Contribution of alpha-2 adrenoceptors to kappa opioid agonist-induced water diuresis in the rat.
Clearance studies in rats using kappa opioid agonists have demonstrated that agonists that can cross the blood-brain barrier are more potent water diuretics than agonists which have limited access to the brain. The mechanism of kappa agonist-induced water diuresis is unclear but may involve inhibition of vasopressin secretion and/or an adrenomedullary factor. In the present study the effect of an alpha-2 adrenoceptor antagonist (yohimbine, 10 micrograms/kg.min i.v.) on kappa agonist-induced water diuresis was evaluated in conscious chronically instrumented rats. BRL 53117 (1-[(3,4-dichlorophenyl)acetyl]-2-[(3-hydroxy-1-pyrrolidinyl) methyl]4,4-dimethyl piperidine), a kappa agonist that can cross the blood-brain barrier, caused a dose-dependent (1-100 micrograms/kg) water diuresis which was attenuated by yohimbine. The effective dose to cause a free water clearnace of zero for BRL 53117 was 13 +/- 5 micrograms/kg in vehicle-treated rats and 37 +/- 12 micrograms/kg in yohimbine-treated rats. BRL 52974 (5-[(3,4-dichlorophenyl)acetyl]4-(1-pyrrolidinylmethyl)-4,5,6,7-te trahydro- 1H-imidazo[4,5-c]pyridine), a compound with limited ability to cross the blood-brain barrier, also caused a dose-dependent water diuresis, albeit at higher doses (30-3000 micrograms/kg), and thus a higher effective dose to cause a free water clearance of zero (129 +/- 61 micrograms/kg); however, the effect was abolished by yohimbine. The data suggest that kappa agonists cause a water diuresis by both a central mechanism involving inhibition of vasopressin secretion and a peripheral mechanism involving stimulation of renal alpha-2 receptors.
Wang
Y X
YX
Department of Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
Clarke
G D
GD
Sbacchi
M
M
Petrone
G
G
Brooks
D P
DP
D000818:Animals; D001812:Blood-Brain Barrier; D004231:Diuresis / Q000187:drug effects*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009994:Osmolar Concentration; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014556:Urine; D014867:Water / Q000378:metabolism*; D015016:Yohimbine / Q000494:pharmacology
D010880:Piperidines; D011725:Pyridines; D011759:Pyrrolidines; D018341:Receptors, Adrenergic, alpha-2; D017473:Receptors, Opioid, kappa; D014867:Water; C088382:BRL 52974; C088381:BRL 53117; D015016:Yohimbine