[Intravesical therapy of interstitial cystitis]. / Intravesikale Therapie bei interstitieller Zystitis.

Intravesically applied medications have the benefit of establishing high concentrations of a therapeutic agent at the intended target tissue along with a low risk for systemic side effects. Pentosanpolysulfate is frequently applied for this purpose and was shown to significantly reduce nycturia while frequency during the day remained unaffected in a controlled study. Heparin reduced nycturia in an open prospective protocol as well. For heparin the maximal onset of a therapeutic effect is often observed as late as 4-6 months after initiation of treatment. Heparin as well as pentosanpolysulfate cause practically no side effects. Dimethylsulfoxide (DMSO), when instilled intravesically, decreases symptoms up to 50-70% for an effective period of 1-2 months. An irritating but harmless side effect of DMSO is the development of a striking garlic-like odor. BCG improved symptoms in 10 of 15 patients after 8 months and in 8 of 15 patients after 24 months. No patient with an initial bladder capacity below 175 cc benefited from BCG instillations. Discomfort in the bladder region was noted as a frequent side effect. Instillations of clorpactin WCS 90 are painful and can thus only be applied under anesthesia. Success rates range between 50-70% and last for 6-12 months.

In vitro electrostimulation-induced urethral relaxation in the guinea pig is blocked by prazosin.

The purpose of this study was to characterize the electrostimulation-induced relaxation in guinea pig urethral rings. From sacrificed male guinea pigs, urethral rings were cut between the bladder neck and the penile crura and mounted in an in vitro bath. The drop in baseline tension in response to electrical stimulation (rectangular pulses of 0.8-msec pulse duration, a frequency of 3, 5, 10, and 20 Hz, and 75-mA current) was measured in the presence of various pharmacologic agents. In urethral tissue precontracted with 10(-5) norepinephrine, a significant relaxation of 34.8% was found at 10 Hz. This relaxation was not affected by the addition of neuropeptide Y (NPY, 10(-8)-10(-6) M), 10(-6) M atropine, 10(-5) M alpha-beta-methylene-adenosine,5'-triphosphate (alpha-beta-methylene-ATP, a purinergic antagonist), and tolazoline (alpha2 antagonist, 10(-8)-10(-4) M). However, with the alpha1 antagonist prazosin (5 x 10(-8)-5 x 10(-7) M), no relaxation occurred. The tissue response was of neurogenic origin as it was blocked by 10(-7) M tetrodotoxin. Norepinephrine-precontracted urethral rings of male guinea pigs exhibit a relaxation response at 10 Hz that is alpha1-adrenergic, non-cholinergic, non-purinergic, and independent of NPY.

Urethral relaxation after electrostimulation in the guinea pig is independent of nitric oxide.

PURPOSE: To investigate whether the relaxation of the striated urethral sphincter in guinea pigs is mediated by nitric oxide. MATERIALS AND METHODS: After sacrifice, urethral rings were cut between the bladder neck and the penile crura and mounted in an in vitro bath. Maximal isometric tension obtained at 1, 3, 10 and 25 Hz electrical stimulation (Tmax) for 5 to 30 sec was measured. RESULTS: Tmax at 25 Hz was not changed by pretreatment with 10(-4)M nitroprusside or 10(-4)M NG-nitro-L-arginine. In urethral tissue precontracted with 10(-4)M noradrenaline, a significant relaxation of 16-25% was found at 10 Hz. This relaxation could not be prevented by pretreatment with 10(-4)M NG-nitro-L-arginine and was not enhanced by the presence of 10(-3)M L-arginine. CONCLUSION: Noradrenaline-precontracted urethral rings of male guinea pigs exhibit a maximal relaxation at 10 Hz, which does not depend on nitric oxide.

Chronic penile denervation in the rat: effect on cavernous tissue morphology and function.

