Reversal by the Calcium Antagonist Nisoldipine of Norepinephrine-lnduced Reduction of GFR: Evidence for Preferential Antagonism of Preglomerular Vasoconstriction’ RODGER LOUTZENHISER, MURRAY EPSTEIN, CHARLES HORTON and PHILLIP SONKE

ABBREVIATiONS: GFR, glomerular filtration rate; RPF, renal perfusate flow; SFP, stop-flow pressure. 382 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Copyright © 1985 by The American Society for Pharmacology and Experimental Therapeutics Reversal by the Calcium Antagonist Nisoldipine of Norepinephrine-lnduced Reduction of GFR: Evidence for Preferential Antagonism of Preglomerular Vasoconstriction’ RODGER LOUTZENHISER, MURRAY EPSTEIN, CHARLES HORTON and PHILLIP SONKE Nephrology Section, Veterans Administration Medical Center and the Department of Medicine, University of Miami School of Medicine. Miami florida Accepted for publication October 29, 1984 We have demonstrated previously that the organic Ca antagonist diltiazem augments the glomerular filtration rate (GFR) of the isolated perfused rat kidney during norepinephnne (NE) induced vasoconstriction. These earlier studies, however, did not elucidate the precise mechanism or site of action responsible for this effect. Nisoldipine (NIS) interacts with the same Ca 2 channels as diltiazem but differs in its physicochemical properties, binding characteristics and tissue specificity. We examined, therefore, the effects of NIS using an identical model. Renal perfusate flow and GFR were assessed in the isolated perfused rat kidney under conditions of constant renal perfusion pressure (1 00 mm Hg). NIS (1 0 M) completely reversed the NE-induced reduction in GFR but was significantly less effective in augmenting renal perfusate flow. In an additional series of experiments, filtration pressure was estimated during these manipulations by monitoring ureteral pressure during ureteral occlusion (stop-flow pressure). The NE-induced decrease in GFR was accompanied by a reduction in stop-flow pressure, which was abolished by the subsequent administration of NlS. Thus, nisoldipine preferentially attenuated NE-induced constriction of preglomerular resistance vessels but was less effective in reversing the effects of NE on postglomerular arterioles. These findings indicate that separate postreceptor mechanisms mediate the activation of preand postglomerular vessels by NE. The primary role of cytosolic Ca as the second messenger mediating vascular smooth muscle tone is firmly established. Most, if not all, vasoconstrictor agents activate vascular smooth muscle by modifying cellular Ca handling (for review, see Bolton, 1979). Postreceptor events mediating the increase in intracellular Ca include the activation of either receptoroperated or potential-dependent Ca channels (Godfraind, 1976; Meisheri et al., 1981), the release of intracellularly bound Ca (Bohr, 1963; Hinke, 1965; Bevan and Waterson, 1971; Deth and van Breemen, 1977) and alterations in intracellular Ca sequestration (Loutzenhiser and van Breemen, 1983a). Organic Ca antagonists alter vascular tone by interacting with membrane-associated Ca channels (Bolger et al., 1983; Triggle and Swamy, 1983; Glossman and Ferry, 1983), thereby modulating Ca entry into vascular smooth muscle (Fleckenstein, 1977; Thorens and Haeusler, 1979; van Breemen et al., 1981). Calcium antagonists of the dihydropyridine class are particularly selective with regard to the type of Ca entry pathway they affect (Triggle and Swamy, 1983). Furthermore, Received for publication May 11, 1984. I This work was supported by designated Veterans Administration Research funds (2456-01) and by a grant from Miles Institute for Preclinical Pharmacology, New Haven, CT. unlike verapamil, dihydropyridines do not interfere with the binding of adrenergic agonists to adrenoceptors (Motulsky et al., 1983), nor do they affect the release of intracellularly bound Ca or Ca -dependent activation of skinned smooth muscle preparations (Saida and van Breemen, 1983). For these reasons, these agents represent unique tools for the study of postreceptor activation processes. Previous studies from our laboratory demonstrated that the Ca antagonist diltiazem causes a striking augmentation of GFR without appreciably increasing RPF when administered to the isolated perfused rat kidney during norepinephrineinduced vasoconstriction (Loutzenhiser et at., 1985). The present study was designed to characterize further the effects of Ca entry blockade upon the renal hemodynamic response to norepinephrine. Because nisoldipine, a dihydropyridine, exhibits greater tissue selectivity than diltiazem (Triggle and Swamy, 1983) and binds to Ca channels at a site different from diltiazem (Bolger et at., 1983; Glossman and Ferry, 1983), it was anticipated that studies with this agent would provide further insight into the pharmacological basis of this phenomenon. The results indicate that nisoldipine completely reverses the norepinephrine-induced decreases in GFR, although only partially reversing the effects of norepinephrine on RPF. Eviat A PE T Jornals on A ril 0, 2017 jpet.asjournals.org D ow nladed from