Impaired endothelium-dependent relaxation after coronary reperfusion injury: evidence for G-protein dysfunction.
This study was done to determine whether abnormal receptor-dependent release of endothelium-derived relaxing factor (EDRF) might be caused by G-protein dysfunction. Dogs were exposed to global myocardial ischemia (45 minutes, induced by aortic cross-clamping) followed by reperfusion (60 minutes) while on cardiopulmonary bypass, and coronary arteries were then studied in vitro in organ chamber experiments. After reperfusion, endothelium-dependent relaxation to the receptor-dependent agonists adenosine diphosphate and acetyl-choline was significantly impaired as well as to sodium fluoride, which acts on a pertussis toxin-sensitive G-protein. In contrast, endothelium-dependent relaxations to the receptor-independent agonists A23187 and phospholipase C were normal. Furthermore, endothelium-dependent relaxation to poly-L-arginine (molecular weight, 139,200), which appears to induce endothelium-dependent relaxation of the canine coronary artery by a nonnitric oxide pathway, was unaffected by ischemia and reperfusion. These experiments suggest that global myocardial ischemia and reperfusion selectively impair receptor-mediated release of EDRF (nitric oxide) but that the ability of the endothelial cell to produce EDRF or generate endothelium-dependent relaxation to nonnitric oxide-dependent agonists remains intact. We hypothesize that coronary reperfusion injury leads to G-protein dysfunction in the endothelium.
Section of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota 55905.
P R
PR
Evora
P J
PJ
Pearson
H V
HV
Schaff
D000109:Acetylcholine / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000077410:Aluminum Chloride; D017607:Aluminum Compounds / Q000494:pharmacology; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002315:Cardiopulmonary Bypass; D002712:Chlorides / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology*; D015237:Dinoprost / Q000494:pharmacology; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000503:physiopathology; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D012969:Sodium Fluoride / Q000494:pharmacology; D010738:Type C Phospholipases / Q000494:pharmacology
D017607:Aluminum Compounds; D002712:Chlorides; D010455:Peptides; C015462:polyarginine; D009569:Nitric Oxide; D000001:Calcimycin; D000077410:Aluminum Chloride; D000244:Adenosine Diphosphate; D012969:Sodium Fluoride; D015237:Dinoprost; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D007545:Isoproterenol; D000109:Acetylcholine