Current Hypertension Reviews - Volume 1, Issue 2, 2005

The Dahl rat is one of the most widely studied rodent models of hypertension with over 1600 references in the literature over the past 35 years. While many studies have focused on physiology, more recent investigations have concentrated on the genetics. While there is already evidence for the Dahl rats' value in probing the genetics of human hypertension, there are several reservations and significant limitations.

The last two decades have witnessed great advances in our understanding of the role of the vascular endothelin (ET) system in the control of blood pressure. The role of ET as one of the most potent endothelium-derived vasoconstrictors is now complemented with a newly discovered role in vascular relaxation. The transcription of the ET genes in endothelial cells leads to the formation of preproET and big ET, which are further metabolized by ET converting enzymes into ET-1, -2, -3 and -4 isoforms. ET isoforms bind with different affinities to ETA and ETB2 receptors in vascular smooth muscle, and stimulate [Ca2+]i and other signaling mechanisms of smooth muscle contraction and growth. ET also binds to endothelial ETB1 receptors, which are coupled to increase production of vasodilator substances such as nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor, and may also function in ET clearance. Despite the prominent effects of ET on vascular function and growth, the role of ET and its receptors in the regulation of blood pressure and in the pathogenesis of hypertension has not been clearly established. Some forms of moderate to severe hypertension in human and salt-dependent hypertension in experimental animals may show elevated levels of plasma or vascular ET; however, other forms of hypertension may show normal levels. Also, while ET antagonists could reverse some forms of experimental hypertension, their potential use in medicine needs to be carefully examined particularly with regard to their effectiveness and specificity.

Angiotensin II (Ang II) receptor blockers (ARBs) are highly selective for the Ang II type 1 receptor (AT1), which is a member of the G protein-coupled receptor superfamily (GPCRs), and block the diverse effects of the agonist Ang II. Many studies have shown that these agents are safe and effective. In addition to their beneficial effects against hypertension, ARBs have also been associated with the regression of left ventricular hypertrophy and a decrease in cardiovascular morbidity and mortality in patients with heart failure or hypertensive diabetic nephropathy with proteinuria. Many ARBs are available for clinical use. Since ARBs do not all have the same effects, the benefits conferred by ARBs may not be class effects. Over the past decade it has become possible to detect agonist-independent signal transduction by GPCRs, and ligands described as inverse agonists, which can block activities, have been described. One type of ARB has been shown to have inverse agonistic action in an in vitro mutagenesis study. In addition, mechanical stretch-induced signals through AT 1 receptor have been shown to be independent of Ang II stimulation, and these signals are blocked by an ARB. These findings represent an exciting new area in ARB treatment. ARB-based therapy holds the promise of reducing the incidence of cardiovascular disease. This review will address the roles of inverse agonistic action and its blockade in the cardiovascular system.

According to the World Health Organization the number of hypertensive people is estimated to be 600 million. Of them, a considerable proportion is untreated, while 12% to 15% is uncontrolled. The association between dietary habits and the development, as well as the control of hypertension has long been investigated in many clinical and epidemiological studies. Moreover, Mediterranean-style diet has been associated with reduced all cause, cardiovascular and cancer mortality. This dietary pattern is high in legumes, cereals, fruits and vegetables intake, moderate in the consumption of fish, wine, dairy products, mostly as cheese and yogurt, and low in the consumption of meat and its products. In addition, alcohol is consumed in moderation and almost always during meals. Mediterranean diet is low in saturated fat (less than about 9% of energy), with total lipid intake ranging from less than 30% to no more than 40% of energy. Moreover, the ratio of monounsaturated (mainly due to olive oil intake)-to-saturated fat is about 2. Nevertheless, the effect of this traditional diet on blood pressure levels has not been well understood and appreciated. In this review we summarize findings from observational and clinical studies that evaluated the association between adherence to the Mediterranean diet and the prevalence of hypertension.

Mounting evidence shows that elevated heart rate is associated with a greater risk of developing hypertension and atherosclerosis and that it is a potent predictor of cardiovascular morbidity and mortality. These relationships have been shown not only in general populations but also among hypertensive individuals, with important implications for the treatment of hypertension. Recent evidence suggests that the predictive power of resting heart rate for cardiovascular mortality is even greater than indices derived from analysis of heart rate variability. In spite of this evidence heart rate is still overlooked as a risk factor, but the fact that in most studies the risk related to fast heart rate remained highly significant after controlling for major risk factors for atherosclerosis suggests that it plays a direct role in the induction of the risk. The clustering of several risk factors for coronary artery disease in subjects with fast heart rate suggests that sympathetic overactivity accounts for the increased cardiovascular morbidity in subjects with tachycardia. Moreover, experimental studies both in animals and human beings suggest that the heamodynamic disturbances related to high heart rate have a direct impact on the arterial wall promoting the development and the rupture of atherosclerotic plaques. Data obtained in the experimental animal and pooled data from intervention studies in patients with myocardial infarction or congestive heart failure suggest that drug-induced reduction of heart rate may be beneficial in several clinical conditions. Tachycardia (heart rate ≥ 80 bpm) has been found in over 30% of the hypertensive patients and thus reduction of high heart rate appears as a desirable additional therapeutic goal in a large proportion of the hypertensive population. Several antihypertensive agents have shown good potential for decreasing the fast heart rate in hypertension. In the future, goal of antihypertensive treatment in patients with tachycardia will be to prevent or reverse those functional abnormalities of the autonomic nervous system which accompany the hypertensive condition.

