Future Trends in
the Pharmacologic Treatment of Hypertension
Robert L. Judd, PhD
Dr. Judd is an Associate Professor of Pharmacology at Auburn University, Graduate Program in Biomedical Sciences, Department of Anatomy, Physiology and Pharmacology, Auburn, Alabama.
Hypertension remains uncontrolled worldwide despite the availability of several classes of antihypertensive agents, including diuretics, alpha blockers, beta blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and a variety of central-acting agents. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) has indicated that a large majority of hypertensive individuals are not being treated
properly.1 Specifically, only 27% of individuals treated for hypertension are controlled at a goal blood pressure of 140/90 mm
Hg.2 There is no currently available monotherapy that consistently reduces blood pressure over a full range of population subgroups with hypertension. There is an increased risk of serious cardiovascular, cerebrovascular, and renal events if the disease goes untreated or is poorly treated. Preventing organ damage requires lowering blood pressure to optimal levels; it may also depend on additional actions of medications that are independent of blood pressure–lowering
effects.3
Despite the many outstanding favorable results achieved in the treatment of hypertension, several unmet goals of antihypertensive therapy remain, such as better blood pressure control, greater protection against the organ damage associated with hypertension, better tolerability, and, ultimately, a more effective prevention of cardiovascular disease. These unmet goals are the reasons why new antihypertensive drugs are synthesized and tested in clinical practice. This article examines the main pharmacologic and clinical features of new and probable future classes of antihypertensive drugs, such as angiotensin II receptor blockers (ARBs), endothelin antagonists, urotensin antagonists, vasopeptidase inhibitors, neutral endopeptidase inhibitors, hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, vasopressin antagonists, and T-type calcium channel antagonists. The results of experimental and clinical studies with these new drugs are reviewed, emphasizing some advantages and potential disadvantages of these drugs compared with currently available antihypertensive
drugs.4
The importance of angiotensin II in regulating cardiovascular function has led to the development of nonpeptide receptor antagonists of the angiotensin II receptor for clinical use. These agents have become a mainstay in the treatment of hypertension. Angiotensin II receptor
antagonists currently available in the United States include losartan potassium (Cozaar), valsartan (Diovan), irbesartan (Avapro), candesartan cilexetil (Atacand), telmisartan (Micardis), and eprosartan mesylate (Teveten). These drugs are selective for angiotensin II (AT1) receptors. The
AT1 angiotensin II receptor subtype is located predominantly in vascular and myocardial tissue and in brain, kidney, and adrenal glomerulosa cells, which secrete aldosterone. The AT2 angiotensin II receptor subtype is found in the adrenal medulla and possibly in the central nervous system, but at present is not thought to play a role in cardiovascular homeostasis. Although all angiotensin II receptor blockers, as a group, block the AT1 receptor, they may differ in pharmacologic characteristics of their binding and be classified as either surmountable or insurmountable
antagonists.5-7 By preventing the binding of angiotensin II to the AT1 receptor, these agents relax smooth muscle and thereby promote vasodilation, increase renal salt and water excretion, reduce plasma volume, and decrease cellular hypertrophy
(Figure 1). Angiotensin II receptor antagonists also theoretically overcome some of the disadvantages of ACE inhibitors, which not only prevent conversion of angiotensin I to angiotensin II but also prevent ACE-mediated degradation of bradykinin and substance P. Reported incidences of angioedema and cough are less with ARBs than with ACE
inhibitors.8,9
Eprosartan is the newest ARB to be approved by the FDA, and the only nonbiphenyl, nontetrazole competitive ARB clinically available. It is a potent AT1 receptor antagonist that in various animal models of disease, including hypertension and stroke, is capable of reducing disease
progression.10 Eprosartan also has sympathoinhibitory activity, as demonstrated by an inhibition of the pressor responses induced by activation of sympathetic outflow through spinal cord stimulation in pithed rats. In contrast, some of the other angiotensin II receptor antagonists, such as losartan, at equivalent angiotensin II blocking doses, have no effect on sympathetic nervous system activity. Because eprosartan can inhibit both the direct effects of angiotensin II as well as the indirect effects that are mediated by enhanced sympathetic neurotransmission, this may represent an important advance in the treatment of elevated systolic blood
pressure.10 In clinical trials, eprosartan has been shown to lower blood pressure effectively in a once-daily regimen in hypertensive
patients.11 In the recommended dose range of 600 to 1,200 mg once daily, eprosartan is effective in patients with all stages of hypertension irrespective of age, sex, or
race.11,12 As with other ARBs, the tolerability of eprosartan is comparable to placebo, and there are no known clinically relevant drug interactions.
