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 myoca rdium 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 chan ges in contractility after 40 min of beta- and alpha-adrenergic stimul ation. Rat hearts (n = 23) were perfused with Krebs-Henseleit buffer i n a modified Langendorff apparatus as a working preparation. The heart s 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 x 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 per fusion 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 inflectio n point at 30 s. Thereafter only a slow increase during the rest of th e perfusion was seen. Dibutyryl cAMP increased (max)dP/dt slowly durin g the whole perfusion period reaching maximum after 40 min. Cyclic-AMP was increased by 21% after 40 min of phenylephrine perfusion while th e corresponding increases by isoproterenol and db-cAMP were 131 and 10 5%, respectively (P < 0.05). Phenylephrine increased IP3 content to th e 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. Cyc lic-AMP per se depressed basal myocardial IP3 content in myocardial ti ssue. Despite normalization of contractility after 40 min of phenyleph rine perfusion the IP3 content was 27% higher than in control hearts p ointing out the unclearness of the relationship between myocardial IP3 content and the contractile system.