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Renal Hemodynamics: Biomolecular Control Mechanisms and Integration of Vascular and Tubular Function

ADP-ribosyl cyclase and ryanodine receptors mediate endothelin ET_A and ET_B receptor-induced renal vasoconstriction in vivo

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

Submitted 10 January 2007 ; accepted in final form 3 June 2008

ADP-ribosyl cyclase (ADPR cyclase) and ryanodine receptors (RyR) participate in calcium transduction in isolated afferent arterioles. We hypothesized that this signaling pathway is activated by ET_A and ET_B receptors in the renal vasculature to mediate vasoconstriction in vivo. To test this, we measured acute renal blood flow (RBF) responses to ET-1 in anesthetized rats and mice in the presence and absence of functional ADPR cyclase and/or RyR. Inhibitors of ADPR cyclase (nicotinamide) or RyR (ruthenium red) reduced RBF responses to ET-1 by 44% (P < 0.04 for both) in Sprague-Dawley rats. Mice lacking the predominant form of ADPR cyclase (CD38–/–) had RBF responses to ET-1 that were 47% weaker than those seen in wild-type mice (P = 0.01). Selective ET_A receptor stimulation (ET-1+BQ788) produced decreases in RBF that were attenuated by 43 and 56% by nicotinamide or ruthenium red, respectively (P < 0.02 for both). ADPR cyclase or RyR inhibition also reduced vasoconstrictor effects of the ET_B receptor agonist sarafotoxin 6c (S6c; 77 and 54%, respectively, P < 0.02 for both). ET_B receptor stimulation by ET-1 + the ET_A receptor antagonist BQ123 elicited responses that were attenuated by 59 and 60% by nicotinamide and ruthenium red, respectively (P < 0.01 for both). Nicotinamide attenuated RBF responses to S6c by 54% during inhibition of nitric oxide synthesis (P = 0.001). We conclude that in the renal microcirculation in vivo 1) ET-1-induced vasoconstriction is mediated by ADPR cyclase and RyR; 2) both ET_A and ET_B receptors activate this pathway; and 3) ADPR cyclase participates in ET_B receptor signaling independently of NO.

endothelin-1; calcium signaling; afferent arteriole; kidney; CD38

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