Mechanisms by which endothelin 1 induces pulmonary vasoconstriction in the rabbit.
To investigate the mechanisms by which endothelin 1 (ET-1) causes pulmonary vasoconstriction, we studied the effect of synthetic ET-1 on pulmonary vascular tone in the buffer-perfused isolated rabbit lung. In nanomolar concentrations (1.2-8 nM), ET-1 causes a dose-dependent increase in pulmonary arterial pressure that persists for greater than or equal to 1 h (increase in pressure 19 +/- 2 mmHg with ET-1 vs. 2 +/- 1 with vehicle, P less than 0.0001). Reduction of calcium availability with verapamil, cadmium, or a calcium-free buffer significantly blunts the increase in pressure caused by ET-1. Pretreatment with a calcium-free buffer plus the chelator ethylene glycol-bis(beta-aminoethyl ether)-N,N,N', N'-tetraacetic acid (EGTA) completely eliminates the vasoconstriction. Three different inhibitors of protein kinase C, phloretin, staurosporine, and dihydrosphingosine, significantly diminish the response to ET-1. Indomethacin and a thromboxane synthase inhibitor partially decrease the response to the highest concentration of ET-1. Isoproterenol and dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP) are significantly more effective in preventing the vasoconstriction caused by ET-1 than are nitroprusside and guanosine 5'-cyclic monophosphate (cGMP) analogues. ET-1 in doses of 1.2-8 nM is a potent pulmonary vasoconstrictor in the isolated rabbit lung. ET-1 appears to cause pulmonary vasoconstriction by increasing calcium entry and by activating protein kinase C. Vasodilators that increase cAMP are substantially more effective in preventing the increase in pressure than are drugs that increase cGMP.
Mann
J
J
Medical Service, Veterans Affairs Medical Center, Salt Lake City, Utah.
Farrukh
I S
IS
Michael
J R
JR
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000502:physiology; D000242:Cyclic AMP / Q000494:pharmacology; D006152:Cyclic GMP / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation; D008168:Lung / Q000187:drug effects; D008297:Male; D009129:Muscle Tonus / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011651:Pulmonary Artery / Q000502:physiology; D011667:Pulmonary Veins / Q000187:drug effects*; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects*
D016232:Endothelins; D000242:Cyclic AMP; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D006152:Cyclic GMP; D002118:Calcium