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Reserpine-induced cardiac supersensitivity to calcium and isoproterenol
I?ESERPINE-INDUCED CARDIAC SUPERSENSITIVITY TO CALCIUM AND ISOPROTERENOL. J.H. McNeill, B.M. Wenkstern, G.D. Lopaschuk and R.L. Rodgers. Division of Pharmacology and Toxicology, Faculty of Pharm. Sciences, Univ. of British Columbia, Vancouver, Canada, V6T lW5. We have previously established that reserpine pretreatment (2.5 mglkgfday - 2 days) of guinea pigs produces an inotropic supersensitivity to both calcium and isoproterenol as measured in the isolated perfused guinea pig working heart preparation. Both (+) and (-) dP/dt were enhanced in reserpine treated animals. Supersensitivity to the two agonists is different. Calcium supersensitivity is frequency dependent and does not occur above 280 beatsfmin while isoproterenol supersensitivity is frequency independent. In the present study we report that the above reserpine pretreatment can also enhance ATP dependent oxalate facilitated cardiac sarcoplasmic reticulum (SR) calcium uptake as well as Ca2+-stimulated Mg dependent ATPase activity. The increase in cyclic AMP produced by isoproterenol was also enhanced in hearts obtained from reserpine treated animals when compared to control hearts. Thus the supersensitivity to calcium could be due to an increased rate of uptake and release by the SR while the supersensitivity to isoproterenol may be related to an increase in the formation of cyclic AMP. In the latter case it is possible that either the number or affinity of the 8-adrenergic receptors increases, or that there is an increase in the coupling of the receptors to adenylate cyclase. (Supported
by MRC(C)
and the
CHF)
DEPRESSED RECOVERY OF VENTRICULAR FUNCTION BY FATTY ACIDS FOLLOWING HYPOTHEPJfIC PERFUSION OF ISOLATED RAT HEARTS. O.D. Mjds, I<. Ichihara and J.R. Neely, Dept. of Physiol., The M.S. Hershey Medical Center, Hershey, PA 17033 Working hearts were perfused for 15 min at 37OC before switching to a Langendorff perfusion (60 mmHg aortic pressure) at 10aC for 40 min of hypothermic arrest. Recovery of ventricular function was followed for 15 min at 37'C by reestablishing the prehypothermic conditions. The perfusate was XrebsHenseleit bicarbonate buffer containing 3% BSA and either glucose (11 mIl> or glucose (11 mM) plus palmitate (1.2 mM) and gassed with 95% 02'5% C02. In hearts receiving glucose alone as the substrate, coronary flow (CF) was maintained constant during the 40 min of hypothermic arrest and with rewarming, ventricular function as estimated by peak systolic pressure (PSP) and heart rate (HR) recovered to the prehypothermic level. When palmitate was added, CF decreased continuously throughout the hypothermic perfusion (22% decrease by 40 min), and ventricular function was lower throughout the rewarming perfusion. After 15 min of rewarming, PSP X HR was still 15% lower than the prehypothermic level. Tissue levels of ATP and creatine-P were lower and long-chain acyl CoA and acyl carniAdditine were higher in those hearts receiving palmitate. tion of oxfenicine to inhibit fatty acid oxidation prevented the effects of palmitate on ventricular function. These data indicate that the combination of high palmitate and hypothermia results in depressed ability of the heart to recover function with rewarming. Supported by grant NHLBI 18206.
by MRC(C)
and the
CHF)
DEPRESSED RECOVERY OF VENTRICULAR FUNCTION BY FATTY ACIDS FOLLOWING HYPOTHEPJfIC PERFUSION OF ISOLATED RAT HEARTS. O.D. Mjds, I<. Ichihara and J.R. Neely, Dept. of Physiol., The M.S. Hershey Medical Center, Hershey, PA 17033 Working hearts were perfused for 15 min at 37OC before switching to a Langendorff perfusion (60 mmHg aortic pressure) at 10aC for 40 min of hypothermic arrest. Recovery of ventricular function was followed for 15 min at 37'C by reestablishing the prehypothermic conditions. The perfusate was XrebsHenseleit bicarbonate buffer containing 3% BSA and either glucose (11 mIl> or glucose (11 mM) plus palmitate (1.2 mM) and gassed with 95% 02'5% C02. In hearts receiving glucose alone as the substrate, coronary flow (CF) was maintained constant during the 40 min of hypothermic arrest and with rewarming, ventricular function as estimated by peak systolic pressure (PSP) and heart rate (HR) recovered to the prehypothermic level. When palmitate was added, CF decreased continuously throughout the hypothermic perfusion (22% decrease by 40 min), and ventricular function was lower throughout the rewarming perfusion. After 15 min of rewarming, PSP X HR was still 15% lower than the prehypothermic level. Tissue levels of ATP and creatine-P were lower and long-chain acyl CoA and acyl carniAdditine were higher in those hearts receiving palmitate. tion of oxfenicine to inhibit fatty acid oxidation prevented the effects of palmitate on ventricular function. These data indicate that the combination of high palmitate and hypothermia results in depressed ability of the heart to recover function with rewarming. Supported by grant NHLBI 18206.