Effects of a novel, selective and potent phosphodiesterase type V inhibitor, E4021, on myocardial ischemia in guinea pigs

Abstract

The anti-ischemic effects of a new, selective and potent cyclic 3′,5′-guanosine monophosphate-specific phosphodiesterase (phosphodiesterase type V) inhibitor, sodium 1-[6-chloro-4-(3,4-methylenedioxybenzyl)aminoquinazolin-2-yl]piperidine-4-carboxylate (E4021), in a vasopressin-induced guinea pig anginal model were examined and compared with those of coronary vasodilators with a guanylate cyclase-activating action. An intravenous injection of vasopressin (0.2 IU/kg) into anesthetized guinea pigs produced ST segment elevation on the electrocardiogram (an index of myocardial ischemia) of 0.28 ± 0.02 mV (n = 10) from the baseline within 30 s. E4021 administered intravenously at doses of 0.03 and 0.1 mg/kg, 5 min before the injection of vasopressin, significantly inhibited the ST segment elevation to 0.15 ± 0.03 mV ( n = 6, P < 0.01) and 0.17 ± 0.02 mV ( n = 6, P < 0.01), respectively. Three guanylate cyclase activators, isosorbide dinitrate (0.1 mg/kg), nicorandil (0.1 mg/kg), and FK409 (0.3 mg/kg), also significantly reduced the ST segment elevation to 0.18 ± 0.03, 0.11 ± 0.02 and 0.17 ± 0.02 mV, respectively. In a second experiment, E4021 was administered intraduodenally 30 min before the injection of vasopressin to examine its oral effectiveness. Intraduodenal E4021, at doses of 1.0 and 3.0 mg/kg, also significantly inhibited the ST segment elevation to 0.16 ± 0.02 mV ( n = 6, P < 0.01) and 0.13 ± 0.02 mV ( n = 6, P < 0.01), respectively. It is concluded that the potent phosphodiesterase type V inhibitor, E4021, administered intravenously or intraduodenally, ameliorated myocardial ischemia similarly to guanylate cyclase activators. Thus, E4021 may be an orally effective drug in the treatment of angina pectoris.