Pharmacology and inotropic potential of forskolin in the human heart.

Abstract

As bstract. We evaluated the effects of the diterpene compound forskolin in human myocardial adenylate cyclase preparations, isolated trabeculae and papillary muscles derived from failing human hearts, and acutely instrumented dogs. Forskolin was a potent, powerful activator of human myocardial adenylate cyclase and produced maximal effects that were 4.82 (normally functioning left ventricle) and 6.13 (failing left ventricle) fold greater than isoproterenol. In contrast to isoproterenol, forskolin retained full activity in membrane preparations derived from failing hearts. In cyclase preparations, forskolin demonstrated unique substrate and Mg2+ kinetic properties that could be distinguished from hormone receptor-coupled agonists or fluoride ion. The adenylate cyclase stimulatory effect of forskolin was synergistic with isoproterenol, apparently due to the location of forskolin activation being beyond the level of hormone receptor-agonist in the receptor-cyclase complex. Forskolin was a potent positive inotrope in failing human myocardium, producing a stimulation ofcontraction that was similar to isoproterenol. Finally, in open chest dogs forskolin was a positive inotropic agent that reduced preload and afterload. We conclude that forskolin belongs to a class of agents that may have therapeutic potential in the treatment of congestive heart failure.

Comparative in Vitro Myocardial Inotropic Effects and in Vivo Hemodynamic Effects of Forskolin and Isoproterenol in Young Lambs

“…In all studies, cardiac output and heart rate increased during forskolin administration, but in two of the animals there was no change in either variable until the last two drug dosages. This blunted increase in cardiac output has also been seen in open-chest dogs, but this was believed to be secondary to a decrease in left atrial mean pressure which occurred to a greater extent with forskolin than isoproterenol (8). In contrast, in the present study we demonstrated no significant difference in mean pulmonary capillary wedge pressure which would suggest there was no significant change in left atrial mean pressures.…”

“…In contrast, in the present study we demonstrated no significant difference in mean pulmonary capillary wedge pressure which would suggest there was no significant change in left atrial mean pressures. Previous work had also demonstrated a significant decrease in mean arterial pressure with administration of isoproterenol and forskolin (8). In our study neither of these variables changed significantly, although the marked increase in cardiac output associated with no change in arterial pressure would indicate that forskolin has pulmonary and systemic vasodilating properties, although again to a lesser extent that isoproterenol.…”

“…It also has positive inotropic and chronotropic actions as well as blood pressure-lowering properties in pig, cat, and dog hearts (16). In open-chest dogs, forskolin increases dP/dt and cardiac output, and decreases peripheral vascular resistance and left ventricular end-diastolic pressure (8). Preliminary work in human adults has shown similar hemodynamic effects (17).…”

“…The reasons why forskolin was not superior to isoproterenol with regards to in vitro inotropic and in vivo hemodynamic responses is not clear, because forskolin produces a much greater stimulation of adenylate cyclase in myocardial membranes than isoproterenol (8). This discrepancy may be secondary to biochemical differences between membrane preparations and intact tissues.…”

Downregulation of adenylylcyclase types V and VI mRNA levels in pacing-induced heart failure in dogs.

“…A recent study has shown that type V mRNA is present also in the kidney in the rat, suggesting that distribution oftype V mRNA expression occurs in a species-specific manner (28). 4 --Reported adenylylcyclase catalytic activities in heart failure have been variable, with some studies demonstrating a decrease in basal activity (5,29) and others demonstrating a normal basal and stimulated adenylylcyclase activity (30). Direct evaluation of catalytic unit activity has been difficult; crude membranes can be variably contaminated with GTP and this could differ among the particular membrane preparations used.…”