Modification of beta-adrenoceptors and adenylyl cyclase in hearts perfused with hypochlorous acid.
It is now well known that the signal transduction pathway involving beta-adrenoceptors and adenylyl cyclase is altered in ischemic heart disease. Since leukocytes accumulate in the ischemic heart and produce hypochlorous acid (HOCl), we investigated the effects of HOCl upon beta-adrenoceptors and adenylyl cyclase activities by perfusing rat hearts with 0.1 mM HOCl for 10 min and isolating cardiac membranes. Marked depressions in both the density and affinity of beta1-adrenoceptors were observed, whereas no significant change in the affinity or density of beta2-adrenoceptors was seen in hearts perfused with HOCl. After treatment of hearts with HOCl, competition curves using isoproterenol, a beta-adrenoceptor agonist, revealed a decrease in the proportion of high affinity binding sites. The adenylyl cyclase activities in the absence and presence of forskolin, NaF, Gpp(NH)p, or isoproterenol were depressed in hearts perfused with HOCl; however, the stimulatory effects of these agents on adenylyl cyclase were either unaltered or augmented. The presence of methionine in the perfusion medium prevented the HOCl-induced changes in beta1-adrenoceptors and adenylyl cyclase activity. These results suggest that HOCl may produce a defect in the beta-adrenoceptor linked signal transduction mechanism by affecting both beta1-adrenoceptors and adenylyl cyclase enzyme in the myocardium.
Persad
S
S
St. Boniface General Hospital Research Centre, and Department of Physiology, Faculty of Medicine, The University of Manitoba, Winnipeg, Canada.
Dhalla
N S
NS
D000262:Adenylyl Cyclases / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002316:Cardiotonic Agents / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006997:Hypochlorous Acid / Q000494:pharmacology*; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008715:Methionine / Q000494:pharmacology; D009206:Myocardium / Q000201:enzymology*; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology; D012969:Sodium Fluoride / Q000494:pharmacology
D002316:Cardiotonic Agents; D007457:Iodine Radioisotopes; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; C047975:cyanopindolol; D006997:Hypochlorous Acid; D012969:Sodium Fluoride; D008715:Methionine; D010869:Pindolol; D000262:Adenylyl Cyclases; D007545:Isoproterenol