We evaluated the effects of chronic penile denervation on cavernous tissue morphology and function in 36 Sprague-Dawley rats. At age seven weeks, 18 animals underwent bilateral cavernous nerve neurectomy: 18 animals underwent sham operation as a control. A functional, biochemical and morphological assessment of the rats' penises was performed at 4 months. In denervated rats, intracavernous pressure failed to rise with electrostimulation of the pelvic plexus. However, a normal rise in pressure was found with direct intracavernous injection of sodium nitroprusside and papaverine. Sodium dodecylsulfate polyacrylamide (SDS) gel electrophoresis of the penile homogenate showed subtle differences between denervated and control animals. Based upon the histological findings there was no difference in staining of the cavernous tissue for acetylcholinesterase- and catecholamine-positive nerve fibers between experimental and control animals, since the innervation density was not quantified and the number of fibers was not counted. We conclude that chronic cavernous nerve neurectomy does not cause significant morphological or functional changes to the penile erectile tissue of rats.

Response of guinea pig smooth and striated urethral sphincter to cromakalim, prazosin, nifedipine, nitroprusside, and electrical stimulation.

Prazosin (an alpha-1-adrenergic blocker) and cromakalim (potassium channel opener), given alone, induced significant fatigue of the urethral sphincter at a concentration of 10(-4) M; both drugs combined achieved a significant sphincteric fatigue at a concentration of 10(-5) M each. To 10(-4) M hexamethonium (ganglionic smooth muscle blocker) and 10(-4) M decamethonium (nicotinic blocker of striated muscle) the striated urethral sphincter responded like striated muscle with no detectable function of its smooth muscle component. Therefore, the striated component seems to play a dominant role in sphincteric function. With calcium depletion or in the presence of a calcium channel blocker (10(-4) M nifedipine) the urethral sphincter showed a relative enhancement of response to electrical field stimulation when compared with smooth and skeletal muscle, whose responses were both significantly reduced. This phenomenon could not be explained with calcium-dependent, inhibitory, nitric oxide-releasing nerves, as the NO-synthase blocker N-nitro-L-arginine (10(-5) M to 5 x 10(-5) M) failed to induce the enhancement of sphincter contraction during electrostimulation found with calcium depletion. Still, NO-releasing nerves might play a role in sphincteric relaxation because sodium nitroprusside (10(-5) M) induced a significant relaxation of the urethral sphincter precontracted with 80 mM potassium. The potential to weaken sphincteric closure with drugs, exemplified by the results obtained in response to prazosin and cromakalim, would represent a therapeutic advance in the patient with neurogenic bladder dysfunction.

Cyclic guanosine monophosphate mediates penile erection in the rat.

Recent in vivo and in vitro studies suggest that nitric oxide or a nitric-oxide-like substance mediates nonadrenergic, noncholinergic relaxation of trabecular smooth muscle through activation of the cyclic guanosine monophosphate (cGMP) pathway. In 60 Sprague-Dawley rats, we investigated the effect of intracavernous administration of different drugs known to act at different levels of the cyclic adenosine monophosphate (cAMP) and cGMP pathways. Neither cAMP nor drugs that stimulate adenylate cyclase activity (vasoactive intestinal peptide, prostaglandin E1, calcitonin gene-related peptide) provoked any change in the basal intracavernous pressure. N-ethylmaleimide, an inhibitor of the enzyme adenylate cyclase, did not modify the response to electrostimulation of the cavernous nerve, indicating that the cAMP pathway does not play a significant role in penile erection in rats. However, intracavernous administration of methylene blue, a guanylate cyclase inhibitor, significantly reduced the response to electrostimulation (p = 0.001). Direct intracavernous injection of cGMP caused a statistically significant, dose-dependent increase in intravenous pressure that was not significantly inhibited by methylene blue. Sodium nitroprusside, a nitric oxide releaser and therefore a guanylate cyclase activator, caused a dose-dependent increase in intracavernous pressure (p < 0.05) that was inhibited almost completely by methylene blue (p = 0.002), supporting the theory that nitric oxide activates the synthesis of cGMP and that cGMP causes cavernous smooth muscle relaxation. Papaverine elicited an intracavernous pressure increase that was not affected by methylene blue or N-ethylmaleimide, indicating that papaverine acts through an independent pathway.(ABSTRACT TRUNCATED AT 250 WORDS)