Positive Inotropic Effects of Dibutyryl Cyclic Adenosine 3',5'-Monophosphate

Abstract

The positive inotropic effects of catecholamines have been postulated to result from an increase in the intracellular level of cyclic AMP (adenosine 3',5'-monophosphate) produced by activation of adenyl cyclase. Although lack of an inotropic effect by exogenously administered cyclic AMP has cast doubt on this hypothesis, cardiac cells are not readily permeable to cyclic AMP. The N⁶-2'-O-dibutyryl derivative of cyclic AMP is thought to enter cells more readily and is resistant to enzymatic degradation by phosphodiesterase. We examined the effects of cyclic AMP and its dibutyryl derivative on the contractile performance of isolated cat right ventricular papillary muscles. Cyclic AMP (1 x 10^-4 to 5 x 10^-3M) had no effect on papillary muscle function. However, dibutyryl cyclic AMP caused a concentration-dependent increase in isometric tension and rate of tension development, the threshold concentration being 5 x 10^-4M. The increments in tension (4.5 ± 0.4 g/mm²) and rate of tension development (58.4 ± 5.4 g/mm²/sec) at peak concentration (3 x 10^-3M) were similar to those found at peak norepinephrine concentration (10^-5M). Dibutyryl cyclic AMP (10^-3M) also caused a marked shift of the force-velocity curve upward and to the right. Although 10^-6M propranolol depressed the inotropic effects of norepinephrine, it did not alter the contractile response to dibutyryl cyclic AMP. These findings are consistent with the hypothesis that the positive inotropic effects of catecholamines are mediated by cyclic AMP.