T-1583 and forskolin are similar in their cardiac effects and dissimilar in their vascular effects

Abstract

The cardiac and coronary vascular effects of T-1583, a selective beta 1-adrenoceptor full agonist, and forskolin, a direct activator of adenylate cyclase, were compared in isolated, blood-perfused papillary muscle, sinoatrial node, and atrioventricular (AV) node preparations of dogs. Both agents were injected intra-arterially. The two agents increased the force of contraction of the paced papillary muscle and the unpaced one, and the rate of automaticity of the latter. They increased sinus rate and accelerated AV nodal conduction. In producing these effects T-1583 was 50 to 80 times more potent than forskolin, indicating that both agents have similar cardiac profiles. At the doses that produced a 50% increase in the force of contraction of the papillary muscle, both agents produced about a 20% increase in sinus rate. Such degrees of force-rate separation were close to those obtained with most new positive inotropic agents with an inhibitory action on cyclic AMP phosphodiesterase. T-1583 differed distinctly from forskolin in that the former increased only slightly coronary blood flow, whereas the latter increased it greatly. Thus, forskolin is more coronary vasodilatory than positively inotropic, and more positively inotropic than positively chronotropic. T-1583 is a more positively inotropic than positively chronotropic and more positively chronotropic than coronary vasodilatory.

Potassium channel activator drugs: Mechanism of action, pharmacological properties, and therapeutic potential

“…Evidence of enhanced ventricular fibrillation has been reported following extremely high doses of nicorandil (21 mg/min intra-arterially) in canine isolated papillary muscle . 270 During ischaemic injury, high doses of nicorandil (50, 100 pM) reduced the incidence of ventricular f i b r i l l a t i~n ,~~~ whilst pinacidil(30 pM) or cromakalim (10 pM) showed arrhythmogenic activity by their ability to shorten APD, together with enhancement of ventricular fibrillation during global ischaemia in rat isolated heart^. "^ Similarly, in conscious dogs, pinacidil(O.3 mg/kg i.v.…”