Long‐term nitric oxide deficiency causes muscarinic supersensitivity and reduces β3‐adrenoceptor‐mediated relaxation, causing rat detrusor overactivity

• Published in: British journal of pharmacology 2008-04, Vol.153 (8), p.1659-1668
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; detrusor smooth muscle; inositol triphosphate; Medical sciences; muscarinic receptors; Nephrology. Urinary tract diseases; overactive bladder; Pharmacology. Drug treatments; Research Papers; trigone; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; β‐adrenoceptors
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/bjp.2008.39

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 Nω‐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 [3H]inositol phosphate, NO synthase (NOS) activity, [3H]quinuclidinyl benzilate ([3H]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 β3‐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 [3H]inositol phosphate in bladder tissue from rats treated with L‐NAME. [3H]QNB was bound with an apparent KD 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 KD values for muscarinic receptors and [3H]inositol phosphate accumulation in bladder. This supersensitivity for muscarinic agonists along with reductions of β3‐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