Mechanisms mediating responsiveness to beta-adrenergic stimulation after coronary reperfusion in conscious dogs.
The goal of this study was to assess beta-adrenergic receptor (beta-AR) signaling mechanisms in mediating physiological responses to sympathomimetic amines after 45 min coronary artery occlusion followed by 45 min reperfusion. At this time, isoproterenol (Iso) infusion (0.1 microgram/kg-1.min-1, n = 5) increased percent wall thickening in previously ischemic subendocardium (Endo) more than in nonischemic Endo (12.6 +/- 1.2 vs. 7.2 +/- 0.6%, P < 0.05), whereas forskolin (25 nmol.kg-1.min-1, n = 6) elicited the opposite effect (3.6 +/- 0.6 vs. 10.4 +/- 2.8%, P < 0.05). During Iso and forskolin infusions increases in regional myocardial blood flow in the previously ischemic zone were similar to the nonischemic zone. In all groups, total beta-AR density was depressed in previously ischemic Endo compared with nonischemic Endo (65 +/- 7 vs. 82 +/- 8 fmol/mg, P < 0.05), but the fraction of beta-AR binding agonist with high affinity increased (82 +/- 4 vs. 49 +/- 1%, P < 0.05). The changes in beta-AR were associated with a decrease in Iso-stimulated adenylyl cyclase (22 +/- 8%), a decrease in guanosine 5'-triphosphate (GTP)-stimulatory protein (Gs) (23 +/- 6%), and a decrease in inhibitory G proteins (16 +/- 4%). However, regional Endo functional responsiveness to beta-AR stimulation was enhanced in reperfused myocardium in response to Iso but not to forskolin. Thus the mechanism of increased number of beta-AR binding agonist with high affinity in previously ischemic myocardium predominated over persistent downregulation of total beta-AR density and reductions in Gs and adenylyl cyclase activity and correlated best with the physiological response to beta-AR stimulation. These data may also suggest that Iso exerts an action distal to adenylyl cyclase in previously ischemic myocardium.
Kiuchi
K
K
Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston 02115.
Shen
Y T
YT
Vatner
S F
SF
Vatner
D E
DE
D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D003331:Coronary Vessels / Q000502:physiology*; D004285:Dogs; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D019204:GTP-Binding Proteins / Q000032:analysis / Q000096:biosynthesis*; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D010446:Peptide Fragments; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D019204:GTP-Binding Proteins; D007545:Isoproterenol