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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.
AuthorsK Kodama, H Adachi, N Mori, I Saito
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 263 Issue 1-2 Pg. 93-9 (Sep 22 1994) ISSN: 0014-2999 [Print] Netherlands
PMID7821368 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • E 4021
  • Nitro Compounds
  • Phosphodiesterase Inhibitors
  • Piperidines
  • Quinazolines
  • Vasodilator Agents
  • Vasopressins
  • Niacinamide
  • Nicorandil
  • FK 409
  • Isosorbide Dinitrate
Topics
  • Animals
  • Drug Interactions
  • Electrocardiography (drug effects)
  • Guinea Pigs
  • Injections, Intravenous
  • Isosorbide Dinitrate (pharmacology)
  • Male
  • Myocardial Ischemia (drug therapy)
  • Niacinamide (analogs & derivatives, pharmacology)
  • Nicorandil
  • Nitro Compounds (pharmacology)
  • Phosphodiesterase Inhibitors (pharmacology)
  • Piperidines (pharmacology)
  • Quinazolines (pharmacology)
  • Vasodilator Agents (pharmacology)
  • Vasopressins (adverse effects)

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