Until equivalent long-term cardiac and renal protection has been demonstrated with the ARBs, ACE inhibitors remain the initial drugs of choice in patients with diabetes, heart failure, or systolic dysfunction after myocardial infarction. At present, ARBs should be used cautiously (because of the possibility of renal impairment) in patients with congestive heart failure who cannot tolerate ACE inhibitors. The advantages of ARBs include good efficacy with once-daily dosing and a safety and tolerability profile that is generally comparable to that of placebo. These drugs are lipid neutral, which may make their use advantageous in patients with hyperlipidemia. All currently approved ARBs do not differ substantially with regard to blood pressure effect, and they all have a somewhat flat dose-response curve. However, better blood pressure– lowering effects are achieved when any of these agents are administered in combination with hydrochlorothiazide than when the dosage of the approved ARB is
increased.7 First-dose hypotension seldom occurs with this class of drugs. The ARBs do not change average heart rate, and no rebound hypertension occurs after these agents are discontinued. A number of large-scale clinical studies are currently under way or planned to determine which of the increasing number of ARBs may reduce cardiovascular morbidity and mortality rates in different groups of hypertensive
patients.11 Other angiotensin II receptor antagonists currently under investigation include tasosartan and
zolarsartan.
It should be noted that a polytherapy approach using ACE inhibitors and ARBs has been
proposed.13 Animal studies have demonstrated that the combination of an ACE inhibitor and an ARB is as effective as either agent alone in slowing the progression of experimental renal disease, and more effective than either agent alone in improving systemic and coronary
hemodynamics.14,15 Human studies have demonstrated that combining maximal ACE inhibition with AT1 receptor blockade appears to be safe and leads to further dilation in patients expressing symptoms of congestive heart
failure.16
Endothelin-1 (ET-1) is a potent vasoconstrictor, and thus its potential role in the development and/or maintenance of hypertension has been studied extensively. ET-1, the predominant isoform of the endothelin peptide family, regulates vasoconstriction and cell proliferation in tissues both within and outside the cardiovascular system through activation of protein-coupled
ETA or ETB receptors. Research efforts have concentrated primarily on its effects on the systemic circulation and the kidney, because the kidney plays a primary role in the long-term control of blood
pressure.17
The endothelin system has been implicated in the pathogenesis of arterial hypertension and renal disorders. When given exogenously, endothelin causes potent vasoconstriction in animals and
humans.18 Chronic elevations of endogenous endothelin in man can also result in hypertension as observed in two patients with malignant hemangioendothelioma resulting in increased circulating
endothelin.19 In these patients, the hypertension disappeared or recurred, depending on the presence of the tumor and elevated plasma endothelin. Long-term infusion of exogenous endothelin to dogs leads to a chronic increase in blood pressure, and overexpression of human prepo-ET-1 in rats leads to sustained elevations in blood pressure. Studies evaluating the levels of circulating endothelin in patients with essential hypertension have produced variable results; however, evidence suggests that endothelin is indeed modestly elevated in hypertension. Plasma endothelin also appears to be greater in obese individuals, particularly obese hypertensives. One group reported that, whereas no change in plasma endothelin levels between normotensives and borderline hypertensives was observed, there was a greater increase in circulating endothelin following a cold pressor stimulus in the hypertensive
