Hemodynamic comparison of diltiazem and TA-3090 in spontaneously hypertensive and normal Wistar-Kyoto rats

Abstract

Systemic and regional hemodynamic effects of 2 benzothiazepine derivatives, diltiazem and its congener TA-3090, were studied both acutely and chronically in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. All hemodynamic data were obtained in the conscious state using the reference sample radiomicrosphere method. Mean arterial pressure was reduced significantly with both immediate and more long-term treatment with both drugs in the SHR. The hypotensive action of TA-3090 was about 3 times as potent as diltiazem. The pressure reduction with both drugs was associated with a decrease in total peripheral resistance. TA-3090 seemed to have lesser effect on heart rate than diltiazem, although its net effect on cardiac output was similar, remaining unchanged in each study group. After intravenous injection, both diltiazem and TA-3090 significantly reduced vascular resistances of the major target organs of hypertension: heart, brain and kidneys in SHR. However, with prolonged treatment, organ vascular resistances seemed to be nonuniformly distributed. Intrarenal hemodynamics revealed significant differences between SHR and WKY rats after intravenous diltiazem and prolonged treatment with TA-3090. Thus, efferent as well as afferent arteriolar resistance decreased and therefore calculated glomerular capillary hydrostatic pressure decreased in SHR; however, efferent resistance and glomerular pressure remained unchanged in WKY rats. In contrast, intravenous TA-3090 evoked no such differences. Thus, diltiazem as well as TA-3090 dilated efferent as well as afferent arterioles in the SHR but not in the WKY rats. This effect was associated with a reduction in glomerular capillary pressure, preventing glomerular hyperfiltration through efferent arteriolar dilation. These hemodynamic effects may be of particular advantage when one considers the renal sequelae of prolonged hypertension.