Preserved beta-adrenoceptor-mediated adenylyl cyclase activity despite receptor and postreceptor dysfunction in acute myocardial ischemia.
To examine responses of the beta-adrenoceptor guanine nucleotide protein (G protein)/adenylyl cyclase complex to acute myocardial ischemia, we measured adenylyl cyclase activity stimulated at the beta-adrenoceptor and postreceptor levels and compared crude homogenates prepared from ischemic and nonischemic rabbit myocardium obtained after 30 minutes of coronary artery occlusion. Basal adenylyl cyclase activity was unchanged, but enzyme activity stimulated by the guanosine triphosphate analog guanyl-5'-imidodiphosphate (GppNHp) at 10 mumol/L was depressed 63% by ischemia (n = 16, p = 0.001). In contrast, adenylyl cyclase activity stimulated by 1 mumol/L (-)-isoproterenol in the presence of 10 mumol/L GppNHp was not significantly reduced (n = 10), a finding that indicates relative preservation of beta-adrenoceptor-mediated adenylyl cyclase activity in ischemia. The ratio of (-)-isoproterenol-stimulated to GppNHp-stimulated adenylyl cyclase activity increased fourfold in ischemic myocardium (n = 6, p = 0.001), consistent with more efficient beta-adrenergic signal transduction via less functional stimulatory G protein (Gs). These data could not be explained by augmented beta-adrenoceptor density or agonist affinity or by a reduction in inhibitory G protein-mediated inhibition of adenylyl cyclase. Forskolin (1 mmol/L) and Mn2+ (1 mmol/L), agents that directly stimulate the catalytic subunit of adenylyl cyclase, each increased enzyme activity significantly more in ischemic than in nonischemic myocardium. We conclude that preservation of (-)-isoproterenol-mediated adenylyl cyclase activity during acute myocardial ischemia in the rabbit results at least in part from enhanced function of the catalytic subunit of adenylyl cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
Wolff
A A
AA
Cardiology Section, Department of Veterans Affairs Medical Center, San Francisco.
Hines
D K
DK
Karliner
J S
JS
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D017202:Myocardial Ischemia / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D011943:Receptors, Adrenergic, beta; D006165:Guanylyl Imidodiphosphate; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D000254:Sodium-Potassium-Exchanging ATPase; D007545:Isoproterenol