group.20 There appears to be some racial differences in plasma ET-1 concentrations in individuals with hypertension. Both male and female black hypertensives have nearly fourfold higher endothelin levels than male and female white
hypertensives.21 Studies measuring plasma endothelin in animal models of hypertension have also provided equivocal data with both increases and decreases being
reported.17
Circulating or urinary endothelin may not necessarily reflect the true role of endothelin in maintaining blood pressure, since endothelin may be having more local effects. Blood vessel endothelin expression and cardiac levels of ET-1–like immunoreactivity have been shown to be increased in various animal models of
hypertension.17 Renal prepro-ET-1 mRNA levels are also increased in DOCA-salt hypertensive animals and endothelin production from cultured endothelial cells is upregulated in hypertensive
rats.17
Studies evaluating endothelin receptors in hypertension have provided inconsistent data. Both
ETA and ETB receptors have been shown to be reduced in mesenteric vessels of spontaneously hypertensive rats; however, augmented expression of
ETA receptor mRNA has been demonstrated in both glomeruli, as well as mesangial cells from spontaneously hypertensive and stroke-prone spontaneously hypertensive rats, respectively. One study demonstrated a significant decrease in
ETA receptors but an increase in ETB receptors in the kidney cortex of spontaneously hypertensive rats, and this change paralleled alterations in the ability of endothelin to produce renal vasoconstriction, which is mediated via
ETB receptors in
rats.17 In addition to possible changes in ET-receptor number in hypertension, there is a change in endothelin
sensitivity.17
There are a number of experimental studies demonstrating that direct and indirect endothelin-antagonists can have beneficial effects in hypertension.
Administration of the endothelin-converting enzyme inhibitor, phosphoramidon, or ET-receptor antagonists (eg, bosentan) have been shown to reduce blood pressure in a number of different hypertensive rat
models.22 An interesting recent study demonstrated that an ETB-selective receptor antagonist increased blood pressure in hypertensive animals, indicating the importance of blockade of vasorelaxant
ETB receptors. In rats made hypertensive by overexpression of prepro-ET-1, intravenous infusion of an
ETA receptor reduced blood pressure to levels seen in the control group and intravenous infusion of an
ETB receptor antagonist caused a small but significant increase in blood pressure in both
groups.23 The ability of ET receptor antagonists to lower blood pressure in animal models has not been limited to
rats because bosentan also lowers blood pressure in renal hypertensive
dogs.17,24
Limited studies have been conducted in humans; however,
ET-1 receptor antagonists can lower blood pressure in patients with congestive heart failure, and endogenous ET-induced vasoconstriction has been demonstrated in humans using phosphoramidon and
ETA receptor-selective antagonists.25 Although endothelin may contribute to maintaining elevated blood pressure in hypertensives, it is not clear whether it is important in maintaining blood pressure in
normotensives.
