Influence of indomethacin and L-NMMA on vascular tone and angiotensin II-induced vasoconstriction in the human forearm.
Stimulated release of vasodilator prostaglandins and nitric oxide by angiotensin II may counteract the vasoconstrictor effects of this octapeptide. We investigated the effects of inhibition of prostaglandin synthesis by indomethacin and of nitric oxide formation by NG-monomethyl-L-arginine (L-NMMA) on baseline forearm blood flow (FBF) and on angiotensin II-induced vasoconstriction in healthy subjects. For comparison, the effects of the AT1-receptor antagonist losartan on these parameters were determined. FBF was measured by venous occlusion plethysmography. Angiotensin II (0.01-10 ng/kg/min) was infused into the brachial artery, in the absence and presence of indomethacin (0.65 micrograms/kg/min; n = 8), L-NMMA (30 micrograms/kg/min; n = 5), and losartan (3 micrograms/kg/min; n = 12), respectively. Sodium nitroprusside was used to submaximally predilate the forearm vascular system. Baseline FBF remained unchanged with indomethacin and losartan, but was significantly decreased by -42 +/- 6% (mean +/- SEM) by L-NMMA. The dose-dependent angiotensin II-induced vasoconstriction was unaffected by indomethacin and L-NMMA, but was inhibited by losartan. Emax was -78 +/- 2% during control conditions, -84 +/- 3% during indomethacin (n.s.), -74 +/- 4% during L-NMMA (n.s.), and -17 +/- 6% during losartan infusion (p < 0.05). None of the interventions significantly changed the EC50 value of angiotensin II of -9.4 +/- 0.14 log M. In conclusion, in the human forearm of healthy subjects, neither endogenous angiotensin II nor cyclooxygenase-dependent prostaglandin synthesis plays a role in the genesis of vascular tone, whereas endogenous nitric oxide production does. The constrictor effects of angiotensin II are counteracted by neither stimulated release of prostaglandins nor by that of nitric oxide.
Baan
J
J
Department of Nephrology, Leiden University Medical Centre, The Netherlands. J.Baan@AMC.UVA.NL
Chang
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PC
Vermeij
P
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Pfaffendorf
M
M
van Zwieten
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D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D012039:Regional Blood Flow / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014666:Vasomotor System / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology*
D000959:Antihypertensive Agents; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D019323:omega-N-Methylarginine; D019808:Losartan; D007213:Indomethacin