Clonidine‐induced increase in osmolar clearance and free water clearance via activation of two distinct α2‐adrenoceptor sites

• Published in: British journal of pharmacology 1996-10, Vol.119 (4), p.663-670
• Main Authors: Intengan, H.D., Smyth, D.D.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cardiovascular system; Clonidine; Medical sciences; moxonidine; Pharmacology. Drug treatments; sodium excretion; UK‐14,304; urine flow; Vasodilator agents. Cerebral vasodilators; α2a‐adrenoceptor; α2b‐adrenoceptor
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1996.tb15724.x

1 Clonidine, an α2‐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 α2b‐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 α2a‐ and α2b‐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 α2b‐adrenoceptor subtype whereas the α2a‐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 α2‐adrenoceptor/imidazoline receptor agonist with selectivity for the α2a‐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 α2a‐/α2b‐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 α2a‐adrenoceptor subtype mediated osmolar clearance whereas the α2b‐subtype mediated free water clearance. The prazosin‐sensitive increase in free water clearance following clonidine suggested a possible role for the α2b‐subtype. The naltrexone‐sensitive increase in osmolar clearance following clonidine and UK‐14,304 (but not moxonidine) suggested a possible role of the α2a‐subtype. Clearly, this postulate requires further study.