Effects of losartan on contractile responses of conductance and resistance arteries from rats.
We investigated the selectivity of losartan as an angiotensin II (ANG II) antagonist in contractile experiments using segments of small mesenteric arteries and rings of aorta from rat. The concentration-effect curve of ANG II was not different in mesenteric arteries with an without endothelium. In both resistance and conductance vessels, it was shifted toward larger concentrations by losartan (3 nM) with similar apparent inhibition constant (KB) values: 4.1 +/- 1.8 nM (n = 6) in small mesenteric arteries and 1.9 nM (n = 6) in aorta. These values agree with the known affinity of losartan for AT1 receptors. At 1 microM, the AT2-selective ligand CGP 42112A had no effect on contractile responses induced by norepinephrine (NE), serotonin, or neuropeptide Y (NPY). However, it inhibited vasoconstriction elicited by prostaglandin F2 alpha (PGF2 alpha). This latter effect was also noted in the aorta. Similarly, losartan also competitively antagonized aortic contractile responses elicited by U 46619, a thromboxane A2 analogue (TXA2), with a pA2 value of 5.7. Two losartan analogues, DuP 532 and EXP 3174 (a metabolite of losartan), < or = 30 microM, did not antagonize U 46619, showing structural requirements for this antagonistic action of losartan. We conclude that in both rat resistance and conductance vessels, ANG II induces vasoconstriction through activation of AT1 receptors which are selectively blocked by losartan at nanomolar concentrations and that at micromolar concentrations, losartan may also block the vascular TXA2/PGF2 alpha (TP) receptor.
Corriu
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Université Louis Pasteur de Strasbourg, Laboratoire de Pharmacologie Cellulaire et Moléculaire, Illkirch, France.
Bernard
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Schott
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Stoclet
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D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015237:Dinoprost / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D011450:Prostaglandin Endoperoxides, Synthetic; D013777:Tetrazoles; D000804:Angiotensin II; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost; D019808:Losartan