Persistent desensitization of the heart to the inotropic action of isoproterenol by adenosine.
Isolated guinea pig hearts were perfused with Krebs buffer in the absence or presence of 10 microM adenosine for 60 to 120 min followed by a 15 min washout with adenosine-free buffer. The effects of isoproterenol on left ventricular dP/dt and heart rate were then determined. Perfusion with adenosine for a minimum of 90 min followed by washout resulted in a 40% depression of the dose-response curve of left ventricular dP/dt to isoproterenol. This depressed inotropic responsiveness persisted for at least 1 hr after cessation of adenosine perfusion. The heart rate response to isoproterenol was unaffected. Also, adenosine perfusion had no effect on ouabain inotropism. Measurement of adenosine in coronary effluent and in ventricular tissue by radioimmunoassay verified that no residual elevated adenosine remained following perfusion and washout. Moreover, isoproterenol-induced release of adenosine into the coronary effluent did not differ between control and adenosine-treated hearts. Addition of 100 microM theophylline, an adenosine receptor antagonist, to the adenosine containing buffer during perfusion prevented the depressed response to isoproterenol. In membrane fractions prepared from ventricles, beta receptors were assessed by (-) [125] iodocyanopindolol binding and neither the density of these receptors nor their affinity for agonists or antagonists was altered by adenosine perfusion. However, activation of adenylate cyclase by isoproterenol (10 microm) was significantly depressed in membranes from adenosine perfused hearts. These findings are consistent with a receptor mediated action of adenosine to produce persistent depression of catecholamine inotropism. Such an effect may be important in heart failure where myocardial levels of adenosine are elevated and circulating levels of catecholamines are high.
Newman
W H
WH
Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston 29425-2251.
Lee
J T
JT
Webb
J G
JG
D000241:Adenosine / Q000494:pharmacology*; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D020120:Iodocyanopindolol; D007545:Isoproterenol / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008566:Membranes / Q000187:drug effects / Q000201:enzymology; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology; D009638:Norepinephrine / Q000378:metabolism; D010042:Ouabain / Q000494:pharmacology; D010477:Perfusion; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011863:Radioimmunoassay; D011983:Receptors, Purinergic / Q000378:metabolism
D011983:Receptors, Purinergic; D010042:Ouabain; D020120:Iodocyanopindolol; D010869:Pindolol; D000262:Adenylyl Cyclases; D000241:Adenosine; D007545:Isoproterenol; D009638:Norepinephrine