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Clonidine‐induced increase in osmolar clearance and free water clearance via activation of two distinct α 2 ‐adrenoceptor sites
Author(s) -
Intengan H.D.,
Smyth D.D.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15724.x
Subject(s) - prazosin , clonidine , free water clearance , moxonidine , naltrexone , imidazoline receptor , agonist , chemistry , endocrinology , medicine , antagonist , pharmacology , receptor , kidney
1 Clonidine, an α 2 ‐adrenoceptor agonist, will increase urine flow rate in the anaesthetized rat by increasing both free water and osmolar clearance. In the present study, we investigated whether these effects of clonidine were mediated at two sites which could be distinguished pharmacologically in uninephrectomized male Sprague‐Dawley rats. 2 Clonidine (1.0 nmol kg −1 min −1 ) infused into the renal artery increased osmolar and free water clearance. Following pretreatment with prazosin (0.15 mg kg −1 , i.v.), an antagonist with reported selectivity for the α 2b ‐adrenoceptor subtype, the increase in free water but not osmolar clearance was decreased. Pretreatment with the opioid receptor antagonist, naltrexone (3.0 mg kg −1 , i.v.) attenuated the increase in osmolar but not free water clearance. This disparate antagonism of clonidine by prazosin and naltrexone was consistent with two distinct sites. 3 We submit the hypothesis that the α 2a ‐ and α 2b ‐adrenoceptor subtypes mediated the clonidine‐induced osmolar and free water clearance. The blockade in free water clearance by prazosin indicated a possible role of the α 2b ‐adrenoceptor subtype whereas the α 2a ‐adrenoceptor subtype was considered as the site mediating the clonidine‐induced increase in osmolar clearance. UK‐14,304 (1.0 nmol kg −1 min −1 ), a mixed α 2 ‐adrenoceptor/imidazoline receptor agonist with selectivity for the α 2a ‐subtype, increased only osmolar clearance. This increase was blocked by naltrexone but not prazosin pretreatment. The imidazoline receptor was not involved, as naltrexone failed to alter the moxonidine (3.0 nmol kg −1 ‐min −1 ) induced increase in osmolar clearance. These data suggested to us that the α 2a ‐/α 2b ‐subtype hypothesis should be investigated more closely in future studies. 4 These findings indicate that the increase in osmolar and free water clearance following clonidine can be distinguished pharmacologically indicating that two sites were involved. Furthermore, we propose the hypothesis that the α 2a ‐adrenoceptor subtype mediated osmolar clearance whereas the α 2b ‐subtype mediated free water clearance. The prazosin‐sensitive increase in free water clearance following clonidine suggested a possible role for the α 2b ‐subtype. The naltrexone‐sensitive increase in osmolar clearance following clonidine and UK‐14,304 (but not moxonidine) suggested a possible role of the α 2a ‐subtype. Clearly, this postulate requires further study.