Specific inhibitors of the endothelin-converting enzyme (ECE) have only recently been introduced, inhibiting ET generation from its precursor, big ET. If the results previously obtained with ET receptor antagonists can be reproduced with ECE inhibitors and transferred to clinical medicine, endopeptidase inhibition might open new horizons in cardiovascular treatment
strategies.26
Since angiotensin II is an established target of pharmacologic interventions, there is an increasing interest in the biological effects and metabolism of other vasoactive peptides, such as atrial natriuretic peptide (ANP) and ET. Exogenous administration of the vasodilatory and natriuretic ANP and of its analogues improved hemodynamics and renal function in cardiovascular disease, including congestive heart failure. Unfortunately, the usefulness of natriuretic peptides is limited because they must be administered parenterally and are rapidly cleared from the circulation. In addition, effects of natriuretic peptides appear to be attenuated during prolonged infusion and in more severe disease states. Promising results have been obtained in animal experiments and initial human clinical studies concerning hemodynamics and kidney function with inhibition of ANP metabolism by inhibitors of neutral endopeptidase (NEP;
Figure 2). In further clinical studies, moderately relevant effects of acute intravenous or oral NEP inhibition were observed, but these effects were blunted with acute drug administration. There is increasing evidence the NEP inhibitors, such as candoxatril and ecadotril, expected to exhibit vasodilatory activity at least at certain doses in certain clinical situations, even induce vasoconstriction. An explanation for the ineffectiveness of NEPs in reducing blood pressure when used alone may lie in the effect of the role of NEP in the metabolism of other peptides besides ANP. In addition to ANP and other natriuretic peptides, NEP also metabolizes the vasoactive peptides ET-1, angiotensin II, and bradykinin. It now appears to be evident, especially from human experiments on human forearm blood flow after intra-arterial infusion of agents, that NEP inhibitor–induced vasoconstriction is mediated by increased ET-1 rather than by angiotensin II. The hypothesis that concurrent ACE would unmask the benefits of NEP inhibitors was not supported by a recent 10-week study in congestive heart failure; with ecadotril given to ACE inhibitor–pretreated patients, there were no clear hints toward improvements of symptoms but troublesome aspects on
mortality.26,27 Future clinical studies on dual inhibitors of NEP and ACE (eg, vasopeptidase inhibitors) will have to reveal the place of NEP inhibition in cardiovascular disease in the presence of established therapeutic standards.
Vasopeptidase inhibition is a novel efficacious strategy for treating cardiovascular disorders, including hypertension and heart failure, that may offer advantages over currently available therapies. Vasopeptidase inhibitors are single molecules that simultaneously inhibit two key enzymes involved in the regulation of cardiovascular function, NEP and ACE
(Figures 1 and 2). Simultaneous inhibition of NEP and ACE increases natriuretic and vasodilatory peptides (including ANP), brain natriuretic peptide of myocardial cell origin, and C-type natriuretic peptide of endothelial origin. This inhibition also increases the half-life of other vasodilator peptides, including bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide system, vasopeptidase inhibitors reduce vasoconstriction and enhance vasodilation, thereby decreasing vascular tone and lowering blood pressure. Several vasopeptidase inhibitors have been synthesized, and a few have been evaluated in clinical
trials.3 Many of the early compounds were limited by low potency, short duration of action, or poor
bioavailability.3 Omapatrilat, a heterocyclic dipeptide mimetic, is the first vasopeptidase inhibitor to reach advanced clinical trials in the United States. Unlike ACE inhibitors, omapatrilat demonstrates antihypertensive efficacy in low-, normal-, and high-renin animal
models.28 Unlike NEP inhibitors, omapatrilat provides a potent and sustained antihypertensive effect in spontaneously hypertensive rats, a model of human essential
hypertension.3 In animal models of heart failure, omapatrilat is more effective than ACE inhibition in improving cardiac performance and ventricular remodeling and prolonging
survival.28 Omapatrilat effectively reduces blood pressure, provides target organ protection, and reduces morbidity and mortality from cardiovascular events in animal models. Human studies with omapatrilat (Vanlev, Bristol-Myers Squibb), administered orally once daily, have demonstrated a dose-dependent reduction of systolic and diastolic blood pressure, regardless of age, race, or gender. Its ability to decrease systolic blood pressure is especially notable, since evidence suggests that systolic blood pressure is a better predictor than diastolic blood pressure of stroke, heart attack, and death. Omapatrilat appears to be a safe, well-tolerated, effective hypertensive agent in humans, and it has the potential to be an effective, broad-spectrum antihypertensive agent. Adverse effects are comparable to those of currently available antihypertensive
agents.3,29
Another vasopeptidase inhibitor that is currently under clinical development is the agent sampatrilat (Chiron). A recent study in black subjects compared the ability of sampatrilat (50 to 100 mg daily) to lower blood pressure with the ACE inhibitor
lisinopril.30 Both sampatrilat and lisinopril decreased plasma ACE concentrations, with the effect being greater with lisinopril. Unlike lisinopril, which produced a transient decrease in arterial blood pressure, sampatrilat produced a sustained decrease in mean arterial blood pressure over the entire 2-month treatment period. Treatment-emergent adverse events were noted to be similar with both treatment groups. This study concluded that the antihypertensive actions of ACE/NEP inhibitor monotherapy in black subjects
offer a novel therapeutic approach to patients otherwise resistant to the sustained antihypertensive actions of ACE.
