Defective response to cAMP-dependent protein kinase in non-insulin-dependent diabetic heart.
Hearts isolated from 1-yr-old non-insulin-dependent diabetic rats exhibited reduced responsiveness to the beta-adrenergic agonist isoproterenol. Over a concentration range of 3 x 10(-9) to 10(-7) M, isoproterenol-mediated stimulation in the rate of left ventricular pressure decline, a measure of myocardial relaxation, and the rate of left ventricular pressure rise, a measure of myocardial contractility, were significantly depressed in the diabetic hearts. To clarify the basis for this defect, individual steps involved in the actions of the beta-adrenergic agonists were examined. Dihydroalprenolol binding assays revealed that neither beta-adrenergic receptor number nor binding affinity was affected by the diabetic condition. Also unaffected by diabetes was isoproterenol-mediated stimulation of adenylate cyclase activity, myocyte accumulation of adenosine 3',5'-cyclic monophosphate (cAMP), or the increase in cAMP-dependent protein kinase activity ratio. However, it was found that both in the presence and absence of cAMP-dependent protein kinase, activity of the sarcolemmal calcium transporter was significantly depressed in the diabetic heart. Also attenuated was protein kinase-induced enhancement of sarcoplasmic reticular calcium transport. The likelihood that these abnormalities contribute to alterations in calcium homeostasis and myocardial contractile function is discussed.
Schaffer
S W
SW
Department of Pharmacology, School of Medicine, University of South Alabama, Mobile 36688.
Allo
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S
Punna
S
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White
T
T
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000503:physiopathology*; D004082:Dihydroalprenolol / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D012016:Reference Values; D012508:Sarcolemma / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D011943:Receptors, Adrenergic, beta; D004082:Dihydroalprenolol; D000242:Cyclic AMP; D003576:Electron Transport Complex IV; D011494:Protein Kinases; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D002118:Calcium