Forskolin and myocardial function in the normal, ischemic and reperfused rat heart

Forskolin increases intracellular cyclic AMP content by direct stimulation of adenylate-cyclase independently of the beta receptor. Studies have been carried out in two different types of isolated rat heart preparation to compare the cardiovascular effects of forskolin and isoprenaline. The inotropic and chronotropic properties of these drugs, together with their ability to increase myocardial cyclic AMP content, have been studied under conditions of aerobic perfusion and also post-ischemic reperfusion. In studies with isolated rat hearts perfused in the Langendorff mode, the dose-response characteristics of forskolin have been characterized. At a concentration of 2 X 10(-7) moles/L, forskolin increased heart rate, coronary flow and left ventricular pressure by 24 +/- 4%, 33 +/- 6% and 33 +/- 3% respectively, and cyclic AMP content was increased seventeen fold (4.0 +/- 0.3 to 68.0 +/- 8.0 nanomoles/g dry wt). Investigation of the effects of three concentrations of forskolin in the isolated working heart revealed that some increases in contractile state could again be achieved. Thus, at a concentration of 5 X 10(-7) moles/L, forskolin increased heart rate by up to 27%, coronary flow by up to 18%, aortic flow by up to 10%, cardiac output by up to 8%, peak aortic pressure by up to 18%, pressure rate product by up to 45% and minute work by up to 25%. These increases, although relatively small, were greater and longer sustained than those seen with isoprenaline (10(-6) moles/L). In additional studies, forskolin (10(-7) moles/L) was included in the reperfusion solution of hearts recovering from a 30 minute period of ischemic cardioplegic arrest. In comparison with controls, which were reperfused without forskolin, small increases in contractile recovery (mostly relating to an increased chronotropic state) were observed. However, upon withdrawal of the drug the functional indices declined such that they were indistinguishable from control hearts which had not received the drug during reperfusion. It is speculated that the relatively poor response to forskolin in the working as opposed to the Langendorff perfused heart may be a reflection of the greater metabolic rate of the working heart and that it may be the rate of turnover of cyclic AMP and other metabolites rather than their steady state cellular level which might determine the responsiveness of tissue to forskolin.