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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Role of Renal Sympathetic Nerves in Regulating Renovascular Responses to Angiotensin II in Spontaneously Hypertensive Rats

Center for Clinical Pharmacology (J.H.D., Z.M., E.K.J.), Departments of Pharmacology (J.H.D., E.K.J.) and Medicine (Z.M., E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

The purpose of this study was to test the hypothesis that renal sympathetic nerves modulate angiotensin II-induced renal vasoconstriction in kidneys from genetically hypertensive rats via Y₁ receptors activating the G_i pathway. In isolated, perfused kidneys from spontaneously hypertensive rats, the naturally occurring renal sympathetic cotransmitter neuropeptide Y at 6 nM enhanced angiotensin II (0.3 nM)-induced changes in perfusion pressure by 47 ± 7 mm Hg, and this effect was inhibited by BIBP3226 [N²-(diphenylacetyl)-N-[(4-hydroxyphenyl)-methyl]-D-arginine amide)], a selective Y₁ receptor antagonist (1 µM). We next examined whether periarterial nerve stimulation (5 Hz) enhances renal vascular responses to a physiological level of angiotensin II (100 pM). Kidneys were pretreated with prazosin (a selective ₁-adrenoceptor antagonist) to block nerve stimulation-induced changes in perfusion pressure. In kidneys from spontaneously hypertensive rats, but not normotensive rats, periarterial nerve stimulation significantly augmented angiotensin II-induced changes in perfusion pressure (177 ± 26% of response in absence of stimulation). BIBP3226, but not rauwolscine (a selective ₂-adrenoceptor antagonist), abolished periarterial nerve stimulation-induced enhancement of angiotensin II-mediated renal vasoconstriction. Pretreatment of hypertensive animals with pertussis toxin 3 days prior to kidney perfusion significantly (p < 0.000001) decreased mean blood pressure (203 ± 2 versus 145 ± 6 mm Hg in nonpretreated versus pertussis toxin-pretreated spontaneously hypertensive rats) and abolished periarterial nerve stimulation-induced enhancement of angiotensin II-mediated renal vasoconstriction. We conclude that, in spontaneously hypertensive rats but not normotensive rats, sympathetic nerve stimulation enhances renal vascular responses to physiological levels of angiotensin II via a mechanism mainly involving Y₁ receptors coupled to G_i proteins.

Address correspondence to: Dr. Edwin K. Jackson, Center for Clinical Pharmacology, 100 Technology Drive, Suite 450, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219. E-mail: edj{at}pitt.edu

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