Inhibition of thrombin-induced endothelium-dependent relaxation after coronary ischemia in the dog: possible role of the coagulation cascade.
Myocardial ischemia inhibits endothelium-dependent relaxation stimulated by the coagulant peptide, thrombin. To investigate whether activation of endogenous thrombin contributed to this reduction in relaxant sensitivity, the effects of pretreatment of dogs with the coumarin anticoagulant, brodifacoum, were studied. Experiments were performed in both normal coronary vasculature and coronary vasculature exposed to 90 min of myocardial ischemia, with or without 60 min of subsequent reperfusion. Ischemia was induced in the left anterior descending artery (LAD); nonischemic vessels from the left circumflex (LCX) artery of the same animals were used as control. Thrombin caused dose-dependent relaxation in isolated LCX preconstricted with prostaglandin F2 alpha (Emax of 89.1 +/- 2.33%). Relaxation was reduced by 90 min of ischemia (Emax of 27.5 +/- 8.0%; p less than 0.05), and further reduced after subsequent reperfusion (Emax of 8.7 +/- 8.7%). However, maximum relaxations to acetylcholine, calcimycin, and isoproterenol were unchanged after ischemia (Emax greater than 90% in all groups). Brodifacoum had no effect on thrombin-induced relaxation in control vessels (Emax of 83.0 +/- 3.5%), or on relaxation in response to acetylcholine, calcimycin, or isoproterenol (Emax greater than 90%). In contrast, brodifacoum markedly reduced thrombin-induced relaxation after ischemia (Emax of 3.3 +/- 3.3%; p less than 0.05) yet significantly preserved the relaxant response to thrombin after ischemia and reperfusion (Emax of 36.6 +/- 4.3%). Infusion of the thrombin inhibitor, D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK), during ischemia and reperfusion also preserved in part the relaxant response induced by thrombin (Emax of 30.0 +/- 5.1%; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Winn
M J
MJ
Department of Pharmacology, University of Alabama, Birmingham 35294.
Ku
D D
DD
Nelson
J M
JM
D015110:4-Hydroxycoumarins / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D000001:Calcimycin / Q000494:pharmacology; D003327:Coronary Disease / Q000503:physiopathology*; D015237:Dinoprost / Q000494:pharmacology; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009569:Nitric Oxide / Q000502:physiology*; D013917:Thrombin / Q000037:antagonists & inhibitors*
D015110:4-Hydroxycoumarins; D000590:Amino Acid Chloromethyl Ketones; D009569:Nitric Oxide; D000001:Calcimycin; C013418:bromfenacoum; D015237:Dinoprost; D013917:Thrombin; D007545:Isoproterenol; C040308:phenylalanyl-prolyl-arginine-chloromethyl ketone; D000109:Acetylcholine