Alterations of beta-adrenoceptor responsiveness in postischemic myocardium after 72 h of reperfusion.
To determine the effect of a completely developed reperfused myocardial infarction model on beta-adrenoceptor responsiveness, we induced a 90-min regional ischemia followed by 72 h of reperfusion in dog hearts. Regional myocardial blood flow was determined after 60 min of ischemia using radioactive microspheres. beta-adrenoceptor density was reduced in the ischemic endocardium (95+/-16 fmol/mg) and epicardium (160+/-13 fmol/mg) compared to the nonischemic region (304+/-21 fmol/mg). beta-adrenoceptor density in the ischemic endocardium varied with the degree of collateral blood flow measured (r2=0.79, P<0.05); this relation was the opposite of that in the ischemic epicardium (r2=0.77, P<0.05). Higher levels of tissue catecholamines and G protein-coupled receptor kinase 2 (GRK2) were observed in the ischemic epicardium as compared to nonischemic tissue. Forskolin-induced adenylyl cyclase activities were depressed in both ischemic regions as compared to nonischemic region, correlating with a reduction in regional myocardial blood flow. Using forskolin stimulation as covariate, no difference in isoproterenol-induced adenylyl cyclase activity was identified in the different regions. It is concluded that cAMP production induced by beta-adrenoceptor activation is dependent upon adenylyl cyclase enzyme activity rather than beta-adrenoceptor density in the ischemic myocardium. However, the density of the beta-adrenoceptor in the viable ischemic regions can be modified by the presence of GRK2 and tissue catecholamines, an index of regional sympathetic efferent postganglionic nerve terminal activity.
Boucher
Matthieu
M
Département de Pharmacologie, Groupe de Recherche sur le Système Nerveux Autonome, Faculté de Médecine, Université de Montréal, and Centre de Biomédecine, Hôpital du Sacré-Coeur de Montréal, 5400 boul. Gouin Ouest, Montréal, Québec, Canada H4J 1C5.
Nim
Satra
S
de Montigny
Chantal
C
Rousseau
Guy
G
D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature; D002395:Catecholamines / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004285:Dogs; D005260:Female; D006400:Hematocrit; D006439:Hemodynamics; D006454:Hemoglobins / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D007958:Leukocyte Count; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010496:Pericardium / Q000378:metabolism / Q000473:pathology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013997:Time Factors; D051552:beta-Adrenergic Receptor Kinases
D000318:Adrenergic beta-Agonists; D002395:Catecholamines; D006454:Hemoglobins; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D000262:Adenylyl Cyclases; D007545:Isoproterenol