Pharmacology and inotropic potential of forskolin in the human heart

As bstract. We evaluated the effects of the di-terpene compound forskolin in human myocardial ad-enylate cyclase preparations, isolated trabeculae and pap-illary muscles derived from failing human hearts, and acutely instrumented dogs. Forskolin was a potent, pow-erful 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 isoproter-enol, forskolin retained full activity in membrane prep-arations derived from failing hearts. In cyclase prepara-tions, forskolin demonstrated unique substrate and Mg2+ kinetic properties that could be distinguished from hor-mone receptor-coupled agonists or fluoride ion. The ad-enylate cyclase stimulatory effect of forskolin was syn-ergistic with isoproterenol, apparently due to the location of forskolin activation being beyond the level ofhormone receptor-agonist in the receptor-cyclase complex. For-skolin 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 pre-load and afterload. We conclude that forskolin belongs to a class of agents that may have therapeutic potential in the treatment of congestive heart failure