Effects of losartan on vasoconstrictor responses to angiotensin II in the forearm vascular bed of healthy volunteers

J. Baan, P. C. Chang, P. Vermeij, M. Pfaffendorf, P. A. van Zwieten
1996 Cardiovascular Research  
Objectives: The angiotensin type 1 (AT,) receptor antagonist, losartan (orally administered), decreases vasoconstrlctor effects of angiotensin II (Ang II). Oral losartan is converted into the active metabolite, Exp3174, which causes most of the antagonistic effects. Effects of losartan as such have not been studied after its intra-arterial administration in humans. Therefore, we investigated the effects of both intra-arterially and orally administered losartan on AT,-receptor-mediated
more » ... iction. Methods: Forearm vascular resistance (FVR) was determined by venous occlusion plethysmography in 24 healthy subjects. Ang II (0.01, 0.1, 1.0, and 10.0 ng/kg/min) was infused into the brachial artery, before and after losartan, administered intra-arterially (dose range 100-3000 ng/kg/min) or orally (50 mg once daily for 5 days). Results: Ang II concentration-dependently increased FVR (P < 0.05); tachyphylaxis did not occur. Losartan alone did not change FVR. In&a-arterially infused losartan dose-dependently inhibited Ang-II-induced vasoconstriction. At a concentration of 10m8 M Ang II, losartan reduced FVR, as a percentage of baseline values, from 287 f 30 to 33 + 8% (mean f s.e.m.; P < 0.05). Orally given losartan reduced FVR from 297 f 40 to 73 + 19% (P < 0.05). Conclusions: Losartan, intra-arterially administered, causes no effect on baseline vascular resistance, but markedly inhibits Ang-II-induced vasoconstriction in the human foreann vascular bed. Relatively high doses of in&a-arterial losartan were required when compared to the antagonism by the orally administered drug. These data indicate that Ang-II-induced vasoconstriction is mediated by AT,-receptors, which are blocked by losartan. The more effective antagonism exerted by oral losartan is presumably explained by the formation of Exp3174. Endogenous Ang II does not contribute to baseline vascular tone in healthy, sodium-replete, subjects. * Corresponding author. Tel.: ( + 3 I-20) 566 48 11; fax: (+ 3 I-20) 696 8704. administered angiotensin I and angiotensin II in the human forearm [4]. After oral administration losartan is converted into the active metabolite, Exp3174, which is presumed to block the AT,-receptor more actively than the parent compound [:5,6]. The efficacy of losartan itself on vascular angiotensin II receptors has not been investigated in humans. In the present study, we investigated the influence of losartan on vascular AT, -receptors and angiotensin-II-induced vasoconstriction in the human forearm, both after infusion into the brachial artery and after oral administration. The 'perfused forearm' is a convenient model for studying human vascular responses to intra-arterially ad-Time for Iprimary review 30 days. OOOS-6363/96/$15.00
doi:10.1016/s0008-6363(96)00133-2 pmid:8944829 fatcat:fe3jsgloi5df7ayxaymzkoo26m