Oral administration of DuP 753, a specific angiotensin II receptor antagonist, to normal male volunteers. Inhibition of pressor response to exogenous angiotensin I and II.

Christen, Yves; Waeber, Bernard; Nussberger, Jürg; Porchet, M; Borland, R.; Lee, R. J.; Maggon, K. K.; Shum, Linyee; Timmermans, Pieter B.M.W.M.; Brunner, Heinrich

doi:10.1161/01.cir.83.4.1333

Cited by 226 publications

(110 citation statements)

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“…Thus, the long duration of the antihypertensive effect of valsartan, observed in renal hypertensive rats, appears to be due to a blockade of the AT,-receptor. Long lasting inhibition of AII-induced pressor responses have also been reported with losartan in normal male volunteers (Christen et al, 1991).…”

Section: -mentioning

confidence: 74%

“…This compound is an efficacious antihypertensive agent in animals (Wong et al, 1990a,d) and is also active in man (Christen et al, 1991). The blood pressure-lowering effect of losartan in rats, however, depends partly on its conversion to the active, hepatically generated carboxylic acid metabolite, EXP3174, which is about 20 times more potent than the parent compound as an AT,-receptor antagonist (Wong et al, 1990c;Timmermans et al, 1991b).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT₁‐receptor subtype

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Gasparo

Bühlmayer

et al. 1993

British J Pharmacology

243

118

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1 The pharmacological profile of valsartan, (S)-N-valeryl-N-([2'-(lH-tetrazol-5-yl) (p.o.). The antihypertensive effect lasted for at least 24 h after either route of administration. After repeated oral administration for 4 days (3 and 10 mg kg-' daily), in 2K1C renal hypertensive rats, systolic blood pressure was consistently decreased, but heart rate was not significantly affected. 7 In conscious, normotensive, sodium-depleted marmosets, valsartan decreased mean arterial pressure, measured by telemetry, after oral doses of 1-30 mg kg'. The hypotensive effect persisted up to 12 h after 3 and l0mgkg-' and up to 24h after 30mgkg-'.8 In sodium-depleted marmosets, the hypotensive effect of valsartan lasted longer than that of losartan (DuP 753). In renal hypertensive rats, both agents had a similar duration (24 h), but a different onset of action (valsartan at 1 h, losartan between 2 h and 24 h). 9 These results demonstrate that valsartan is a potent, specific, highly selective antagonist of AII at the AT,-receptor subtype and does not possess agonistic activity. Furthermore, it is an efficacious, orally active, blood pressure-lowering agent in conscious renal hypertensive rats and in conscious normotensive, sodium-depleted primates.

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Section: -mentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT₁‐receptor subtype

Criscione

Gasparo

Bühlmayer

et al. 1993

British J Pharmacology

243

118

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“…2 Clinical pharmacology studies have confirmed that losartan blocks the Ang II receptor. 3 Clinical trials have demonstrated that losartan potassium given alone lowers blood pressure (BP) and is well tolerated in longterm trials in patients with essential hypertension. 4 Despite the efficacy of losartan potassium or other monotherapy agents such as hydrochlorothiazide (HCTZ), some patients with more resistant forms of hypertension may require concomitant antihypertensive therapy to control their BP.…”

Section: Introductionmentioning

confidence: 99%

Comparative effects of chronic ACE inhibition and AT1 receptor blocked losartan on cardiac hypertrophy and renal function in hypertensive patients

et al. 2002

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The present study describes the effects of losartan and the angiotensin-converting enzyme inhibitor enalapril on blood pressure, echocardiographically calculated left ventricular mass, renal function evaluated by glomerular filtration rate and quality of life. The renin-angiotensin-aldosterone system is of importance for cardiovascular growth. There is substantial experimental documentation in animals that the angiotensin II antagonist, losartan, decreases the cardiac hypertrophy response caused by elevated arterial pressure as well as intravascular volume overload. However, data in humans is scarce. This is a 3-year, randomised, doubleblind study with parallel group design in 50 patients with essential hypertension. The results show that both drugs reduced blood pressure equally effectively, and also left ventricular mass (P Ͻ 0.001). After 3 years of treatment glomerular filtration rate significantly increased with losartan (P Ͻ 0.005). Serum uric acid fell modestly although significantly, dose-dependent in los-

