypertensive (Figure 2). They are selective for a1-adrenoceptors, but not for any of the three subclasses (a1A, a1B, and a1D) Unlike older a-adrenoceptor antagonists phenoxybenzamine and phentolamine, quinazolines do not increase heart rate. Prazosin was widely used in the treatment of hypertension for a quarter of a century. The onset of action of prazosin is rapid the maximal antihypertensive effect is usually reached within 2 h of oral administration of the drug. An important advantage of prazosin and other quinazolines over thiazides or -adrenoceptor antagonists is their favorable effect on blood lipids they tend to decrease triglycerides and low-density lipoprotein, while increasing high-density lipoprotein cholesterol levels. Terazosin inhibits ex vivo platelet aggregation induced by...

Ca2 Channel Antagonists Ca2Antagonists Ca2 Channel Blockers CCAs

Fleckenstein, late Professor of Physiology at the University of Freiburg, Germany, observed that drugs could mimic the effects of calcium withdrawal from the medium surrounding the cells. He termed such drugs calcium antagonists (Figure 3 and Tables 3 and 4). The first compound reported by him to have such activity was verapamil, which is still used today in the treatment of hypertension. Subsequently, Fleckenstein found that nifedipine, discovered at Bayer AG in Germany,33 is ''the most potent and the most specific inhibitor of calcium entry into cells.'' In 1970 the first clinical studies with nifedipine were performed in patients with angina pectoris. The drug reduced the incidence of anginal attacks and was marketed for this purpose. Subsequently, nifedipine was found to reduce arterial pressure in patients with severe hypertension who did not previously respond to any other antihypertensive drugs available. Sato and his associates at Tanabe Seiyaku Company in Japan discovered a...

Dialysis deferral 4 years

A striking example is Lynne Bright, a 39-year-old secretary at a clinical laboratory in Indiana, who came to Johns Hopkins in February 2000. Two years earlier she had learned that she had kidney failure, when a routine exam revealed an elevated serum creatinine. At that time she had already had high blood pressure for about a year. Urine protein was also abnormal (3 g per day) but serum albumin concentration was normal. She had felt tired for about seven months, but denied loss of Physical exam was normal (blood pressure was 124 76, reflecting her antihypertensive drug regimen). Laboratory data showed severe kidney failure serum creatinine 8.9 mg per dl, serum urea nitrogen 92 mg per dl, hematocrit 31 percent, serum potassium 5.6 mEq per liter, serum CO2 19 mM. Creatinine clearance after cimetidine was 6.9, 5.7, and 5.6 ml per minute (average is 6.1 ml per minute normal is 120 ml per minute). She was instructed on a very-low-protein diet, told where to get essential amino acids, given...

Angiotensin II Ang II Antagonists or Blockers

The discovery of clinically useful nonpeptide antagonists of Ang II led to the recognition of the importance of this hormone in the control of circulation and to a new approach to the treatment of hypertension. Although at least four different types of Ang II receptors (AT1-4) have been identified, pressor and other undesirable effects of Ang II are mediated by AT1 receptors. Furukawa et al. from Takeda Chemical Industries initially described the antagonism of Ang II by N-benzylimidazole derivatives. Intensive structure-activity and optimization studies at DuPont Merck Pharmaceutical Company led to the discovery and development of the first marketed ARB, losartan (Table 6). Its discovery was followed by the development of a series of chemically related compounds, known as 'sartans.' Losartan and other 'sartans' block vasoconstrictor, aldosterone-releasing, and adrenergic-facilitating effects of Ang II. Losartan is converted in the liver to two carboxylic acid derivatives that are...

Vasopeptidase Inhibitors

Vasopeptidase inhibitors are drugs that are capable of simultaneously inhibiting ACE and the neutral endopeptidase (NEP, also known as EC 24.11). NEP is a cell surface metalloprotease that degrades various bioactive peptides, including big endothelin-1. Inhibition of NEP is anticipated to reduce the formation of endothelin-1 from big endothelin-1. None of the vasopeptidase inhibitors are currently marketed in the US. The first dual inhibitors, thiazepinones and oxazepinones, were synthesized at Bristol-Myers Squibb. In 1998 Trippodo et al. described the antihypertensive activity of the lead compound from this series, omapatrilat (see Figure 4).43 Omapatrilat lowered arterial pressure in normal and high renin models of hypertension, prevented vascular remodeling, and provided long-term renoprotection to rats. In the initial clinical studies omapatrilat appeared to be highly promising, but a subsequent large clinical trial found that the rate of angioedema with omapatrilat was three...

