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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Chronic high-NaCl intake prolongs the cardiorenal responses to central N/OFQ and produces regional changes in the endogenous brain NOP receptor system

¹Departments of Pharmacology and Experimental Therapeutics and ²Anesthesiology and the Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana

Submitted 8 February 2008 ; accepted in final form 28 October 2008

Intracerebroventricular nociceptin/orphanin FQ (N/OFQ) produces cardiovascular depressor, diuretic, and renal sympathoinhibitory responses in conscious rats. These studies examined how a chronic high-NaCl intake alters these peptide-evoked responses and the activity of the endogenous central N/OFQ peptide (NOP) receptor system. In normotensive Sprague-Dawley rats fed a chronic (3-wk) high (8%)-NaCl diet, intracerebroventricular N/OFQ (5.5 nmol) produced prolonged bradycardic, hypotensive, and diuretic responses but failed to suppress renal sympathetic nerve activity. In a separate group of rats maintained on a high-NaCl diet, intracerebroventricular infusion of the NOP receptor antagonist UFP-101 significantly decreased urine output. At the tissue level, high-NaCl treatment of rats significantly increased NOP receptor density, without altering endogenous N/OFQ peptide levels in whole hypothalamus (control, 712 ± 35 fmol/mg vs. 8% NaCl, 883 ± 49 fmol/mg, P < 0.05) and paraventricular nucleus. Furthermore, in the hypothalamus, basal GTPS binding was increased without altering the sensitivity of N/OFQ-stimulated G protein coupling. In contrast, in whole medulla and the ventrolateral medulla (VLM), high-NaCl treatment decreased NOP receptor density (medulla: control, 1,473 ± 131 fmol/mg vs. 8% NaCl, 327 ± 31 fmol/mg, P < 0.05) and endogenous N/OFQ peptide levels (medulla: control, 35.3 ± 2 fmol/mg vs. 8% NaCl, 11.9 ± 3 fmol/mg, P < 0.05), while increasing the sensitivity of G protein signaling pathways to N/OFQ stimulation. Together, these findings suggest that during a chronic high-salt intake, regional changes in the activity of the N/OFQ-NOP system in the brain may contribute to the tonic regulation of cardiovascular function and urine output and to the altered physiological responses to exogenous central N/OFQ.

sodium-chloride diet; cardiovascular function; renal excretory function; central nervous system; renal sympathetic nerve activity