In vitro investigation of the bladder-vascular selectivity of levcromakalim and YM934 in human tissues.
OBJECTIVE
To examine the potencies of the potassium-channel openers (KCOs) levcromakalim and YM934 as relaxing agents on human detrusor and human mesenteric artery smooth muscle, and to determine their bladder-vascular selectivity in vitro.


METHODS
Strips of human detrusor muscle and mesenteric artery (with the endothelium removed) were set up in physiological salt solution and the tension developed by the tissues recorded. Tissues were precontracted with a concentration of carbachol (detrusor) or phenylephrine (artery) which caused 80% of maximal contraction, and relaxation responses to levcromakalim and YM934 were then obtained.


RESULTS
Both KCOs caused relaxation of the bladder detrusor muscle and the mesenteric artery. Maximal responses, when plotted as a percentage of the precontraction, were greater for both KCOs in the bladder muscle than the artery, but the differences were small and not statistically significant. The sensitivity (drug potency) of the detrusor muscle to the KCOs was more than twice that of the artery but this selectivity was only statistically significant for YM934.


CONCLUSIONS
Only minor bladder-vascular selectivity for levcromakalim and YM934 could be detected in vitro. This suggests that neither drug would be tolerated clinically, although the results suggest that further development of bladder-selective KCO agents appears feasible.
Chess-Williams
R
R
Department of Biomedical Science, University of Sheffield, UK.
Martin
S W
SW
Korstanje
C
C
Chapple
C R
CR
D048588:Benzoxazines; D019806:Cromakalim / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D015653:Cystectomy; D006801:Humans; D008638:Mesenteric Arteries / Q000502:physiology; D009126:Muscle Relaxation / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D010078:Oxazines / Q000494:pharmacology*; D001743:Urinary Bladder / Q000294:innervation*; D001749:Urinary Bladder Neoplasms / Q000503:physiopathology
D048588:Benzoxazines; D003497:Cyclic N-Oxides; D010078:Oxazines; D019806:Cromakalim; C084963:2H-1,4-benzoxazine, 3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-pyridinyl)-, N-oxide