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“…Losartan is an angiotensin II receptor antagonist with dilatory effects on arteries and veins. 18 The substance has recently been approved for the treatment of arterial hypertension. As yet, its influence on portal hypertension has not been investigated.…”

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confidence: 99%

Effect of losartan, an Angiotensin II receptor antagonist, on portal pressure in cirrhosis

1999

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The primary objective of drug therapy in portal hypertension is the prevention of variceal bleeding. The use of nonselective ␤-blockers that reduce portal pressure by lowering splanchnic blood inflow 1 has proved effective in this indication. Treatment with propranolol or nadolol reduces the risk of first hemorrhage 2 as well as that of further bleeding episodes in patients with a history of variceal bleeding. 3 However, the average reduction in portal pressure by 15% achieved with ␤-blockers is moderate, 4 and no relevant decrease is observed in more than 30% of patients despite adequate dosage. 5 To enhance the pressure-lowering effect on portal hypertension, ␤-blockers are combined with isosorbide-5 mononitrate, 6 an agent that reduces portal pressure in cirrhosis because of its vasodilator properties. 7 One study demonstrated a mean reduction in portal pressure of 19% during therapy with the combination of propranolol and isosorbide-5 mononitrate. 6 In patients with sodium retention and ascites, however, serious deterioration of renal function was observed with the combination of ␤-blockers and nitrates. 8 The limited effect on portal pressure, the incidence of adverse effects-15% for nonselective ␤-blockers alone, 9 16% for nadolol plus isosorbide-5 mononitrate 10 -and the timeconsuming dose-finding are a stimulant for the search for new antihypertensive substances.Angiotensin II is considered a potential mediator of intrahepatic portal hypertension, because its plasma level is elevated in cirrhosis 11 and its administration induces a rise in portal pressure. 12 Enhancement of the adrenergic vasoconstrictor influence on the portal systems, 13 direct contractile influence on stellate cells, 14 which serve as regulators of the sinusoidal blood flow, 15,16 and sodium and fluid retention induced by the stimulation of aldosterone secretion 17 may be mechanisms that contribute to the portal hypertensive effect of angiotensin II. Losartan is an angiotensin II receptor antagonist with dilatory effects on arteries and veins. 18 The substance has recently been approved for the treatment of arterial hypertension. As yet, its influence on portal hypertension has not been investigated. The aim of this study was to determine the antihypertensive effects of losartan on portal pressure with particular attention paid to potential side effects. PATIENTS AND METHODSPatients. In patients with cirrhosis and esophageal varices, portal hypertension was evaluated by the determination of hepatic venous pressure gradient (HVPG). Thirty consecutive patients with HVPG Ն 20 mm Hg (severe portal hypertension) were assigned to losartan treatment according to the below-mentioned protocol. In accordance with Armonis et al., 19 our preliminary investigations had shown a variability of Ϯ 1 mm Hg in the measurement of HVPG independent from the height of the values. Therefore, this initial selection of patients with high HVPG values was performed to reduce the influence of variability on the percentage change in HVPG caused by losartan. Later,...

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Oral administration of DuP 753, a specific angiotensin II receptor antagonist, to normal male volunteers. Inhibition of pressor response to exogenous angiotensin I and II.

Abstract: DuP 753 appears to be a well-tolerated, orally active, potent, and long-lasting antagonist of angiotensin II in men.

Cited by 226 publications

References 32 publications

Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT₁‐receptor subtype

Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT₁‐receptor subtype

Comparative effects of chronic ACE inhibition and AT1 receptor blocked losartan on cardiac hypertrophy and renal function in hypertensive patients

Effect of losartan, an Angiotensin II receptor antagonist, on portal pressure in cirrhosis

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Oral administration of DuP 753, a specific angiotensin II receptor antagonist, to normal male volunteers. Inhibition of pressor response to exogenous angiotensin I and II.

Abstract: DuP 753 appears to be a well-tolerated, orally active, potent, and long-lasting antagonist of angiotensin II in men.

Cited by 226 publications

References 32 publications

Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT1‐receptor subtype

Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT1‐receptor subtype

Comparative effects of chronic ACE inhibition and AT1 receptor blocked losartan on cardiac hypertrophy and renal function in hypertensive patients

Effect of losartan, an Angiotensin II receptor antagonist, on portal pressure in cirrhosis

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Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT₁‐receptor subtype

Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT₁‐receptor subtype