Role of thromboxane A2/prostaglandin H2 receptor in the vasoconstrictor response of rat aorta to endothelin.
Endothelin stimulates the release of arachidonic acid in vascular smooth muscle cells, raising the possibility that eicosanoid metabolites of arachidonic acid may be involved in mediating the contractile effects of endothelin. We have investigated the hypothesis that endothelin-1 stimulates formation of thromboxane A2 in rat aorta and that this thromboxane A2 mediates part of the contractile response to endothelin-1. Preincubation of rat aorta with 10 microM SQ 29,548, a "selective" antagonist of thromboxane A2/prostaglandin H2 (TP) receptors, caused a rightward shift in the dose-response curve and a reduction in the maximal response to endothelin-1. Preincubation with SQ 29,548 had no effect on the dose-response curves to either norepinephrine or KCl. In rings of rat aorta that had been precontracted with 1 nM endothelin-1, addition of either 10 microM SQ 29,548 or 10 microM indomethacin (cyclooxygenase inhibitor) caused a relaxation of 50-65% of developed tension. The inhibitory effect of SQ 29,548 on endothelin-induced contraction was greater when it was added after endothelin than when added before endothelin, suggesting that activation of the TP receptor may be more important in the maintenance of developed tension than in the initiation of contraction. Finally, 100 nM endothelin-1 stimulated the indomethacin-sensitive formation of thromboxane A2 in rings of rat aorta. These results suggest that a significant portion of the sustained contraction induced by endothelin in rat aorta requires the persistent activation of the TP receptor by a cyclooxygenase product, most likely thromboxane A2 or prostaglandin H2.
Reynolds
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Department of Heart and Hypertension Research, Cleveland Clinic Foundation, Ohio.
Mok
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D000818:Animals; D001011:Aorta; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002478:Cells, Cultured; D016232:Endothelins; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000378:metabolism / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010455:Peptides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D016232:Endothelins; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010455:Peptides; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013928:Thromboxane A2; D011189:Potassium Chloride; C045749:SQ 29548; D009638:Norepinephrine; D007213:Indomethacin