Drugs Targeting Protease

Retroviral proteases are unique proteins in the sense that they are the only known homodimeric enzymes containing a single, symmetric active site, which includes two adjacent aspartic acid side chains (Figure 6). One aspartate is protonated and the complex is stabilized by a hydrogen bond between them (Pearl, 1987). While each of the two molecules forming a retroviral protease resembles a domain of a single-chain aspartic protease such as pepsin or renin, the latter enzymes retain only approximate twofold symmetry. However, the similarity of the retroviral protease to cellular aspartic proteases was invoked early on as the reason to concentrate on designing inhibitors of that enzyme as potential AIDS drugs. There was a long history of attempts to design renin inhibitors as antihypertensive drugs (Greenlee, 1990). While no such drugs have ever been successfully introduced, the immense experience gained in that work turned out to be invaluable for designing pharmacologically successful...

Patients with Diseases of the Glomeruli

Cary Moulin, a 40-year-old laboratory technician, was referred for treatment of glomerulonephritis, known to be progressive for the previous 19 years. He was an avid jogger, running about 48 miles a week. Physical exam showed only high blood pressure. His serum creatinine level was quite high (5.5 mg per dl), as was his serum urea nitrogen level (95 mg per dl normal is less than 22 mg per dl) yet he had few symptoms. In response to a very low-protein diet supplemented by essential amino acids, serum urea nitrogen fell to 33 mg per dl. He also received antihypertensive drugs. He alternately took supplements of either essential amino acids or ketoacids for the next five years, at which point he finally went on dialysis. Subsequently he received a transplant.

Overview and Comparison of Drug Classes

Historically the treatment of ADHD relied on agents affecting monoaminergic neurotransmission, and largely consisted of the stimulants, antidepressants, and antihypertensive agents (Table 1).1'65 The primary pharmacological treatment for ADHD continues to be the use of stimulants, particularly methylphenidate and amphetamines. Methylphenidate has long been the leading treatment for ADHD however it has a short duration of action and a midday dose is required. In schoolchildren, this necessitates dosing during the school day and contributes to poor compliance and social stigma. The importance of avoiding this midday dose is underscored by the success of Concerta (J & J), a novel formulation of methylphenidate designed to provide both rapid and sustained release, and Adderall XR (Shire), a QD formulation of mixed amphetamine salts.

Patients with Hypertensive Kidney Disease

Chester Land, a black retired postal supervisor, was referred at age 61 with a 20-year history of hypertension. By age 59 his serum creatinine level was elevated, though he had no symptoms of kidney disease. Physical exam showed only hypertension, but kidney function was severely reduced. He was prescribed a very-low-protein diet supplemented by essential amino acids or ketoacids (in addition to his antihypertensive drugs and diuretics). A few years later a routine lab report raised the spectre of severe intestinal bleeding, until the lab error was discovered. At age 66 a blood test for prostate cancer was reported as abnormal and confirmed by prostate biopsy. He underwent a course of radiotherapy. During eight years of dietary treatment, kidney function did not worsen nevertheless, he eventually started dialysis. Despite some complications, he is still doing fairly well, having received a transplant. In retrospect, dietary treatment probably deferred dialysis for about four years.

The Withholding and Withdrawal of Dialysis

A simple and generally useful criterion for starting dialysis is the presence of symptoms that can be expected to improve on dialysis. This criterion would exclude high blood potassium (which can always be treated see Chapter 12) and almost every instance of hypertension (almost always, a combination of drugs will lower blood pressure into the desired range see Chapter 9). Others have included intractable acidosis this simply means that the patient has not consumed enough alkali (see Chapter 10). (Sodium retention secondary to alkali administration can always be treated by diuretics.)

