Abstract
The purpose of this study was to determine whether the selectivealpha-2 agonist dexmedetomidine inhibits basic transport properties in the rat cortical collecting duct (CCD). Sprague-Dawley rat CCDs were isolated and perfused to allow measurement of osmotic water permeability (Pf), transepithelial voltage (Vt) and resistance (Rt). Arginine vasopressin (AVP) increases Pf, hyperpolarizes Vt and decreases Rt in the CCD via stimulation of adenylyl cyclase. Dexmedetomidine at 100 nM added to the basolateral side of the CCD reduced AVP-stimulated Pf by 95% to 100%, and the alpha-2 antagonist atipamezole reversed the inhibition. In the presence of the protein kinase C inhibitor staurosporine, dexmedetomidine reduced AVP-stimulated Pf by 70% to 75% compared with the complete inhibition without staurosporine. When Pf was increased by the use of the nonhydrolyzable analog of cAMP, 8-chlorophenylthio-cAMP, in lieu of AVP, dexmedetomidine inhibited Pf by ∼35%. This demonstrated alpha-2-mediated inhibition of Pf despite the presence of constant cellular cAMP levels. Dexmedetomidine reversed AVP-induced effects on Vt and Rt, indicating inhibition of Na+ transport. Results confirm an alpha-2-mediated mechanism that reduces Na+ and water transport in the CCD and suggest that a cellular messenger other than cAMP is involved. This messenger could be protein kinase C.
Footnotes
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Send reprint requests to: Dr. Alexander J. Rouch, Oklahoma State University College of Osteopathic Medicine, 1111 West 17th Street, Tulsa, OK 74107.
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↵1 This work was supported by National Science Foundation CAREER Grant IBN 9507444. Dr. Kudo is the recipient of CNPq Grant 303259 from Brazil.
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↵2 Present address: Faculdade de Medicina, USP, CEP 01246, Sao Paulo, Brasil.
- Abbreviations:
- CCD
- cortical collecting duct
- IMCD
- inner medullary collecting duct
- Jlb
- lumen-to-bath Na+ flux
- Pf
- osmotic water permeability
- Lp
- hydraulic conductivity
- Vt
- transepithelial voltage
- Rt
- transepithelial resistance
- PKC
- protein kinase C
- 8-CPT-cAMP
- 8-chlorophenylthio-cAMP
- AVP
- arginine vasopressin
- Received July 22, 1996.
- Accepted December 6, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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