HMG-CoA reductase inhibitors (eg, statins) are increasingly being used to treat high cholesterol levels and have been shown to prevent heart attacks and strokes. Many individuals with high cholesterol also have high blood pressure, so the effect of the statins on blood pressure is of great interest. Certain HMG-CoA reductase inhibitors may cause vasodilation by restoring endothelial dysfunction, which frequently accompanies hypertension and hypercholesterolemia. There have also been reports of a synergistic effect on vasodilation between ACE inhibitors and
statins.31 Several studies have found that a blood pressure reduction is associated with the use of statins, but conclusive evidence from controlled trials is
lacking.31,32 In a recent clinical study in individuals with moderate hypercholesterolemia and untreated hypertension, the HMG-CoA reductase inhibitor pravastatin (20 to 40 mg/day, 16 weeks) decreased total (6.29 to 5.28 mmol/L) and low-density lipoprotein (4.31 to 3.22 mmol/L) cholesterol, systolic and diastolic blood pressure (149/97 to 131/91), and pulse
pressure.33 In this same study, circulating ET-1 levels were decreased by pretreatment with pravastatin. The increase in blood pressure associated with the cold pressor test was also blunted with pravastatin compared with placebo. The blood pressure results were not affected by the gender or age of the study participants. In conclusion, clinical studies have demonstrated that a specific statin, pravastatin, decreases systolic, diastolic, and pulse pressures in persons with moderate hypercholesterolemia and
hypertension.33 The mechanism responsible for such effects is not clear, but it may involve effects on the endothelium, the inner lining of the arteries. The endothelium makes a number of hormones, some of which dilate the blood vessels, and others (such as endothelin) constrict them. Cholesterol impairs the normal functioning of the endothelium, which tends to make the blood vessels less able to dilate. It is highly likely that similar effects will be observed with other
statins.34 This antihypertensive effect may contribute to the documented health benefits of certain
statins.
After the success of hormone blockers for catecholamines, aldosterone, and angiotensin II and their successful implementation into clinical practice, another endocrine cardiovascular system has come into focus. It has long been known that the hormone vasopressin plays an important role in peripheral vasoconstriction, hypertension, and in several disease conditions with dilutional hyponatremia in edematous disorders, such as congestive heart failure, liver cirrhosis, syndrome of inappropriate secretion of antidiuretic hormone, and nephrotic syndrome. These effects of vasopressin are mediated through vascular (V1a) and renal (V2) receptors. A series of orally active nonpeptide antagonists against the vasopressin receptor subtypes have recently been synthesized and are now under intensive examination. Nonpeptide V1a-receptor antagonists, OPC21268 and SR49059, nonpeptide V2-receptor–specific antagonists, SR121463A and VPA985, and combined V1a/V2-receptor antagonists, OPC31260 and YM087, have become available for clinical
research.35,36
The potential clinical significance of vasopressin antagonists in hypertension was recently demonstrated in a clinical study using
SR49059.37 Vasopressin release was initiated in hypertensive patients by osmotic stimulation with hypertonic saline infusion. SR49059 did not alter blood pressure or heart rate before the saline infusion and did not reduce the blood pressure increment induced by the hypertonic saline infusion. However, the blood pressure peak at the end of the hypertonic saline infusion was slightly lower in the presence of SR49059. Clinical trials are continuing with both vascularly selective and nonselective vasopressin antagonists.
