Losartan attenuates modest but not strong renal vasoconstriction induced by nitric oxide inhibition.
Previous studies showed variable success of angiotensin II (ANG II) antagonists to oppose systemic and renal vasoconstriction during long-term nitric oxide synthase (NOS) inhibition. We explored in short-term experiments whether the systemic and renal vasodilatory response to angiotensin II type 1 (AT1)-receptor blockade depends on the extent of NOS blockade. In the first series of experiments, anesthetized rats underwent clearance studies during continuous monitoring of mean arterial pressure (MAP), renal blood flow (RBF, flow probe), and renal vascular resistance (RVR). Compared with control animals, low-dose infusion of the NOS-inhibitor nitro-L-arginine (NLA) increased MAP and RVR, decreased glomerular filtration rate, RBF, and sodium excretion, and had no effect on plasma and kidney ANG II content. High-dose NLA induced stronger effects, did not affect plasma ANG II, and reduced kidney ANG II to approximately 60%. In the second series of experiments, we studied the effect of low- and high-dose NLA on autoregulation of RBF. NLA induced a dose-dependent increase in MAP and decrease in RBF but left autoregulation intact. The AT1-receptor antagonist losartan restored MAP and RBF during low-dose NLA but had no depressor or renal vasodilating effect during high-dose NLA. In summary, short-term NOS blockade causes a dose-dependent pressor and renal vasoconstrictor response, without affecting renal autoregulation, and AT1-receptor blockade restores systemic pressor and renal vasoconstrictive effects of mild NOS inhibition but fails to exert vasorelaxation during strong NOS blockade. Both levels of NOS inhibition did not importantly alter intrarenal ANG II levels. Apparently the functional role of endogenous ANG II as determinant of vascular tone is diminished during strong NOS inhibition.
Department of Nephrology and Hypertension, University Hospital Utrecht, The Netherlands.
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E
Turkstra
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Braam
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Koomans
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D007668:Kidney / Q000187:drug effects*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D000804:Angiotensin II; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D019808:Losartan