Pharmacological characterization of urinary bladder smooth muscle contractility following partial bladder outlet obstruction in pigs.
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.
Milicic
Ivan
I
Neuroscience Research, Department R4MN, Building AP9, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. ivan.milicic@abbott.com
Buckner
Steven A
SA
Daza
Anthony
A
Coghlan
Michael
M
Fey
Thomas A
TA
Brune
Michael E
ME
Gopalakrishnan
Murali
M
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D019806:Cromakalim / Q000494:pharmacology; D003499:Cyclic S-Oxides / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D006984:Hypertrophy; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology*; D015221:Potassium Channels / Q000819:agonists / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology; D013552:Swine; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001748:Urinary Bladder Neck Obstruction / Q000503:physiopathology*; D014665:Vasodilator Agents / Q000494:pharmacology
C466801:9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno(3,2-b)quinolin-8(4H)-one 1,1-dioxide; D000577:Amides; D001577:Benzophenones; D018679:Cholinergic Agonists; D003499:Cyclic S-Oxides; D006146:Guanidines; D015221:Potassium Channels; D011725:Pyridines; D015363:Quinolones; D018490:Serotonin Agents; D014665:Vasodilator Agents; C095007:Zeneca ZD 6169; D019806:Cromakalim; D012701:Serotonin; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; D011189:Potassium Chloride; D006632:Histamine; D000255:Adenosine Triphosphate; D002217:Carbachol; D003981:Diazoxide