Effects of NKH477, a water-soluble forskolin derivative, on cardiac function in rats with chronic heart failure after myocardial infarction.

Our study was designed to determine whether NKH477, a novel, potent and water-soluble forskolin derivative, may exert a positive inotropic effect in rats with chronic heart failure (CHF) after myocardial infarction. Cardiac output and stroke volume indices were decreased and systemic vascular resistance was increased 12 wk after left coronary artery ligation, suggesting that CHF has developed at this time. Dobutamine (4 micrograms/kg i.v.) increased the cardiac output and stroke volume indices in sham-operated rats (22.7 +/- 1.9 and 15.1 +/- 2.0% increase, respectively), whereas such increases were attenuated in rats 12 wk after the induction of myocardial infarction (cardiac output index: 4.0 +/- 1.4% increase and stroke volume index: 2.2 +/- 1.8% increase, respectively). In contrast to beta-adrenoceptor agonist, NKH477 (3, 10 and 30 micrograms/kg i.v.) increased cardiac output and stroke volume indices in the rats with CHF. The beta-adrenergic receptor density, measured by [3H] CGP-12177 binding assay, was reduced in homogenates of the failing heart. These results suggest that the decrease in cardiac beta-adrenergic receptor density may account, in part, for the reduction in the responsiveness to beta-adrenoceptor agonists. The primary defects in the signal transduction from beta-adrenergic receptor to adenylate cyclase, such as the receptor down-regulation and the failure in signaling from adenylate cyclase, may be present in the CHF heart. It may be possible to reverse the cardiac dysfunction associated with CHF with NKH477.