Abstract
We have previously demonstrated that the osmolar and free water responses to an intrarenal infusion of clonidine could be dissociated pharmacologically into naltrexone-sensitive and prazosin-sensitive responses, respectively. These results supported the notion that two distinct alpha-2 adrenoceptor sites were mediating the effects of clonidine. The ability of prazosin to selectively block the increase in free water clearance suggested the involvement of thealpha-2b subtype. Based on the identification by others of only the alpha-2a/d and alpha-2b subtypes in the rat kidney, the osmolar response was, by deduction only, speculated but not proven to involve thealpha-2a/d subtype. To provide evidence that thealpha-2a/d subtype mediated osmolar clearance, we investigated the effects of intrarenal infusion of the selectivealpha-2a/d adrenoceptor agonist guanfacine. Studies were conducted in anesthetized Sprague-Dawley rats that were unilaterally nephrectomized 7 to 10 days before the experiment. The infusion of guanfacine (3.0 nmol/kg/min) into the remaining renal artery increased urine flow without altering blood pressure or creatinine clearance. The increase in urine flow was associated with an increase in osmolar clearance but no increase in free water clearance. The effects of thealpha-2a/d adrenoceptor selective antagonist, RX-821002, on the renal actions of guanfacine were determined. RX-821002 (3.0 mg/kg) attenuated the ability of guanfacine to increase urine flow rate and osmolar clearance. Similarly to the increase in osmolar clearance observed with clonidine, the guanfacine-induced increase in osmolar clearance was attenuated by naltrexone (3.0 mg/kg) and unaltered by prazosin (0.15 mg/kg) pretreatment (i.e.,naltrexone-sensitive and prazosin-insensitive). These results were consistent with the alpha-2a/d adrenoceptor subtype in the rat kidney which mediated an increase in osmolar clearance. A physiological function of this alpha-2a/d adrenoceptor subtype may therefore involve regulation of solute/sodium excretion.
Footnotes
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Send reprint requests to: Donald D. Smyth, Ph.D., Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba, Canada. R3E 0W3.
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↵1 This work was supported by the Medical Research Council of Canada.
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↵2 Recipient of a Canadian Hypertension Society/Pfizer/Medical Research Council of Canada Graduate Studentship.
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↵3 Recipient of a Scientist Award from the Medical Research Council of Canada.
- Abbreviations:
- RX
- RX-821002
- GF
- guanfacine
- PZ
- prazosin
- NX
- naltrexone
- Received May 29, 1996.
- Accepted December 13, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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