Valsartan: Preclinical and Clinical Profile of an Antihypertensive Angiotensin‐II Antagonist

Abstract

Angiotensin I1 (Ang II), an octapeptide formed from the decapeptide angiotensin I by the proteolytic action of angiotensin-converting enzyme (ACE), plays a key role in the regulation of blood pressure and fluid and electrolyte homeostasis (for review see ref. 16). Inhibitors of ACE are used for the treatment of hypertension and congestive heart failure and in patients with left-ventricular dysfunction after myocardial infarction (22,26,27). In the past, attempts to develop Ang I1 receptor antagonists failed because they lack oral activity (25) and have unwanted agonistic properties (24). More recently specific, nonpeptide, orally active Ang 11-receptor antagonists have been developed (1,12,15,20,33,37,41,44) from imidazole derivatives first described by Furukawa et al. ( 1 3). This new class of agents provides selective blockade of the AT,-Ang I1 receptor subtype without interfering with the AT2-receptor subtype. The AT,-receptor subtype is responsible for the well-known effects of Ang 11, such as vasoconstriction, aldosterone and epinephrine release, water intake, and cellular proliferation (6,32,36), whereas the pathophysiological role of the AT2-receptor subtype is not yet well understood (63).Losartan (originally known as DuP 753) was the first orally active antagonist of the AT,-receptor subtype (1 2,32,44,46). The blood pressure-lowering effect of losartan is enhanced by its conversion to the active, hepatically-generated carboxylic acid metabolite, EXP3174 or E3174, which is about 20 times more potent than the parent compound as an AT,-receptor antagonist (47). By contrast, valsartan (originally CGP 48933) is a novel and orally active Ang I1 antagonist that does not require hepatic metabolism (5,lO). It is a highly selective antagonist of Ang 11 at the AT,-receptor subtype and does not possess agonistic properties (5). Furthermore, it is an efficacious, orally active, blood pressure-lowering agent in conscious renal hypertensive rats ( 5 ) , conscious normotensive,

Dose-response efficacy of valsartan, a new angiotensin II receptor blocker

“…9 Plasma concentrations of valsartan were similar on Days 14 and 28, indicating that there was no significant accumulation of drug. This is as expected since the half-life of valsartan is 6 h and the dosing interval was 24 h. Maximum pharmacodynamic effect (measured by net effect on MSuDBP) was reached at 2-6 h post dose and, as expected, was later than the maximum plasma concentration of valsartan, which was observed at 2 h. The net effect was consistent for Days 14 and 28 for all valsartan doses, suggesting that patients reach pharmacodynamic steady state for diastolic blood pressure by 2-4 weeks of valsartan therapy.…”

“…[5][6][7][8] These agents effectively block the RAS by competitive antagonism of the action of angiotensin II at its cellular receptor site. 5,6,7,9 The AT 1 cellular receptor site appears to mediate most of the known actions of angiotensin II, although a second receptor site exists, AT 2 , 10 which appears to play an important role in apoptosis 11 and inhibition of cell growth and fibrillar collagen metabolism. 12 Valsartan is a new orally active angiotensin II antagonist which inhibits the RAS by selectively preventing the interaction of angiotensin II at its AT 1 cellular receptor site 9,13 Previous Phase I trials with valsartan have shown it to be well tolerated in single doses ranging from 10 to 400 mg once daily.…”

Angiotensin II receptor antagonists in arterial hypertension

“…It has also been described as sensitising in baroreceptors, the stimulation of prostacyclin release, and at long-term reduction in the proliferative effect (antiproliferative effect). 7 In volunteers the administration of AT-1 receptor antagonists increase plasma renin activity and angiotensin II levels either in acute administration or multiple dose administration; 16,17 but the pressure effect of angiotensin II is blocked. Whereas ACE inhibitors reduce plasma level of angiotensin II and increase bradykinin levels.…”

Angiotensin II receptor pharmacology and AT1-receptor blockers

“…This was the basis for the further development of highly specific and selective angiotensin AT 1 -receptor binding substances such as losartan, [16][17][18][19] valsartan, [20][21][22][23] irbesartan, [24][25][26][27] candesartan, 28 eprosartan, 29 telmisartan, 30 and others (overview 31 ), and AT 2 -receptor ligands/antagonists, for example, PD123177, PD123319, and CGP42112. 32,33 Ang II receptor subtypes…”

“…In the adult organism, the AT 2 receptor is present at high concentrations in the adrenal medulla, uterus, and ovary, and is also found in vascular endothelium and in distinct brain areas. 14,20 The fact that it is expressed at high levels in embryonic tissues, but to a much lesser extent in normal adult tissues, has raised speculations as to its possible role in development and cell differentiation.…”