ADP Ribosyl Cyclase and Ryanodine Receptors Mediate G‐Protein Coupled Receptor‐Induced Renal Vasoconstriction in vivo

Abstract

Renal vasoconstriction is mediated by an increase in cytosolic calcium concentration ([Ca2+]i). ADP ribosyl cyclase (ADPR cyclase) activation leads to the formation of cyclic ADP ribose (cADPR) or nicotinic acid ADP (NAADP), both of which result in activation of ryanodine receptors (RYR) on the sarcoplasmic reticulum to cause Ca2+ release. We tested the hypothesis that interruption of the ADPR cyclase / RyR pathway inhibits angiotensin II (Ang II)-, norepinephrine (NE)-, and endothelin-1 (ET-1)- induced renal vasoconstriction. Using an ultrasonic flow transducer, we continuously measured renal blood flow in anesthetized Sprague-Dawley rats. Inhibitory agents were infused into the renal artery 2 min before a 10 μl injection of Ang II, NE, ET-1, or the ETB receptor agonist sarafotoxin (S6c). Infusion of ruthenium red, a RyR inhibitor (50 μg/kg/min), reduced Ang II,-, NE-, and S6c- induced renal vasoconstriction by 60 ± 8% and ET-1- induced constriction by 43 ± 12% (n ≥ 5/ group). Nicotinamide, an ADPR cyclase inhibitor (8 mg/kg/min), reduced Ang II-, NE-, and S6c- induced constriction by 75 ± 2% and ET-1- induced constriction by 43 ± 7%. These results show that Ang II, NE, and ET-1 activate ADPR cyclase and RyR signaling to produce renal vasoconstriction. ET-1 activation of this pathway in the renal microcirculation is likely mediated predominantly by ETB receptors. (This work was funded by NIH research grant HL-02334)