Involvement of spinal tachykinin NK1 and NK2 receptors in detrusor hyperreflexia during chemical cystitis in anaesthetized rats.
The intraperitoneal administration of cyclophosphamide (150 mg/kg, 48 h before cystometry) induced detrusor hyperreflexia in urethane-anaesthetized rats. Intrathecal administration of the selective tachykinin NK1 receptor antagonist, GR 82,334 ([D-Pro9(spiro-gamma-lactam)Leu10,Trp11]physalaemin-(1-11)) (1 nmol/rat i.t.) had no significant effect on micturition in normal rats but increased the volume threshold In cyclophosphamide-treated rats. Another tachykinin NK1 receptor antagonist, RP 67,580 ((3aR,7aR)-7,7-diphenyl-2-[1-imino-2(2-methoxyphenyl)ethyl]+ ++perhydroisoindol -4-one) (10 nmol/rat i.t.) increased the volume threshold to a similar extent in both vehicle- and cyclophosphamide-treated animals. The tachykinin NK2 receptor antagonist, SR 48,968 (S7-N-methyl-N[4-(acetylamino-4-phenylpiperidino)-2-(3,4- dichlorophenyl)butyl]benzamide hydrochloride (10 nmol/rat i.t.) did not modify micturition parameters in normal rats but antagonized bladder hyperreflexia in cyclophosphamide-treated animals; SR 48,968 restored the volume threshold for the micturition reflex to values close to control values. SR 48,965 (R7-N-methyl-N[4-(acetylamino-4-phenylpiperidino)-2-(3,4- dichlorophenyl)butyl]benzamide hydrochloride) (10 nmol/rat i.t.), the enantiomer of SR 48,968 devoid of affinity for tachykinin NK2 receptors, was inactive. 2-Amino-5-phosphonovaleric acid (25 and 250 nmol/rat i.t.), a selective antagonist of NMDA receptors, augmented the volume threshold both in controls and in rats with detrusor hyperreflexia; after administration of this antagonist, however, the volume threshold in cyclophosphamide-treated animals was still lower than in controls. Intravenous administration of SR 48,968, RP 67,580, or the combined administration of SR 48,968 and RP 67,580 had no effect on cystometry variables either in rats with detrusor hyperreflexia or in controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacology Research Department Menarini Pharmaceuticals, Florence, Italy.
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Lecci
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Giuliani
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Santicioli
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Maggi
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D003520:Cyclophosphamide / Q000009:adverse effects; D003556:Cystitis / Q000139:chemically induced / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D007275:Injections, Intravenous; D007278:Injections, Spinal; D054833:Isoindoles; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010803:Physalaemin / Q000031:analogs & derivatives / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*; D014549:Urinary Incontinence / Q000139:chemically induced / Q000378:metabolism*; D014554:Urination / Q000187:drug effects
D001549:Benzamides; D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; C079014:GR 82334; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D010803:Physalaemin; C073839:SR 48968; D015763:2-Amino-5-phosphonovalerate; D003520:Cyclophosphamide