Inotropic, chronotropic and coronary vasodilator potency of forskolin

The cardiodynamic profile of forskolin, a direct activator of adenylate cyclase, was examined in an isovolumic left ventricular (LV) preparation of coronary-perfused guinea-pig hearts. Forskolin consistently induced concentration-dependent increases in LV systolic pressure development, increases in spontaneous beating frequency and decreases in coronary vascular resistance. However, the forskolin concentration required for one-half of the maximal effect (EC50) for coronary vasodilation (3.8 +/- 0.6 X 10(-8) M, n = 6) was 7- to 10-fold less than the EC50 for positive chronotropy (29.3 +/- 4.6 X 10(-8) M, P less than 0.01) and 17- to 20-fold less than the EC50 for positive inotropy (66.3 +/- 7.4 X 10(-8) M, P less than 0.001). The inotropic response to forskolin was not secondary to the concomitant increase in bearing frequency. Also, the coronary vasodilator response persisted in K+-depolarized non-beating hearts, and therefore did not depend on endogeneous coronary vascular autoregulation secondary to increased myocardial oxygen demand. We conclude that forskolin induces direct pharmacologic effects in ventricular muscle, pacemaker cells and the coronary vasculature, but add that the coronary vasculature is over one order of magnitude more sensitive to forskolin than is ventricular muscle. Perhaps adenylate cyclase systems in the heart exist as different subtypes with different affinity characteristics for forskolin-like drugs.