Pharmacological characterization of urinary bladder smooth muscle contractility following partial bladder outlet obstruction in pigs

• Published in: European journal of pharmacology 2006-02, Vol.532 (1), p.107-114
• Main Authors: Milicic, Ivan, Buckner, Steven A., Daza, Anthony, Coghlan, Michael, Fey, Thomas A., Brune, Michael E., Gopalakrishnan, Murali
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - pharmacology; Amides - pharmacology; Animals; ATP-sensitive potassium channels; Benzophenones - pharmacology; Biological and medical sciences; Carbachol - pharmacology; Cholinergic Agonists - pharmacology; Cromakalim - pharmacology; Cyclic S-Oxides - pharmacology; Detrusor smooth muscle; Diazoxide - pharmacology; Dose-Response Relationship, Drug; Electric Stimulation; Female; Guanidines - pharmacology; Histamine - pharmacology; Hypertrophy; In Vitro Techniques; Medical sciences; Muscle Contraction - drug effects; Muscle Contraction - physiology; Muscle, Smooth - drug effects; Muscle, Smooth - physiopathology; Nephrology. Urinary tract diseases; Outlet obstruction; Overactive bladder; Pharmacology. Drug treatments; Potassium channel opener; Potassium Channels - agonists; Potassium Channels - physiology; Potassium Chloride - pharmacology; Pyridines - pharmacology; Quinolones - pharmacology; Serotonin - pharmacology; Serotonin Agents - pharmacology; Smooth muscle relaxation; Sulfonylurea receptor; Swine; Urinary Bladder - drug effects; Urinary Bladder - pathology; Urinary Bladder - physiopathology; Urinary Bladder Neck Obstruction - physiopathology; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Vasodilator Agents - pharmacology
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2005.12.076

Partial bladder outlet obstruction of the pig is considered as a valuable preclinical model for evaluating the profile of compounds for the treatment of bladder overactivity. In this study, we characterized the pharmacological properties of isolated bladder smooth muscle from pigs following partial outlet obstruction and its sensitivity to potassium channel openers. Bladder strips from obstructed animals showed significantly lower maximal efficacy ( E max) and sensitivity to stimulation by ATP and carbachol, but not to those evoked by serotonin, compared to age-matched controls. Tissue strips from obstructed animals also showed a 2.5-fold increase in the potency and significantly reduced maximum response following K + depolarization. With respect to spontaneous activity, bladder strips from control strips demonstrated little spontaneous phasic activity at all preloads examined. In contrast, bladder strips from obstructed animals showed large preload-dependent increases in spontaneous phasic activity at preload values of 16–32 g. The potencies of K ATP channel openers to relax carbachol-evoked contractions showed a good 1 : 1 correlation ( r 2 = 0.90) between obstructed and control bladder strips. These studies demonstrate that obstructed pig bladders show enhanced spontaneous phasic activity especially at elevated preloads, which may underlie unstable myogenic bladder contractions reported in cystometrographic measurements in vivo. The impaired responses to electrical field stimulation could be attributed to reduced efficacies and/or lower sensitivities of muscarinic and purinergic signaling pathways. K ATP channel sensitivities remain essentially unimpaired in the obstructed bladder and could be effectively modulated by openers with potential for the treatment of overactive bladder secondary to outlet obstruction.