CALCIUM-ENTRY AND MOBILIZATION SIGNALING PATHWAYS IN ANG II-INDUCED RENAL VASOCONSTRICTION IN-VIVO

The purpose of this study was to determine the relative importance of calcium signaling pathways in angiotensin II (ANG II)-induced renal va soconstriction in vivo. Nifedipine was used to antagonize dihydropyrid ine-sensitive voltage-dependent calcium channels; BAY K 8644 was emplo yed to activate these calcium channels. Intracellular calcium mobiliza tion was evaluated using TMB-8 or heparin to inhibit calcium release f rom sarcoplasmic reticulum. Renal blood flow was measured by electroma gnetic flowmetry in anesthetized euvolemic Wistar-Kyoto rats. The anim als were pretreated with indomethacin to avoid interactions with prost aglandins. ANG II (2 ng) or BAY K 8644 (1 mu g) was injected into the renal artery to produce a transient 30-50% decrease in renal blood flo w without affecting arterial pressure. Coadministration of nifedipine with BAY K 8644 produced dose-dependent inhibition of the maximum rena l vasoconstriction elicited by BAY K 8644. The calcium-channel antagon ist had similar effects on ANG II-induced renal vasoconstriction. Nife dipine exerted maximum inhibition by blocking 50% of the peak ANG II r esponse. To evaluate intracellular calcium mobilization, TMB-8 or hepa rin was coadministered with ANG II. Each agent produced dose-dependent inhibition of up to 50% of the maximum renal vasoconstriction produce d by ANG II. The inhibitory effects of nifedipine and TMB-8 were addit ive; neither agent had an effect when ANG II AT(1) receptors were anta gonized with losartan. These observations indicate that one-half of th e ANG II-induced constriction of renal resistance vessels is mediated by voltage-dependent L-type calcium channels responsive to the dihydro pyridine nifedipine. The remaining 50% of the renal vasoconstriction e licited by ANG II is mediated by inositol 1,4,5-trisphosphate-mediated calcium mobilization from intracellular sources. The additive nature of the inhibitory effects indicates distinct mechanisms involving calc ium mobilization and calcium entry signaling pathways that are of equa l importance in ANG II activation of AT(1) receptors to trigger constr iction of renal resistance vessels under basal conditions.