NEURALLY-MEDIATED CARDIAC EFFECTS OF FORSKOLIN IN CONSCIOUS DOGS

Because major cardiovascular disease states are characterized by defec ts in adenylyl cyclase regulation, it becomes important to understand the mechanisms by which adenylyl cyclase activators affect inotropy an d chronotropy in intact conscious animals. Accordingly, we examined th e inotropic and chronotropic responses to forskolin in 11 normal consc ious, chronically instrumented dogs and 3 dogs with ventricular denerv ation (VD). Left ventricular first derivative of pressure (LV dP/dt) i ncreased by 96 +/- 7%, P < 0.05, in response to forskolin (50 nmol . k g(-1). min(-1)) in normal dogs and by significantly less, 52 +/- 14%, in VD dogs. Circulating norepinephrine (NE) levels increased similarly in both groups (from 226 +/- 18 to 389 +/- 33 pg/ml in normal dogs, f rom 177 +/- 23 to 329 +/- 71 pg/ml in VD dogs). In the presence of gan glionic blockade, the increase in LV dP/dt in response to forskolin wa s reduced (+62 +/- 4%) in normal dogs but was unchanged in VD dogs (+5 2 +/- 12%). Ganglionic blockade abolished the increase in circulating NE levels in both groups. Increases in heart rate in the presence of g anglionic blockade (+54 +/- 6 beats/min) were less than in the presenc e of atropine alone (+92 +/- 10 beats/min). Notably, the LV dP/dt and heart rate responses to forskolin were further attenuated by beta-adre nergic receptor blockade in the presence and absence of ganglionic blo ckade. Morphine also attenuated the increases in both LV dP/dt and pla sma NE in response to forskolin. Increases in LV dP/dt in response to NKH-477 (30 mu g/kg), a water-soluble forskolin derivative, were simil ar before and after ganglionic blockade (+63 +/- 8 and +51 +/- 10%, re spectively). However, in vitro experiments in LV sarcolemmal membrane preparations demonstrated that stimulation of adenylyl cyclase by fors kolin and NKH-477 was not affected by beta-adrenergic receptor blockad e. These results indicate that in conscious dogs, inotropic and chrono tropic effects of forskolin are not only due to direct activation of a denylyl cyclase, but the effects also are mediated by neural mechanism s and potentiated by the prevailing level of sympathetic tone.