Recent clinical trials have been conducted with a new class of calcium channel antagonists that selectively block T-type voltage-gated plasma membrane calcium channels in vascular smooth
muscle.38 The prototypical member of this group is the agent mibefradil (Roche), which is 10 to 50 times more selective for blocking T-type than L-type calcium
channels.39 This drug is structurally and pharmacologically different from traditional calcium antagonists. It does not produce negative inotropic effects at therapeutic concentrations and is not associated with reflex activation of neurohormonal and sympathetic
systems.40 In clinical studies of hypertension, mibefradil (50 and 100 mg/day) reduced trough sitting diastolic and systolic blood pressure in a dose-related manner. Dosages exceeding 100 mg/day generally did not result in significantly greater efficacy, but were associated with a higher frequency of adverse events. No first-dose hypotensive phenomenon was observed. Mibefradil has anti-schemic properties resulting from dilation of coronary and peripheral vascular smooth muscle, and a slight reduction in heart rate. Mibefradil (Posicor) was approved by the FDA in June 1997 for the treatment of hypertension and angina. However, because of severe drug interactions, Roche withdrew the drug from the market in 1998. Since the effects of this type of calcium channel blocker were so profound on hypertension, studies with other selective T-type calcium channel antagonists have continued.
Urotensin-II (U-II), a cyclic dodecapeptide, was originally isolated from the urophysis, the hormone-secretory organ of the caudal neurosecretory system of teleost fish, and the sequence was determined nearly 20 years
ago.41 Subsequently, U-II has recently been cloned from man.42 Recent discoveries have identified U-II as an important regulator of the cardiovascular system, working to constrict arteries and possibly to increase blood pressure in response to exercise and
stress.43 Nothacker and colleagues found that U-II constricts arteries more mildly and for a longer period than other chemicals known for similar effects on blood
pressure.43 The potency of vasoconstriction of U-II is an order of magnitude greater than that of ET-1, making human U-II the most potent mammalian vasoconstrictor identified to
date.42 In vivo, human U-II markedly increases total peripheral resistance in anesthetized nonhuman primates, a response associated with profound cardiac contractile dysfunction. These effects are mediated by U-II binding to receptors in the brainstem, heart, and in major blood vessels, including the pulmonary artery, which supplies blood to the lungs, and the aorta, the major vessel leading from the heart. However, because U–II immunoreactivity is also found within the central nervous system and endocrine tissues, it may have additional activities. U-II is manufactured by the kidney, indicating that this organ plays an important role in how the protein regulates blood pressure. Unlike ET-1, there are currently no U-II antagonists under clinical development. However, based on the demonstration of U-II’s critical role in the regulation of blood pressure and circulatory function, it is highly possible that studies will be undertaken to develop drugs that target the U-II system.
It is clear from the JNC-VI study that a significant number of patients diagnosed with hypertension are receiving inadequate treatment. It is equally clear that the explosion of new knowledge about the complex mechanisms mediating high blood pressure is providing new targets for drug therapy of hypertension and other cardiovascular disorders. Knowledge obtained from long-term clinical trials comparing the effectiveness of currently utilized antihypertensive drugs on the important end points of morbidity and mortality will aid in our understanding as to which currently utilized drugs are most helpful. These studies will also aid in the identification of target systems that should be the focus of future pharmacologic interventions.
1. National High Blood Pressure Education Program. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. NIH publication 98-4080. 1997. Bethesda, Md: National Institutes of Health; 1997.
2. Epstein M. The latest options in hypertension treatment. Clinician Rev. 1999;4(3):1-6.
3. Weber M. Emerging treatments for hypertension: potential role for vasopeptidase inhibition. Am J Hypertens. 1999;12(11):139S-147S.
4. Mancia G, Stella M, Grassi G. New drugs for the treatment of hypertension. Curr Opinions Cardiol. 1999;14(5):375-380.
5. Timmermans P. Angiotensin II receptor antagonists: an emerging new class of cardiovascular therapeutics. Hypertens Res. 1999;22(2):147-153.
