Effect of Pinacidil on Spontaneous and Evoked Contractile Activity

Abstract

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. 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. 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. In general, intravesical pinacidil may be useful in the treatment of hyperreflexia.

In vitro investigation of the bladder‐vascular selectivity of levcromakalim and YM934 in human tissues

“…The potency of KCOs on human detrusor activity is variable when electrical field‐stimulated tissues are examined, the potency being greater at lower than at higher frequencies of electrical stimulation [ 20]. On potassium‐depolarized tissues, relaxatory responses to KCOs are also variable, relaxations occurring when tissues are precontracted with low (20 mmol/L) but not when high concentrations of potassium (60 mmol/L) are used to raise muscle tone [ 21].…”

Advances in the pharmacological control of the bladder

“…Pinacidil given intravesically significantly reduced bladder overactivity induced by penile ligation in anaesthetized rabbits (Levin et al 1992). Yu et al (1996), giving ZD6169 intravesically, found the drug to increase the intercontraction interval in normal, but not in capsaicin-treated rats.…”

Bladder instability: a re‐appraisal of classical experimental approaches and development of new therapeutic strategies

“…Hyperreflexia has been described also in the rabbit in an acute model by penis ligation under anaesthesia, resulting in phasic bladder contractions not seen without ligation (Levin et al ., 1992). However, it is worth noting that the effect of anaesthesia on the storage process is disputed.…”

“…Models of obstructive instability were previously described in the rat and the guinea‐pig, although there is less clear evidence that outflow obstruction results in bladder instability as a result of the inconsistence of phasic activity during filling (Williams, Turner, Sainsbury & Brading, 1993). Partial obstruction in a rabbit model was extensively investigated in several studies by Levin and coworkers in Philadelphia, although functional symptoms resembling instability in humans were not urodynamically recorded in that model (Levin, Hayes, Zhao & Wein, 1992; Levin, Longhurst, Monson, Haugaard & Wein, 1993).…”