Introduction: Despite improved control rates of hypertension in the United States during the last twenty years, the rate of chronic kidney disease (CKD) and end-stage renal disease (ESRD) has steadily increased for the same time period. Purpose: The purpose for this review is to examine the evidence that the choice of antihypertensive therapy makes a difference in the promotion of nephroprotection. Method: A systematic comprehensive search of the National Library of Medicine utilizing Medline was conducted. Search terms included “antihypertensive therapy chronic kidney disease” and “nephropathy;” search limits were confined to randomized clinical trials. Results: Angiotensin receptor blockers (ARBs) and Angiotensin-converting enzyme inhibitors (ACEIs) are nephroprotective alone, and particularly in combination. Calcium channel blockers (CCBs) can be effective nephroprotective agents when combined with ACEIs and ARBs. Thiazide-type diuretics (TTDs) and beta-blockiers (BB) are not nephroprotective and TTDs may have nephrotoxic properties. Conclusion: Government sponsored guidelines that recommend TTDs as first line antihypertensive agents because of their lower acquisition costs may be contributing to the current epidemic of CKD and ESRD. ACEIs and ARBs are preferred first-line agents because they are effective in the prevention of renal as well as cardiovascular and cerebrovascular target organ damage associated with hypertension. When diuretic therapy is indicated for hypertension control, indapamide is preferred over TTDs for nephroprotection.

Chymase generates angiotensin II which plays a crucial role in vascular remodeling. In clinical studies, an angiotensin II receptor blocker was successful in preventing restenosis after percutaneous coronary intervention, but an angiotensin II-converting enzyme inhibitor was not. In dog, chymase activity was significantly increased in vessels injured by a balloon catheter, and a chymase inhibitor and an angiotensin II receptor blocker were effective in preventing the vascular proliferation, but an angiotensin-converting enzyme inhibitor was ineffective. Chymase also activates matrix metalloproteinase-9, and their function may play an important role in development of atherosclerosis and aneurysmal aorta. In human atherosclerosis and aneurysmal aorta, chymase activity was significantly increased. In the experimental models, chymase activity and mRNA level were also significantly increased in atherosclerotic lesions and aneurysmal aorta, but chymase inhibitors prevented the vascular remodeling. On the other hand, chymase activates latent transforming growth factor-β-binding protein to transforming growth factor-β, and its function may be related in promoting tissue fibrosis. Chymase promotes activations of angiotensin II, matrix metalloproteinase-9 and transforming growth factor-β, and chymase inhibitors may promise to prevent vascular remodeling and tissue fibrosis.

Adrenomedullin (AM) is a potent vasodilatory peptide originally discovered in human pheochromocytoma tissue. The gene expression of AM is widely distributed in the cardiovascular system and many physiological actions of AM on cardiovascular system have been reported. Previous studies demonstrated that the plasma AM level is increased in patients with hypertension and further increased in patients with organ damage. We and other groups recently showed that two molecular forms of AM, AM-glycine, an inactive form, and AM-mature, an active form, circulate in human plasma and that the major molecular form in plasma is AM-glycine. Recent studies using AM antagonist or AM knockout mice confirmed the role of AM in the regulation of blood pressure. Indeed, administration of AM is beneficial in patients with hypertension, renal disease, and heart failure. In addition, recent studies revealed that AM and its receptor components such as calcitonin receptor like receptor (CRLR), receptor activity modifying protein (RAMP) 2, and RAMP3 are colocalized in peripheral tissues, including the heart, kidney, and vasculature, suggesting a role of AM as a regulator of local function. In fact, tissue AM levels and the gene expression levels of AM and its receptor are altered in hypertension. We recently showed that cardiac tissue AM levels and the gene expression levels of AM, CRLR, RAMP2, and RAMP3 are increased in left ventricular hypertrophy and further increased in hypertensive heart failure. These findings imply that increased expression of the AM system including the ligand and receptor components may modulate the pathophysiology in hypertension via the effects of AM not only as a circulating factor, but also as a local regulator. This review describes the structure, structure-activity relationships, tissue distribution, receptors, physiological action, and circulating levels of AM and also discusses what is known about the pathophysiological role of AM in hypertension.

Excessive salt intake is well-known to be one of the major environmental factor not only to develop human hypertension but also to induce cardiovascular damages. On the other hand, dietary potassium supplementation exerts both anti-hypertensive and cardiovascular protective effects in salt-induced hypertension. In the earlier studies including us, it was suggested that the anti-hypertensive mechanism of dietary potassium is natriuresis and sympatho-inhibitory action. Recently, it has been clarified that salt loading increases production of reactive oxygen species (ROS) in saltsensitive hypertension model animals. Because ROS overproduction induces several disadvantages, such as insulin resistance, the peripheral and central sympathetic overactivity, and an enhanced oxidized low density lipoprotein (LDL) receptor-1, lectin-like oxidized LDL receptor (LOX-1) expression, antioxidants may prevent salt-induced hypertension and cardiovascular damages. Interestingly, some investigators have demonstrated that potassium has antioxidant effect. Indeed, dietary potassium supplementation ameliorates insulin resistance, sympathetic overactivity and LOX-1 upregulation associated with decrement of ROS production. Thus, opposite actions between salt and potassium on ROS production may play an important role of their influences on blood pressure and cardiovascular effects.