Tetsuji Imamoto

Protective effect of a novel thromboxane synthetase inhibitor, CV-4151, on myocardial damage due to coronary occlusion and reperfusion in the hearts of anesthetized dogs

The protective effect of a novel thromboxane (TX) synthetase inhibitor, (E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (CV-4151), on myocardial damage due to an ischemic episode and reperfusion was investigated in anesthetized, open-chested dogs. The left anterior descending coronary artery (LAD) was occluded for 60 min and subsequently reperfused for 60 min. CV-4151 was infused i.v. at a dose of 1 mg/kg over a 10-min period starting 20 min before the LAD occlusion. The agent had no acute hemodynamic effects. Within 30 min after LAD occlusion, 15.6-33.3% of dogs experienced ventricular fibrillation (VF); CV-4151 had no significant effect on the incidence of VF. After reperfusion, the frequency of ventricular extrasystoles (PVCs) was markedly increased, and 33.3% (9 of 27 dogs) died of VF in the control group. CV-4151 suppressed the exaggerated PVCs, and the incidence of VF in the group was 0% (0/18, p less than 0.05). Myocardial infarct size determined 60 min after reperfusion by a p-nitroblue tetrazolium (p-NBT) staining technique was significantly reduced by CV-4151. Increase in TXB2 release into the great coronary vein during reperfusion was completely inhibited by CV-4151, whereas release of 6-keto-PGF1 alpha tended to increase during occlusion and reperfusion. Thus, the ratio of 6-keto-PGF1 alpha to TXB2 levels was significantly increased throughout occlusion and reperfusion periods. These results suggest that inhibition of TXA2 synthesis is beneficial for protection of the myocardium during reperfusion from ischemic damage.

Beneficial effects of TDN-345, a novel Ca2+ antagonist, on ischemic brain injury and cerebral glucose metabolism in experimental animal models with cerebrovascular lesions

The effects of TDN-345 on mortality and ischemic neurological deficit following transient global cerebral ischemia in Mongolian gerbils and also the rate of local cerebral glucose utilization (LCGU) in stroke-prone spontaneously hypertensive rats (SHRSP) with cerebrovascular lesions were investigated. In Mongolian gerbils, ischemia was produced by clamping the bilateral common carotid arteries for 15 min. TDN-345 (0.1-1.0 mg/kg) dose-dependently decreased the mortality and ischemic neurological deficit score when administered orally twice, 60 min before ischemia and 90 min after recirculation. Additionally, TDN-345 (0.2 or 1.0 mg/kg, p.o. once daily for 3 weeks after the onset of stroke) decreased the mortality and recurrence of stroke in SHRSP. To determine the site of action of TDN-345 in the brain, the rate of LCGU in various brain regions in SHRSP with stroke was examined using a [14C]2-deoxy-D-glucose method. The rate of LCGU decreased significantly in all the brain regions in SHRSP with stroke compared with Wistar-Kyoto (WKY) control rats, whereas the reduction in the rate of LCGU in SHRSP with stroke was prevented by TDN-345 treatment, especially in the sensorimotor cortex and locus coeruleus. These results suggest that TDN-345 has therapeutic efficacy in the treatment of cerebrovascular disease.

Effect of 2-phenylaminoadenosine (CV-1808) on ischemic ST-segment elevation in anesthetized dogs.

The effect of 2-phenylaminoadenosine (CV-1808) against myocardial ischemia was studied in anesthetized dogs. During intravenous infusion of CV-1808 (0.25 and 0.5 μg/kg/min for 10 min) the ST-segment elevation in the epicardial ECG induced by a 5-min occlusion of a coronary arterial branch was occasionally enhanced in association with cardiac acceleration. In a dose of 0.5 μg/kg/min, the agent inhibited the ST elevation 30 and 60 min after administration. The same dose did not change myocardial blood flow in the ischemic area despite significant systemic hypotension. In hearts with continuous coronary occlusion, CV-1808 (0.3 and 1.0 μg/kg, i.v. bolus) increased the retrograde blood flow from the ischemic area immediately after administration, suggesting a collateral vasodilating action. Nifedipine (0.5 and 2.5 μg/kg/min, i.v. for 10 min) and nitroglycerin (0.5 and 5.0 μg/kg/min, i.v. for 10 min) had no influence on the ischemic ST-segment elevation, while a significant inhibition was seen with propranolol (0.5 mg/kg, i.v.). A moderate hypotension was induced by CV-1808, nifedipine, and nitroglycerin, while a significant reduction in cardiac function was seen after dosing with propranolol.