Effect of pinacidil on spontaneous and evoked contractile activity.
Uninhibited bladder contractions have been associated with a variety of bladder dysfunctions including outlet obstruction, neurogenic bladder, incontinence, and other neurologic and nonneurogenic bladder disorders. One class of compounds that is gaining popularity and support for the treatment of hyperreflexia is potassium channel openers, such as pinacidil and cromakalim. In general, these agents act by hyperpolarizing the smooth muscle membrane, resulting in an increase in membrane stability which in turn would be expected to inhibit spontaneous and evoked contraction. It is the purpose of this study to compare the potency and selectivity of pinacidil at inhibiting both hyperreflexia in vivo, and several forms of in vitro contractile stimulation in the rabbit. The following is a summary of the results. (1) Pinacidil is an effective inhibitor of hyperreflexia in the in vivo rabbit model. (2) Pinacidil is a substantially more potent inhibitor of the amplitude of the hyperreflexia than the frequency. (3) Pinacidil was substantially more potent at inhibiting the contractile response to 2-Hz stimulation than to 32-Hz stimulation, but was equally effective at inhibiting field stimulation of the bladder base and body. (4) Pinacidil was significantly more potent at inhibiting the peak response to field stimulation than the rate of tension generation. (5) Pinacidil was equally potent and effective at inhibiting the phasic and tonic components of the response to field stimulation. (6) Pinacidil was a more potent inhibitor of methoxamine stimulation of the bladder base than bethanechol stimulation of the bladder body. (7) Pinacidil was a noncompetitive or mixed inhibitor of both methoxamine and bethanechol stimulation, whereas it was a competitive inhibitor of KCl stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Levin
R M
RM
Division of Urology, University of Pennsylvania School of Medicine, Philadelphia Veterans Administration Medical Center.
Hayes
L
L
Zhao
Y
Y
Wein
A J
AJ
D000818:Animals; D018723:Bethanechol; D001626:Bethanechol Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008729:Methoxamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D020110:Pinacidil; D011817:Rabbits; D013237:Stereoisomerism; D001743:Urinary Bladder / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001626:Bethanechol Compounds; D006146:Guanidines; D014665:Vasodilator Agents; D018723:Bethanechol; D020110:Pinacidil; D008729:Methoxamine