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.