Latest Update About The Linalool To Kill Insect

The numerous reported effects of neem on insects include repellence, feeding deterrence, oviposition deterrence, reduced growth and development, and interference with reproduction (Schmutterer 1990), but the biochemical or molecular mode of action for such effects remain unknown. Neem and its principal component, azidarachtin, are extremely low in mammalian toxicity (Schmutterer 1990 see Table 4.1), and most forms are nonirritating to skin and mucous membranes. Neem extracts have been used medicinally for centuries in Asia and India to lower blood pressure, reduce inflammation, and reduce fevers. Exposure to seed dusts causes dermal or respiratory tract irritation in some individuals.

Diseases That Lead to an Increased Risk of Kidney Failure

Sometimes it's the diseases you already have that can cause trouble for your kidneys. The most common culprits include diabetes and hypertension. A few patients develop kidney failure secondary to potassium deficiency. Hypertension High blood pressure is one of the most common disorders in the United States. The majority of people over 50 suffer from it. Thanks to a persistent campaign by the American Heart Association and others, the importance of controlling blood pressure is more and more widely known, and most patients now get at least some treatment for hypertension. Undertreated or untreated, hypertension can lead to heart failure, strokes, and kidney failure. It was widely assumed in the past that hypertension causes kidney failure. However, a recent analysis of 10 large trials shows that controlling blood pressure in nonmalignant hypertension (the commonest kind) doesn't make any difference in the development of kidney failure. Among 26,521 people with high blood pressure...

Patients with Kidney Disease Secondary to Obstructed Outflow of Urine Interstitial Nephritis

Ernie Ball is a computer systems analyst. When he was 38, he visited his doctor because he had pain in his flanks. A urine test showed protein plus red cells, and his doctor told him that he had a urinary tract infection and urethral stricture. Leg swelling appeared soon thereafter. He had taken analgesics (aspirin or Anacin plus Dristan) daily for years because of headaches. By age 40, he had high blood pressure and signs of moderately severe kidney failure. At age 56, by which time his serum creatinine concentration was 6.4 mg per dl, indicating severe kidney failure, he started a supplemented very-low-protein diet. He succeeded in deferring dialysis for four more years by means of a very-low-protein, low-salt diet plus either amino acids or ketoacids, antihypertensive drugs, diuretics, calcium, zinc, iron, vitamins, and sodium polystyrene sulfonate.

Dialysis deferral 5 years

Denton Farris, a former businessman, developed urinary protein and red cells at age 65. Blood tests showed that he had a kind of kidney disease called IgA nephropathy but only mild loss of kidney function. Because of recurrent muscle pains caused by a rare disorder called polymyalgia, he was taking 5 mg per day of prednisone. An ACE inhibitor was prescribed for hypertension, which necessitated the addition of sodium polystyrene sulfonate to prevent high blood potassium concentration. As his renal function declined, a very-low-protein diet was added, supplemented alternately by amino acids or ketoacids. Later, additional antihypertensive drugs and diuretics were also added. He took ketoconazole intermittently, with uncertain effects on progression. Erythropoietin injections were added. Finally, at age 74, he went on dialysis and died a year later, after withdrawing from dialysis.


The opioid withdrawal syndrome can easily be suppressed by administering any opioid with significant same-receptor agonism as the drug that originally produced the addiction. However, it is more useful to prevent opioid withdrawal symptoms pharmacologically with a nonaddicting drug. This approach furthers the goals of detoxification and abstinence. When circumstances force addicts to treat their withdrawal symptoms without opioids, they most commonly use alcohol and or benzodiazepines. The main disadvantage to this approach is that because of the lack of cross-tolerance between opioids and alcohol benzo-diazepines, blockade of withdrawal symptoms requires the ingestion of large amounts of these sedatives to achieve suppression. Clonidine, a presynaptic alpha2 agonist originally marketed as an antihypertensive, represents an effective and safer alternative for the treatment of opiate withdrawal symptoms (Koob & Bloom, 1988 O'Connor et al., 1995). It can partially suppress many (but...

