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 (N-[1-[4-(4-fluorophenoxy)-butyl]-4-piperidinyl-N-methyl-2-benzothiazolamine) (Fig. 1) on postischemic ventricular function, an inhibitor of the Na+/Ca2+ overload, in the working heart preparation of the rat. The hearts were paced at 5 Hz and perfused with Tyrode solution of 37°C at a physiological pH. After 15 min of pretreatment with R 56865, low-flow ischemia (30 min) was induced by reducing the perfusion pressure from 51.5 mmHg to 11.0 mmHg and R 56865 was infused simultaneously. The hemodynamic effects of R 56865 were evaluated in the concentration range [10−8-3·10−6M]. The five parameters measured were: LVP (Left Ventricular Pressure), +dP/dtmax (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 of the experiment. From these data the recovery percentages were calculated. The recovery percentages for the LVP, +dP/dtmax, AO, CF and CO for the control hearts (3.3%, 0.0%, 7.9%, 10.4% and 8.5%, respectively) 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 highest at 10−6 M (79.6%, 82.1%, 54.7%, 92.7% and 67.2%, respectively). The concentration of 10−7 M was associated with a smaller reduction in LVP (12.9%) than at ·10−6 M (25.7%). In separate experiments the hemodynamic 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 induced by intravenous (i.v.) Streptozotocin (60 mg/kg), administered at 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 preparations from normal Wistar rats. The recovery percentages with R 56865 for the LVP in hearts derived from the WKY, diabetic WKY, SHR and diabetic SHR were: 88.8%, 82.0%, 49.8% and 53.2% respectively. These percentages were significantly different from the data derived from the vehicle treated hearts (14.6%, 35.7%, 3.2%, 10.7%, respectively). Similar differences also hold true for the other parameters. Accordingly, R 56865 also improves postischemic ventricular function significantly under pathologic conditions, where the recovery of the hearts from SHR was improved less than that of WKY.