Antagonistic effects of losartan on thromboxane A2-receptors in human isolated gastroepiploic artery and saphenous vein.
In addition to its AT1-receptor antagonist activity, losartan has been shown to antagonize thromboxane A2 (TXA2)-induced contraction of animal vessels. We investigated for the first time in human isolated gastroepiploic artery (GEA) and saphenous vein (SV) the TXA2/PGH2-receptor antagonist activity of losartan in the presence of indomethacin (1 microM) and N(omega)-nitro-L-arginine (100 microg). Losartan at concentrations of > or =1 microM on GEA and from 10 microM on SV significantly shifted U46619-induced contractions to the right. In addition, 100 microM losartan decreased by 34% the amplitude of the contraction to U46619 on both GEA and SV. The potency of losartan for the TXA2 receptor was 50- and 80-fold lower than that for the AT1 receptor on human GEA and SV, respectively. This inhibitory effect of losartan appeared selective for angiotensin II and TXA2-induced contractions because 100 microM losartan did not modify either endothelin-1- or KCl-induced contraction in human SV, although a reduction of norepinephrine- and 5-hydroxytryptamine-induced contraction was observed in human GEA and SV, respectively. In conclusion, losartan is an antagonist of TXA2 receptor on human GEA and SV. However, this antagonist activity occurred for a relative high dose of losartan, suggesting that it contributes at a low level, if any, to its antihypertensive effect.
Tripodi
F
F
Laboratory of Pharmacology, PCEBM, Faculté de Médecine, Hopital Michallon, CHU Grenoble, France.
Stanke-Labesque
F
F
Devillier
P
P
Chavanon
O
O
Sessa
C
C
Bessard
G
G
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D019335:Nitroarginine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D012501:Saphenous Vein / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D013270:Stomach / Q000098:blood supply*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D000804:Angiotensin II; D019335:Nitroarginine; D012701:Serotonin; D011189:Potassium Chloride; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019808:Losartan; D009638:Norepinephrine; D007213:Indomethacin