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Redundant signaling mechanisms contribute to the vasodilatory response of the afferent arteriole to proteinase-activated receptor-2

Department of Pharmacology and Therapeutics, Smooth Muscle Research Group, University of Calgary, Calgary, Alberta, Canada

Submitted 27 March 2004 ; accepted in final form 20 August 2004

We previously demonstrated that stimulation of proteinase-activated receptor-2 (PAR-2) by SLIGRL-NH₂ elicits afferent arteriolar vasodilation, in part, by elaborating nitric oxide (NO), suggesting an endothelium-dependent mechanism (Trottier G, Hollenberg M, Wang X, Gui Y, Loutzenhiser K, and Loutzenhiser R. Am J Physiol Renal Physiol 282: F891–F897, 2002). In the present study, we characterized the NO-independent component of this response, using the in vitro perfused hydronephrotic rat kidney. SLIGRL-NH₂ (10 µmol/l) dilated afferent arterioles preconstricted with ANG II, and the initial transient component of this response was resistant to NO synthase (NOS) and cyclooxygenase inhibition. This NO-independent response was not prevented by treatment with 10 nmol/l charybdotoxin and 1 µmol/l apamin, a manipulation that prevents the endothelium-derived hyperpolarizing factor (EDHF)-like response of the afferent arteriole to acetylcholine, nor was it blocked by the addition of 1 mmol/l tetraethylammonium (TEA) or 50 µmol/l 17-octadecynoic acid, treatments that block the EDHF-like response to bradykinin. To determine whether the PAR-2 response additionally involves the electrogenic Na⁺-K⁺-ATPase, responses were evaluated in the presence of 3 mmol/l ouabain. In this setting, SLIGRL-NH₂ induced a biphasic dilation in control and a transient response after NOS inhibition. The latter was not prevented by charybdotoxin plus apamin or by TEA alone but was abolished by combined treatment with charybdotoxin, apamin, and TEA. This treatment did not prevent the NO-dependent dilation evoked in the absence of NOS inhibition. Our findings indicate a remarkable redundancy in the signaling cascade mediating PAR-2 -induced afferent arteriolar vasodilation, suggesting an importance in settings such as inflamation or ischemia, in which vascular mechanisms might be impaired and the PAR system is thought to be activated.

nitric oxide; SLIGRL-NH₂; potassium channels; ouabain-sensitive Na⁺-K⁺-ATPase; tetrathylammonium; apamin; charybdotoxin; 17-octadecynoic acid; endothelium-dependent hyperpolarizing factor

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