Novel Drugs Targeting Hypertension Revisited
Year: 2010
Type: editorial
Abstract: Three years ago, The Journal of Cardiovascular Pharmacology published a review series on novel drugs targeting hypertension. In the current issue and the next one, a series of articles appear that discuss 4 new areas for drug development, which have evolved in recent years and have relevance for treating hypertension and other cardiovascular diseases. Unfortunately, the need for such drugs is as great as ever. According to the most recent report of the American Heart Association, 1 in 3 adults in the United States has high blood pressure, as evidenced by having systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, being on antihypertensive medicine, or being told by their doctor or health care professional in 2 separate visits that they have high blood pressure.1 For 2010, the estimated direct and indirect cost for high blood pressure is estimated to be $76.6 billion. The most recent statistics available from 2006 show that the overall death rate due to high blood pressure was 17.8: among white men, 15.6; black men, 51.1; white women, 14.3; and black women, 37.7. Blood pressure >140/90 mm Hg is found in approximately 69% of those who have a first heart attack, 77% of those who have a first stroke, and 74% of those who have congestive heart failure. Overall, almost 75% of adults with cardiovascular disease comorbidities have hypertension, which is associated with a shorter overall life expectancy. Alarmingly, rates of prehypertension and hypertension are increasing among children and 8- to 17-years-old adolescents due in part to the obesity epidemic we currently face. Poor control of systolic hypertension remains a principal problem in treating hypertension and further compromises the risk of cardiovascular disease due to end organ damage. The latest statistics from 2003 to 2006 reveal that of those with high blood pressure, 55.9% do not have it under control.1 Therefore, new drug discoveries are needed to treat the majority of individuals who have high blood pressure. An additional need for novel antihypertensive drugs comes from the growing rates of diabetes and obesity, as well as an aging population, all factors that are associated with high blood pressure.2 An article by Dr. Hai Wang and colleagues on iptakalim leads off the series.3 Iptakalim is a novel adenosine triphosphate-sensitive potassium (KATP) channel opener that shows high selectivity for the cell surface SUR2B/Kir6.1 channels, which are expressed by vascular smooth muscle and endothelial cells. Because of this high selectivity, iptakalim does not exhibit the adverse side effects associated with older nonspecific K+ channel openers that limit their use to treating severe or refractory hypertension. Iptakalim produces arteriolar and small artery vasodilation with no significant effect on capacitance vessels or large arteries, by causing cellular hyperpolarization via the opening of K+ channels, which in turn decreases the opening probability of L-type Ca2+ channels. Of particular note, iptakalim is very effective in lowering the blood pressure of hypertensive humans but not of those with normal blood pressure. In preclinical trials, iptakalim has been shown to protect against hypertension end organ damage and to improve endothelial dysfunction. Early clinical trials in China have shown that iptakalim has a favorable safety and tolerability profile. The next article in the series deals with heme-dependent and heme-independent soluble and guanylate cyclase activators and is by Drs. Priviero and Webb.4 Nitric oxide (NO) produced by endothelial cells activates the soluble guanylyl cyclase (sGC) of vascular smooth muscle cells, thereby increasing intracellular cyclic guanosine monophosphate levels, which in turn leads to contractile relaxation and vasodilation. However, because of tolerance and pharmacokinetic considerations, the use of NO donors for managing high blood pressure has been limited in the past to treating pulmonary hypertension. Drugs that directly target sGC overcome these limitations of NO donors and hold great promise as antihypertensives. As discussed by Drs. Priviero and Webb, these drugs can be classified as heme-dependent sGC stimulators and heme-independent sGC activators. Because of the increased oxidative stress associated with cardiovascular diseases, the effectiveness of heme-dependent sGC stimulators may be diminished. In contrast, heme-independent sGC activators exhibit a higher affinity for the oxidized enzyme and would seem to have utility for treating systemic and pulmonary hypertension, particularly in advance cases and in the elderly. The third article in the series by Dr. Imig5 deals with the therapeutic utility of drugs that mimic epoxyeicosatrienoic acids (EETs) or block their breakdown by inhibiting soluble epoxide hydrolase. In the systemic circulation, the EETs of endothelial cells are vasodilators and contribute to blood pressure regulation.6 The EETs also have protective actions against hypertension-related end organ remodeling and damage.6,7 One note of caution, however, should be sounded. In the pulmonary circulation, EETs, generated by vascular smooth muscle cells, potentiate hypoxia-induced vasoconstriction and are implicated in vascular remodeling associated with chronic hypoxia and pulmonary hypertension.8 The final article comes from Dr. Roman and colleagues9, who discuss the Janus-like contribution made by 20-hydroxyeicosatetraenoic acid (20-HETE) to hypertension and the challenges faced in designing drugs to target this arachidonic acid metabolite. In the vasculature, 20-HETE is a potent vasoconstrictor and promotes hypertension, whereas in the kidney, 20-HETE inhibits Na+ transport and protects against hypertension-related kidney damage. Thus, a 20-HETE antagonist might be of benefit in treating patients with hypertension who have elevated vascular production of 20-HETE, whereas a 20-HETE mimetic could be of benefit in treating salt-sensitive hypertension. Not addressed by the authors is the possible utility in treating hypertension of combining a 20-HETE antagonist or mimetic with another class of drug. For instance, a recent study found that selective inhibition of 20-HETE formation together with a soluble epoxide hydrolase inhibitor, so as to elevate ETTs, attenuated hypertension and associated end organ damage in a mouse model of angiotensin II-dependent hypertension.10 Also left unmentioned by the authors is the recent finding that mechanical forces may potentiate agonist-driven activation of vascular transient receptor potential canonical 6 (TRPC6) channels via formation of 20-HETE.11 This is notable in light of a recent report that the vascular endothelium of preglomerular arterioles from patients with malignant hypertension exhibits a more prominent expression of TRPC3.12 The TRPC channels constitute a subfamily of the TRP cation channel superfamily of proteins and were identified in the mid 1990s as candidate mammalian mechanosensitive cation channels.13 The 7 TRPC proteins can be further divided into 2 groups. TRPC3 and TRPC6 show an approximate 73% sequence identity and fall into the group that is directly activated by diacylglycerol. Thus, both are likely targets of activation by 20-HETE. Hypertension is a multifactorial disorder, and combination therapy is known to be essential for effective management of high blood pressure.14 Yet, effective blood pressure control is not achieved in most individuals for a number of reasons: poor compliance due to the adverse side effects of some antihypertensive medications, diminished drug effectiveness with time or age, life style issues, and drug efficacy. Thus, the need is great for novel drugs that target other contributing causes of hypertension, and the processes leading to end organ damage. The 4 articles in this series present 4 different areas that hold great potential for hypertension drug development. Although, research in these areas have already produced exciting discoveries, only time will tell whether drugs arising from the knowledge that is gained will help stem the accelerating burden of hypertension in our society.
Author: George W Booz
Institution: University of Mississippi Medical Center
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1994435371