EFFECTS OF R-56865 ON POSTISCHEMIC VENTRICULAR-FUNCTION IN ISOLATED RAT WORKING HEART PREPARATIONS OBTAINED FROM HEALTHY, DIABETIC AND HYPERTENSIVE ANIMALS

The present study was undertaken to evaluate the effects of R 56865 xy )-butyl]4-piperidinyl)-N-methyl-2-benzothiazolam (Fig. 1) on postische mic ventricular function, an inhibitor of the Na+/Ca2+ overload, in th e working heart preparation of the rat. The hearts were paced at 5 Hz and perfused with Tyrode solution of 37 degrees C at a physiological p H. After 15 min of pretreatment with R 56865, low-flow ischemia (30 mi n) was induced by reducing the perfusion pressure from 51.5 mmHg to 11 .0 mmHg and R 56865 was infused simultaneously. The hemodynamic effect s of R 56865 were evaluated in the concentration range [10-(8)-3.10(-6 ) M]. The five parameters measured were: LVP (Left Ventricular Pressur e), +dP/dt(max) (maximal rate of pressure increase), AO (Aortic Output ), CF (Coronary Flow) and CO (Cardiac Output). They were determined in the working heart mode after 15 min of equilibration and at the end o f the experiment. From these data the recovery percentages were calcul ated. The recovery percentages for the LVP, +dP/dt(max), AO, CF and CO for the control hearts (3.3%, 0.0%, 7.9%, 10.4% and 8.5%, respectivel y) differed significantly from those at 10(-7) M (39.6%, 40.8%, 25.0%, 41.8% and 29.9% respectively). The recovery percentage were the highe st at 10(-6) M (79.6%, 82.1%, 54.7%, 92.7% and 67.2%, respectively). T he concentration of 10(-7) M was associated with a smaller reduction i n LVP (12.9%) than at 10(-6) M (25.7%). In separate experiments the he modynamic effects of R 56865 were investigated in working hearts taken from age-matched normotensive Wistar Kyoto rats (WKY), diabetic WKY, spontaneously hypertensive rats (SHR) and diabetic SHR. Diabetes was i nduced by intravenous (i.v.) streptozotocin (60 mg/kg), administered a t 12 weeks of age. The diabetic animals were kept diabetic for 8 weeks . In this stage there was no difference in mortality rate between the 4 groups. In the four groups studied the R 56865 concentration was 10( -6) M, which had been found as optimal in the experiments with prepara tions fromnormal Wistar rats. The recovery percentages with R 56865 fo r the LVP in hearts derived from the WKY, diabetic WKY, SHR and diabet ic SHR were: 88.8%, 82.0%, 49.8% and 53.2% respectively. These percent ages were significantly different from the data derived from the vehic le treated hearts (14.6%, 35.7%, 3.2%, 10.7%, respectively). Similar d ifferences-also hold true for the other parameters. Accordingly, R 568 65 also improves postischemic ventricular function significantly under pathologic conditions, where the recovery of the hearts from SHR was improved less than that of WKY.