Excessive Potassium

Albert Prendergass,a 22-year-old college student from Annapolis,was referred to Johns Hopkins by an Annapolis physician. He had had kidney disease since the age of 14, when he developed ankle and facial swelling, fatigue, and severe hypertension. A kidney biopsy showed glomerulonephritis. A course of prednisone therapy didn't help. For several years he had taken a variety of antihypertensive medications, including captopril, an ACE inhibitor. Serum creatinine concentration was first noted to be elevated (to 2.1 mg per dl) three years ago. He has recently developed muscle cramps, headaches, and loss of appetite. A few hours after he left the clinic, the lab called with a panic value serum potassium 7.6 mEq per liter, close to the level at which cardiac arrest occurs. Serum creatinine was 7.9 mg per dl. Albert had left no phone number because he didn't have a phone. He had left a work number, but it was by now after hours. I recalled that he had said that his parents lived somewhere in...

Cellular Response

The heart possesses a great capacity to produce CO because the substrate for CO production, heme, is readily available and localized in the vasculature and blood vessels.6061 The heme-catalyzing enzyme, heme oxygenase, is highly inducible in the heart. A several-fold induction of HO-1 was observed in the heart in response to ischemia reperfusion and oxidative stress.1718 A significant number of studies demonstrate a role for CO signaling in the modulation of cardiovascular function.6263 CO is believed to function in the heart by activating soluble guanine cyclase, leading to the activation of cGMP, a second messenger responsible for the modulation of physiological function. The NO-CO signaling pathway plays a crucial role in the pathologic heart including ischemia reperfusion, hypertension, and atherosclerosis. 1. Johnson, R.A. et al., A heme oxygenase product, presumably carbon monoxide, mediates a vasodepressor function in rats, Hypertension, 25, 166, 1995. 24. Johnson, R.A. et al.,...


In glaucoma, impaired fluid circulation in the eye produces high pressure in the posterior chamber that damages the optic nerve. Glaucoma is the second leading cause of blindness (after diabetes) in the developed countries of the world. Glaucoma usually develops slowly over months to years. The warning signs are halos appearing around lights, blurred vision, watering in the eyes, headache, and, when advanced, constriction of the visual field. Those with a family history of glaucoma, who are nearsighted, or who are taking antihypertensive drugs or steroids have a greater risk of glaucoma.

Anti Arrhythmic

The majority of anti-arrhythmic drugs are basic compounds and many also act as antihypertensive agents. These compounds migrate rapidly and are seen in the first part of the electropherogram. However, they can be difficult to separate since they tend to bind to the capillary walls, making analysis and especially stacking difficult. Recently (24), we have shown that buffers containing amines and zwitterions are useful not only in analysis but also stacking of these compounds. The analysis of procainamide and N-acetylprocainamide is a good example of stacking of basic drugs on the capillary. In this method, which correlated well with immunoassay, about 10 of the capillary volume was injected with sample (63). Using the same method, urinary procainamide also has been analyzed by CE (64).

Cyp2c Cyp2j Endothelin in hypertension Endothelin (ET-1) is a potent vasoconstrictor and mitogen that is thought to play a role in the development of hypertension. The vascular endothelium is a major source of ET-1 production. ET-1 is believed to act in a paracrine manner on ETA and ETB receptors on smooth muscle that mediate contraction, cell proliferation, and hypertrophy. Activation of ETB receptors on endothelial cells stimulates the production of prostacyclin and NO to induce vasorelaxation. ETB receptor activation also inhibits sodium transport in renal tubules. Renal ET-1 is increased in saltsensitive hypertension and this effect is attenuated with ETA receptor antagonists.37 Interestingly, plasma ET-1 increases in hypertensive African American populations.37 ET-1 levels are also increased in streptozotocin-induced diabetic rats where the diabetes-induced vascular hypertrophy and remodeling is ET-dependent. Patients with diabetes or hypertension have elevated ET-1 levels, but do...

