Myocardial inositoltrisphosphate is depressed by dibutyryl cAMP. An experimental study in the isolated working rat heart

A possible interrelation between IP₃ and cAMP was studied in rat myocardium through circumvention of the receptor mediated stimulatory step of adenylyl cyclase by the administration of dibutyryl cAMP (db-cAMP). Changes in IP₃ and cyclic nucleotide contents were correlated to changes in contractility after 40 min of β- and α-adrenergic stimulation. Rat hearts (n= 23) were perfused with Krebs-Henseleit buffer in a modified Langendorff apparatus as a working preparation. The hearts were allocated to perfusion as control (n= 6); or with phenylephrine (10^-6 mol L^-1, n= 6); (—)-isoproterenol (10^-6 mol L^-1, n= 6); db-cAMP (2 times 10^-4 mol L^-1, n= 5). All hearts were freeze-clamped after 40 min of perfusion. Phenylephrine produced a slow increase in _max dP/dt reaching a maximal value after 10 min (P < 0.05); thereafter it decreased, reaching the control level at 30 min. Isoproterenol perfusion resulted in an early (20 s) increase in _max dP/dt (P < 0.05). Over the next 10 s _max dP/dt decreased markedly reaching an inflection point at 30 s. Thereafter only a slow increase during the rest of the perfusion was seen. Dibutyryl cAMP increased _max dP/dt slowly during the whole perfusion period reaching maximum after 40 min. Cyclic-AMP was increased by 21% after 40 min of phenylephrine perfusion while the corresponding increases by isoproterenol and db-cAMP were 131 and 105%, respectively (P < 0.05). Phenlyephrine increased IP₃ content to the same extent as isoproterenol perfusion (P < 0.05). On the other hand, a decreased IP₃ content was seen at 40 min of db-cAMP perfusion. Cyclic-AMP per se depressed basal myocardial IP₃ content in myocardial tissue. Despite normalization of contractility after 40 min of phenylephrine perfusion the IP₃ content was 27% higher than in control hearts pointing out the unclearness of the relationship between myocardial IP₃ content and the contractile system.