title: 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.
authors: Department of Cardiovascular Disease Research, Eisai Tsukuba Research Laboratories, Ibaraki, Japan.
authors: K
authors: K
authors: Kodama
authors: H
authors: H
authors: Adachi
authors: N
authors: N
authors: Mori
authors: I
authors: I
authors: Saito
mesh_terms: D000818:Animals; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D007275:Injections, Intravenous; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D020108:Nicorandil; D009574:Nitro Compounds / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology; D014667:Vasopressins / Q000009:adverse effects
chemical_list: C091517:E 4021; D009574:Nitro Compounds; D010726:Phosphodiesterase Inhibitors; D010880:Piperidines; D011799:Quinazolines; D014665:Vasodilator Agents; D014667:Vasopressins; D009536:Niacinamide; D020108:Nicorandil; C061872:FK 409; D007548:Isosorbide Dinitrate