The role of melanin-concentrating hormone-1 receptors in the voiding reflex in rats.
We have used the selective melanin-concentrating hormone-1 (MCH(1)) receptor antagonist SNAP 7941 [((+)-methyl (4S)-3-{[(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl) amino]carbonyl}-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate hydrochloride)] to investigate the role of the hypothalamic neuropeptide MCH in the control of voiding in rats. Intravenous administration of SNAP 7941 (3 and 10 mg/kg i.v.) produced dose-related inhibition of rhythmic, distension-induced voiding contractions in anesthetized rats. In conscious rats in which repeated voiding cycles were evoked by continuous slow transvesicular infusion of saline, intragastric SNAP 7941 [0.03-1 mg/kg intragastrically (i.g.)] produced sustained increases in infusion capacity (maximum = 220% basal), comparable with the effects of the 5-hydroxytryptamine(1A) antagonist WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide maleate salt), and the muscarinic antagonist, oxybutynin (4-diethylaminobut-2-ynyl 2-cyclohexyl-2-hydroxy-2-phenylacetate hydrochloride). SNAP 7941 produced similar results when administered at a low dose (0.01 nmol) into the lateral ventricle (intracerebroventricular). The opposite effect was produced when MCH (20 nmol) was delivered intracerebroventricularly, resulting in a 34% decrease in apparent bladder capacity with increased urinary frequency. The effect of MCH was blocked by the prior intragastric administration of SNAP 7941 (0.1 mg/kg), but oxybutynin (1 mg/kg) was ineffective. Finally, in conscious spontaneously hypertensive rats, SNAP 7941 (0.1 mg/kg i.g.) produced a 31% reduction in micturition frequency, accompanied by a 36% increase in bladder capacity, with no effect on total volume voided over 6 h. The data indicate that MCH acts via MCH(1) receptors within the CNS to modulate the voiding reflex in rats. The striking effects of the MCH(1) antagonist SNAP 7941 to increase bladder capacity and reduce voiding frequency indicate that MCH(1) antagonists may offer a potential novel approach for treating overactive bladder syndrome.
Department of Target Discovery and Assessment, Lundbeck Research USA, Inc., 215 College Road, Paramus, NJ 07652-1431, USA.
Laxminarayan G
LG
Hegde
Xiao Li
XL
Ping
Nina
N
Jochnowitz
Douglas A
DA
Craig
D000818:Animals; D004231:Diuresis / Q000187:drug effects / Q000502:physiology*; D005260:Female; D007276:Injections, Intraventricular; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000502:physiology*; D012016:Reference Values; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology; D001745:Urinary Bladder Diseases / Q000503:physiopathology / Q000517:prevention & control
C491208:MCHR1 protein, rat; D010880:Piperidines; D011743:Pyrimidines; D017481:Receptors, Somatostatin; C464854:SNAP7941