Cardiotonic activities of pumiliotoxin B, pyrethroids and a phorbol ester and their relationships with phosphatidylinositol turnover

The cardiotonic activities of pumiliotoxins, pyrethroids and sodium and calcium channel activators were assessed in vitro with spontaneously beating guinea pig atria. The ability of these compounds to stimulate phosphoinositide turnover was assessed in guinea pig cerebral cortical synaptoneurosomes. The activity of pumiliotoxins for both cardiotonic activity and phosphoinositide breakdown was strongly dependent on the structure and configuration of the side chain and there was a correlation between structure and activity in the two systems. Pyrethroids that had cardiotonic activity also induced phosphoinositide breakdown. Other sodium channel and calcium channel activators that induced phosphoinositide breakdown were also cardiotonic. It is suggested that phosphoinositide breakdown leading to inositol phosphates and diacylglycerols may represent a mechanism underlying the cardiotonic effects of certain agents. A phorbol ester, phorbol 12-myristate 13-acetate, that mimics the activation of protein kinase C elicited by diacylglycerols, had cardiotonic activity.