Opiate receptors within the blood-brain barrier mediate kappa agonist-induced water diuresis.
Data suggest that kappa opioid agonist-induced water diuresis involves inhibition of vasopressin (AVP) secretion; however, it is not clear whether this action involves kappa receptors in the neurohypophysis or receptors behind the blood-brain barrier (BBB). We have investigated the site of action using three selective kappa agonists, BRL 52656 (S(-)-2-(1-pyrrolidinylmethyl)-1-(4-trifluoromethylphenyl) acetyl piperidine hydrochloride), BRL 53114 ((-)-1-(4-trifluoromethylphenyl) acetyl-2-(1-pyrrolidinymethyl)3,3- dimethyl piperidine hydrochloride) and BRL 52974 (4-(1-pyrrolidinylmethyl)5-(3,4-dichlorophenyl)acetyl-4,5,6,7-t etrahydroimidazo [4,5-c] pyridine), with varying abilities to cross the BBB. Chemical and functional assays indicate that BRL 52974 has limited ability to cross the BBB, whereas BRL 53114 and BRL 52656 can freely penetrate. BRL 52974 was significantly less potent than BRL 52656 and BRL 53114 in causing a water diuresis in conscious rats. The ED10S (i.v. doses to cause a positive free water clearance of 10 microliters/min.100 g) for BRL 52974, BRL 52656 and BRL 53114 were 181, 9 and 3.4 mg/kg, respectively. Furthermore, in dogs BRL 52656 and BRL 53114 but not BRL 52974 (30 micrograms/kg i.v.) were able to cause a significant water diuresis. The data demonstrate that opiate receptors behind the BBB are primarily involved in kappa agonist-induced water diuresis and possibly inhibition of AVP secretion.
Department of Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
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DP
Brooks
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Giardina
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M
Gellai
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Dondio
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Edwards
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Petrone
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DePalma
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Sbacchi
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Jugus
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Misiano
D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D004231:Diuresis / Q000502:physiology*; D004232:Diuretics / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000502:physiology*; D013268:Stimulation, Chemical; D014667:Vasopressins / Q000494:pharmacology; D014867:Water / Q000378:metabolism*
C094082:BRL 52656; C094083:BRL 53114; D004232:Diuretics; D010880:Piperidines; D011725:Pyridines; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D014867:Water; D014667:Vasopressins; D001127:Arginine Vasopressin; C088382:BRL 52974; D000242:Cyclic AMP