Cardiac disease

Currently, LVH, most commonly caused by hypertension, is diagnosed by echocardiography (ECG). LVH is associated with a very poor prognosis, particularly if diagnosed using ECG criteria. Broadly, LVH can be subdivided into physiological LVH, which occurs in athletes and in which collagen deposition in the left ventricle is normal, and pathological LVH which is associated with an increase in tissue collagen. The increase in collagen within the left ventricle is associated with a reduction in its elasticity, an increase in the number of ectopics and a reduction in coronary arteriole dilatation due to collagen deposition within the vessel. Two mechanisms are involved in the pathophysiology of LVH. Firstly, the myocyte, which is a terminally differentiated cell, hypertrophies due to increased blood pressure. Secondly, Brilla and coworkers 15 showed in a series of experimental models of hypertension that upregulation of angiotensin II (the one clip model) was associated with increased...

The Problem

Increasing alcohol levels are associated with increased risk of accidents, but fatigue, drug abuse, and even the use of prescription medication can also increase risk (62). The danger associated with sedatives and hypnotics is readily appreciated, but other drugs, such as anticholinergics, antidepressants, anti-histamines, and antihypertensive medications, may occasionally cause drowsiness. Patients should be warned about this, and after starting therapy or after a significant change in dose, they should avoid driving until it is known that unwanted effects do not occur (63,64).


The antihypertensive activity of diuretics was discovered in the clinic. Diuretics do not lower arterial pressure in acute experiments on normotensive animals. Only in chronic experiments on DSS or SH rats can the mild antihypertensive effect of diuretics be detected. The first diuretic found to lower arterial pressure in hypertensive patients was chlorothiazide, discovered by Beyer and his colleagues at Merck. Its discovery was soon followed by the introduction of hydrochlorothiazide, a closely related derivative with much higher relative potency that was discovered at Merck as well as at Ciba-Geigy. Many similar thiazides have been subsequently developed and marketed, but only a few are still available on the American market. The major side effect of thiazides is hypokalemia, due to the excessive excretion of K+ ions. Other side effects include hyperuricemia and hyperglycemia. The search for diuretics with longer duration of action and fewer side effects led to the discovery of...

Combination Therapy

Very few hypertensive patients are currently being treated with one drug only, unless this drug is a fixed combination. The use of thiazide diuretics concurrently with -adrenoceptor antagonists has been advocated ever since these drugs were discovered and is being currently recommended by JNC VII,1 if a thiazide diuretic alone does not adequately lower arterial pressure. Almost all subsequently developed antihypertensive drugs have been used successfully with thiazide diuretics. There is currently substantially less opposition to the use of fixed combinations. The advantages of such combinations - better compliance, fewer side effects than with a higher dose of one of the components, and lower cost - appear to outweigh the disadvantages - less flexibility with dose adjustments and differences in the pharmacokinetic parameters of the two drugs. Fixed combinations of ACEIs, or ARBs with thiazide diuretics or of ACEIs with CCAs, are currently available and more combinations are likely to...

Unmet Clinical Needs

In the US only 59 of hypertensive patients are being treated. Forty-one percent of patients are either unaware of their hypertension, of the consequences of not treating it, or they are not insured and cannot afford the drugs. It is obvious that improvements in medical care delivery, patient education, and coverage of prescription drugs by Medicare and private insurance companies are urgently needed. There is also a need for new drugs for the treatment of drug-resistant, pulmonary, and portal hypertension.

Atrial Arrhythmias

Better antiarrhythmic drugs for the control of ventricular rate during atrial fibrillation. The current drugs (b-adrenoceptor blockers, calcium channel blockers, cardiac glycosides) are far from ideal. For instance, a cardiac selective L-type calcium channel blocker might have advantages in that it would be less likely to lower blood pressure.

Renin Inhibitors

The first and rate-limiting step in RAS, the conversion of angiotensinogen to Ang I, is catalyzed by renin. Several renin inhibitors have been synthesized, but low efficacy, poor oral bioavailability, high cost of synthesis, and the availability of highly successful ARBs prevented their development. One of the first clinically tested renin inhibitors was enalkiren (ABT-64662) (Figure 4). More recently developed, aliskiren42 is currently in advanced clinical evaluation. At 75, 150, or 300 mg single doses, aliskiren effectively lowers ambulatory systolic pressure in hypertensive patients and is well tolerated. Its effects appear to be synergistic with valsartan. It still remains to be shown that aliskiren can affect vascular pathology and reduce morbidity and mortality in cardiovascular disease.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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