6. Oparil S. Newly emerging pharmacologic differences in angiotensin II receptor blockers. Am J Hypertens. 2000;13:18S-24S.
7. McConnaughey M, McConnaughey J, Ingenito A. Practical considerations of the pharmacology of angiotensin receptor blockers. J Clin Pharmacol. 1999; 39(6):547-549.
8. Oates J. Antihypertensive agents and the drug therapy of hypertension. In: Hardman J, Gilman A, Limbard L, ed. The Pharmacological Basis of Therapeutics. New York, NY: McGraw-Hill; 1996:780-808.
9. Oparil S. Eprosartan versus enalapril in hypertensive patients with angiotensin-converting enzyme inhibitor cough. Cur Therapeutic Res-Clin Exp. 1999;60:1-14.
10. Brooks D, Ohlstein E, Ruffolo R. Pharmacology of eprosartan, an angiotensin II receptor antagonist. Am Heart J. 1999;138(3):S246-S251.
11. Shusterman N. Safety and efficacy of eprosartan, a new angiotensin II receptor blocker. Am Heart J. 1999;138:238-245.
12. Levine B. Effect of eprosartan and enalapril in the treatment of black hypertensive patients: subgroup analysis of a 26 week, double-blind, multicentre study. Eprosartan Multinational Study Group. Curr Med Res Opinion. 1999;15(1):25-32.
13. Kirk J. Angiotensin-II receptor antagonists: their place in therapy. Am Fam Physician. 1999;59(11):3140-3148.
14. Ots M, Mackenzie H, Troy J, Rennke H, Brenner B. Effects of combination therapy with enalapril and losartan on the rate of progression of renal injury in rats with 5/6 renal mass ablation. J Am Soc Nephrol. 1998;9(2):224-230.
15. Nunez E, Hosoya K, Susie D, Frohlich E. Enalapril and losartan reduced cardiac mass and improved coronary hemodynamics in SHR. Hypertension. 1997;29:519-524.
16. Hamroff G, Blaufarb I, Mancini D, et al. Angiotensin II-receptor blockade further reduces afterload safely in patients maximally treated with angiotensin-converting enzyme inhibitors for heart failure. J Cardiovasc Pharmacol. 1997;30(4):533-536.
17. Brooks D, Jorkasky D, Freed M, Ohlstein E. Pathophysiological role of endothelin and potential therapeutic targets for receptor antagonists. In: Highsmith R, ed. Endothelin: Molecular Biology, Physiology and Pathology. Totowa, NJ: Humana Press; 1998:223-268.
18. Vierhapper H, Wagner O, Nowotny P, Waldhausl W. Effect of endothelin-1 in man. Circulation. 1990;81:1415-1418.
19. Yokokawa K, Tahara H, Kohno M, et al. Hypertension associated with endothelin-secreting malignant hemangioendothelioma. Ann Intern Med. 1991; 114:213-215.
20. Letizia C, Cerci S, De Ciocchis A, D’Ambrosio C, Scuro L, Scavo D. Plasma endothelin-1 levels in normotensive and borderline hypertensive subjects during a standard cold pressor test. J Hum Hypertens. 1995;9:903-907.
21. Ergul S, Parish D, Puett D, Ergul A. Racial differences in plasma endothelin-1 concentrations in individuals with essential hypertension. Hypertension. 1996;28:652-655.
22. McMahon E, Palomo M, Moore W. Phosphoramidon blocks the pressor activity of big endothelin (1-39) and lowers blood pressure in spontaneously hypertensive rats. J Cardiovasc Pharmacol. 1991;17:S29-S33.
23. Niranjan V, Telemaque S, Dewit D, Gerard R, Yanagisawa M. Systemic hypertension induced by hepatic overexpression of human prepro-endothelin-1 in rats. J Clin Invest. 1996;98:2364-2372.
24. Barton M, Luscher T. Endothelin antagonists for hypertension and renal disease. Curr Opinions Nephrol Hypertens. 1999;8(5):549-556.
