Activation of the cAMP system by medorinone correlates with positive inotropy or vasorelaxation

Abstract

AbstractMedorinone is a structurally novel positive inotropic/vasodilator agent that selectively inhibits cardiovascular low Km cAMP phosphodiesterase (PDE). As inhibitors of this PDE isozyme would be expected to activate the cAMP system, the objectives of the present study were to quantitate changes in cAMP content, activation of cAMP protein kinase (cAPK), and positive inotropy in isolated guinea pig papillary muscles or vasorelaxation in aortic smooth muscle by medorinone. In papillary muscles, positive and significant correlations were evident between isometric force development as a function of cAMP content (r = 0.92; P <0.01) or cAPK activity ratio, an index of activation of cAPK (r = 0.78, P <0.05) for concentrations of medorinone from 1 to 300 μM. Similar correlations were evident in aortic smooth muscles frozen during medorinone‐mediated relaxation of phenylephrine contractions (r = 0.89, P <0.05). These correlations and lines of regression were similar to those obtained for milrinone, papaverine, and isoproterenol; the correlation was similar for forskolin while the slope of the regression line was less. The temporal sequence of these events was also quantitated for a concentration of medorinone (100 μM) that produced approximately a 100% increase in papillary muscle isometric force and 90% vasorelaxation. Significant increases in either cAMP content or cAPK activity ratio paralleled increases in force development (papillary muscle) or vasorelaxation (aortic smooth muscle). In summary, these results show that significant increases in cAMP content or cAPK activation are correlated with modulation of cardiac or vascular force by medorinone and thus support the hypothesis that inhibition of the low Km cAMP PDE is a mechanism by which medorinone effects positive inotropy and vasodilation.