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Endothelin-A and -B receptors, superoxide, and Ca²⁺ signaling in afferent arterioles

Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Submitted 13 February 2006 ; accepted in final form 14 June 2006

It is unknown if endothelin-A and -B receptors (ET_AR and ET_BR) activate the production of superoxide via NAD(P)H oxidase and subsequently stimulate the formation of cyclic adenine diphosphate ribose (cADPR) in afferent arterioles. Vessels were isolated from rat kidney and loaded with fura 2. Endothelin-1 (ET-1) rapidly increased cytosolic Ca²⁺ concentration ([Ca²⁺]_i) by 303 nM. The superoxide dismutase mimetic tempol, the NAD(P)H oxidase inhibitor apocynin, and nicotinamide, an inhibitor of ADPR cyclase, diminished the response by 60%. The ET_BR agonist sarafotoxin 6c (S6c) increased peak [Ca²⁺]_i by 117 nM. Subsequent addition of ET-1 in the continued presence of S6c caused an additional [Ca²⁺]_i peak of 225 nM. Neither nicotinamide or 8-bromo- (8-Br) cADPR nor apocynin decreased the [Ca²⁺]_i response to S6c, but inhibited the subsequent [Ca²⁺]_i response to ET-1. The ET_BR blockers BQ-788 and A-192621 prevented the S6c [Ca²⁺]_i peak and reduced the ET-1 response by more than one-half, suggesting an ET_BR/ET_AR interaction. In contrast, the ET_AR blocker BQ-123 had no effect on the S6c [Ca²⁺]_i peak and obliterated the subsequent ET-1 response. ET-1 immediately stimulated superoxide formation (measured with TEMPO-9-AC, 68 arbitrary units) that was inhibited 95% by apocynin or diphenyl iodonium. S6c or IRL-1620 increased superoxide by 8% of that caused by subsequent ET-1 addition. We conclude that ET_AR activation of afferent arterioles increases the formation of superoxide that accounts for 60% of subsequent Ca²⁺ signaling. ET_BR activation appears to result in only minor increases in superoxide production. Nicotinamide and 8-Br-cADPR results suggest that ET-1 (and primarily ET_AR) causes the activation of vascular smooth muscle cell-ADPR cyclase.

renal microcirculation; TEMPO-9-AC; ryanodine receptor; cyclic adenine diphosphate ribose; reduced nicotinamide adenine dinucleotide phosphate oxidase; heterodimerization

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