The effect of acetylcholine, ischemia, and anoxia on rat heart purine cyclic nucleotides and contractility.

The effects of acetylcholine, ischemia, and anoxia on myocardial cyclic GMP and cyclic AMP were investigated in isolated rat hearts perfused under either constant flow (14 ml/min) or constant pressure (100 cm H,O) conditions with physiological saline gassed with 95% O,-5% COj. In paced, constant flow-perfused hearts, cyclic GMP increased from a control of 35 to 62 fmol/mg protein and remained elevated, while dP/dt, an index of contractility, decreased only transiently from 2,650 to 1,750 mm Hg/sec then returned toward control levels during the first 2 minutes of 1 pM acetylcholine. In paced, constant pressure-perfused hearts, the acetylcholine caused a persistent decrease in dP/dt and a transient increase in coronary perfusate flow, followed by a marked decrease in flow. Reduction of coronary perfusion to one-half control flow and ischemia (termination of perfusion) increased cyclic GMP from 43 to 85 and 127 fmol/mg protein, respectively. Anoxia (perfusion with physiological saline gassed with 95% Nj-5% COi) did not produce a significant change in cyclic GMP. Neither atropine nor Indomethacln at 10 fiM prevented the increase in cyclic GMP produced by ischemia, but the musearinic blocking agent did block the increase caused by acetylcholine. Cyclic AMP increased from a control of 3.8 to 6.0 pmol/mg protein with anoxia and to 12.8 pmol/mg protein with 1 /iM isoproterenol, but was not affected by acetylcholine or ischemia. Myocardial lactate increased significantly only with ischemia. Ca-free perfusion for 1 minute partially blocked the increase in cyclic GMP caused by ischemia, but did not prevent the acetylcholine-induced increase in the cyclic nucleotide. These results indicate: (1) that there is not always an inverse relationship between myocardial cyclic GMP and contractility and (2) that limitation of coronary perfusion augments cardiac cyclic GMP by a mechanism^) that is independent of acetylcholine but largely dependent on external Ca. Ore Res 49: 912-932, 1981