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Long‐term nitric oxide deficiency causes muscarinic supersensitivity and reduces β 3 ‐adrenoceptor‐mediated relaxation, causing rat detrusor overactivity
Author(s) -
Mónica F Z T,
Bricola A A O,
Báu F R,
Freitas L L Lopes,
Teixeira S A,
Muscará M N,
Abdalla F M F,
Porto C S,
Nucci G,
Zanesco A,
Antunes E
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.39
Subject(s) - carbachol , muscarinic acetylcholine receptor , endocrinology , medicine , chemistry , detrusor muscle , muscarinic agonist , agonist , inositol phosphate , muscarinic acetylcholine receptor m3 , nitric oxide , nitric oxide synthase , inositol , atropine , receptor , urinary bladder , biology
Background and purpose: Overactive bladder is a complex and widely prevalent condition, but little is known about its physiopathology. We have carried out morphological, biochemical and functional assays to investigate the effects of long‐term nitric oxide (NO) deficiency on muscarinic receptor and β‐adrenoceptor modulation leading to overactivity of rat detrusor muscle. Experimental approach: Male Wistar rats received N ω ‐nitro‐ L ‐arginine methyl ester ( L ‐NAME) in drinking water for 7–30 days. Functional responses to muscarinic and β‐adrenoceptor agonists were measured in detrusor smooth muscle (DSM) strips in Krebs–Henseleit solution. Measurements of [ 3 H]inositol phosphate, NO synthase (NOS) activity, [ 3 H]quinuclidinyl benzilate ([ 3 H]QNB) binding and bladder morphology were also performed. Key results: Long‐term L ‐NAME treatment significantly increased carbachol‐induced DSM contractile responses after 15 and 30 days; relaxing responses to the β 3 ‐adrenoceptor agonist BRL 37‐344 were significantly reduced at 30 days. Constitutive NOS activity in bladder was reduced by 86% after 7 days and maintained up to 30 days of L ‐NAME treatment. Carbachol increased sixfold the [ 3 H]inositol phosphate in bladder tissue from rats treated with L ‐NAME. [ 3 H]QNB was bound with an apparent K D twofold higher in bladder membranes after L ‐NAME treatment compared with that in control. No morphological alterations in DSM were found. Conclusions and implications: Long‐term NO deficiency increased rat DSM contractile responses to a muscarinic agonist, accompanied by significantly enhanced K D values for muscarinic receptors and [ 3 H]inositol phosphate accumulation in bladder. This supersensitivity for muscarinic agonists along with reductions of β 3 ‐adrenoceptor‐mediated relaxations indicated that overactive DSM resulted from chronic NO deficiency. British Journal of Pharmacology (2008) 153 , 1659–1668; doi: 10.1038/bjp.2008.39 ; published online 25 February 2008