Abstract
The present studies examined the cardiovascular and renal responses produced by activation of central nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors in conscious mice. To assess this, we examined changes in heart rate (HR), mean arterial pressure (MAP), urine output (V), urinary sodium excretion (UNaV), and free water clearance (CH2O) produced by acute i.c.v. injection of N/OFQ (0.03, 0.3, 1, or 3 nmol) or isotonic saline vehicle (2 μl) in conscious telemetered ICR-CD1 mice. After i.c.v. injection, N/OFQ, but not vehicle, dose dependently decreased HR and MAP and increased V. At 3 nmol, N/OFQ reduced HR [control (C), 672 ± 23 beats/min; 20 min, 411 ± 30 beats/min] and MAP (C, 108 ± 4 mm Hg; 20 min, 62 ± 6 mm Hg). In the same telemetered mice, i.c.v. N/OFQ significantly elevated V (0.65 ± 0.03 cc/2 h) compared with levels for the vehicle-treated group (0.15 ± 0.09 cc/2 h). Central N/OFQ/vehicle did not alter UNaV or CH2O. In separate studies, 2-h i.c.v. pretreatment with the NOP receptor antagonist UFP-101 ([Nphe1,Arg14,Lys15]N/OFQ-NH2) (10 or 30 nmol) markedly, but transiently, reduced HR but not MAP, V, UNaV, or CH2O. After 2-h UFP-101 (10 or 30 nmol) pretreatment, subsequent i.c.v. injection of N/OFQ (1 or 3 nmol) failed to alter cardiovascular or renal function. In contrast, in separate mice, 2-h pretreatment with N/OFQ (1 or 3 nmol) or vehicle failed to prevent the cardiodepressor and diuretic responses to a subsequent i.c.v. injection of the same dose of N/OFQ. Together, these findings demonstrate that in conscious mice, the central administration of N/OFQ evokes marked bradycardia, hypotension, and diuresis by selective activation of central NOP receptors.
Footnotes
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This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (Grants DK-43337 and DK-02605 to D.R.K.) and by the Heart Blood and Lung Institute (Grant HL71212 to D.R.K.). Additional funding for this work was provided to the Cardiac and Vascular Core Facility in the Department of Pharmacology and Center of Excellence in Cardiovascular Research at Louisiana State University Health Sciences Center by COBRE Grant P20 RR018766 (to D.R.K.) from the National Center for Research Resources, a component of the National Institutes of Health.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.120394.
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ABBREVIATIONS: N/OFQ, nociceptin/orphanin FQ; NOP, nociceptin/orphanin FQ peptide; HR, heart rate; MAP, mean arterial pressure; V, urine output; UFP-101, [Nphe1,Arg14,Lys15]N/OFQ-NH2; ANOVA, analysis of variance; C, control.
- Received January 23, 2007.
- Accepted April 19, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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