25. Haynes W, Webb D. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet. 1994;344: 852-854.
26. Kentsch M, Otter W. Novel neurohormonal modulators in cardiovascular disorders. The therapeutic potential of endopeptidase inhibitors. Drugs R D. 1999;1(4):331-338.
27. O’Connor C, Gattis W, Gheorghiade M, et al. A randomized trial of ecadotril versus placebo in patients with mild to moderate heart failure: The U.S. Ecadotril Pilot Safety Study. Am Heart J. 1999;138:1140-1148.
28. Trippodo N, Robl J, Asaad M, Fox M, Panchal B, Schaeffer T. Effect of omapatrilat in low, normal and high renin experimental hypertension. Am J Hypertens. 1998;11(3):363-372.
29. Burnett J. Vasopeptidase inhibition: a new concept in blood pressure management. J Hypertens. 1999;17(1):S37-S43.
30. Norton G, Woodiwiss A, Hartford C, et al. Sustained antihypertensive actions of a dual angiotensin-converting enzyme neutral endopeptidase inhibitor, sampatrilat, in black hypertensive subjects. Am J Hypertens. 1999;12(6):563-571.
31. Sposito A, Mansur A, Coelho O, Nicolau J, Ramires J. Additional reduction in blood pressure after cholesterol-lowering treatment by statins (lovastatin or pravastatin) in hypercholesterolemic patients using angiotensin-converting enzyme inhibitors (enalapril or lisinopril). Am J Cardiol. 1999; 83(10):1497-1499.
32. Jackson G. Statins and strokes--reducing the risk. Int J Clin Pract. 1999;53(3):159.
33. Glorioso N, Troffa C, Filigheddu F, et al. Effect of the HMG-CoA reductase inhibitors on blood pressure in patients with essential hypertension and primary hypercholesterolemia. Hypertension. 1999;34:1281-1286.
34. Haq I, Wallis E, Jackson P, Yeo W, Ramsay L. Implication of recent trials with b-hydroxy-b-methylglutaryl coenzyme A reductase inhibitors for hypertension management. J Hypertens. 1999; 17(11):1641-1646.
35. Mayinger B, Hensen J. Nonpeptide vasopressin antagonists: a new group of hormone blockers entering the scene. Exp Clin Endocrinol Diabetes. 1999;107(3):157-165.
36. Yatsu T, Tomura Y, Tahara A, et al. Pharmacology of conivaptan hydrochloride (YM087), a novel vasopressin V1A/V2 receptor antagonist. Nippon Yakurigaku Zasshi. 1999;114(suppl 1):113P-117P.
37. Thibonnier M, Kilani A, Rahman M, et al. Effects of the nonpeptide V(1) vasopressin receptor antagonist SR49059 in hypertensive patients. Hypertension. 1999;34(6):1293-1300.
38. Van der Lee R, Pfaffendorf M, Van Zwieten P. Comparative effects of mibefradil and other calcium antagonists on resistance arteries of different end organs. Fundam Clin Pharmacol. 1999;13(2):198-203.
39. Clozel J, Ertel E, Ertel S. Voltage-gated T-type Ca2+ channels and heart failure. Proc Assoc Am Physicians. 1999;111(5):429-437.
40. Ernst M, Kelly M. Mibefradil, a pharmacologically distinct calcium antagonist. Pharmacotherapy. 1998;18(3):463-485.
41. Davenport A, Maguire J. Urotensin II: fish neuropeptide catches orphan receptor. Trends Pharmacological Sci. 2000; 21(3):80-82.
42. Ames R, Sarau H, Chambers J, et al. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature. 1999;401(6750):282-286.
43. Nothacker H, Wang Z, McNeill A, et al. Identification of the natural ligand of an orphan G-protein-coupled receptor involved in the regulation of vasoconstriction. Nat Cell Biol. 1999;1(6):383-385.
[Introduction]
[References]
