Raj Kumar Pandita

Spinal and peripheral mechanisms contributing to hyperactive voiding in spontaneously hypertensive rats

The influence of noradrenergic mechanisms involved in micturition in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats was investigated using continuous cystometry in in vivo and in vitro studies on isolated bladder and urethral tissues. Compared with WKY rats, SHR had a significantly lower bladder capacity (SHR: 0.7 +/- 0. 05 ml; WKY rats: 1.3 +/- 0.06 ml; P < 0.001), micturition volume (SHR: 0.4 +/- 0.04 ml, WKY rats: 1.2 +/- 0.05 ml; P < 0.001), and an increased amplitude of nonvoiding (unstable) bladder contractions. The effects of intrathecal and intra-arterial doxazosin on cystometric parameters were more pronounced in SHR than in WKY rats. There was a marked reduction in nonvoiding contractions after intrathecal (but not intra-arterial) doxazosin in SHR. Norepinephrine (0.1 microM-1 mM) failed to evoke contractions in bladder strips from WKY rats, in contrast to a weak contractile response in SHR. The response to electrical field stimulation was significantly less in bladder strips from SHR than from WKY rats. In WKY rats, norepinephrine produced concentration-dependent inhibition (87 +/- 5%, n = 6) of nerve-evoked bladder contractions. Almost no inhibition (11 +/- 8%, n = 6) was found in SHR. Alterations in bladder function of SHR appear to be associated with changes in the noradrenergic control of the micturition reflex, in addition to an increased smooth muscle and decreased neuronal responsiveness to norepinephrine. The marked reduction in nonvoiding contractions after intrathecal doxazosin suggests that the bladder hyperactivity in SHR has at least part of its origin in supraspinal and/or spinal structures.

INTRAVESICAL OXYHEMOGLOBIN INITIATES BLADDER OVERACTIVITY IN CONSCIOUS, NORMAL RATS

PURPOSE To investigate whether intravesical oxyhemoglobin, a nitric oxide scavenger, changes bladder activity in normal rats. MATERIALS AND METHODS Oxyhemoglobin was given intravesically at different concentrations to conscious, female Sprague-Dawley rats undergoing continuous cystometry. RESULTS Intravesical oxyhemoglobin increased bladder activity in a concentration-dependent way. At a concentration of 2.5 x 10-4 M (n = 8), micturition pressure (p <0. 01), basal pressure (p <0.01), and residual volume (p <0.05) increased, and bladder capacity (p <0.001) and micturition volume (p <0.001) decreased. The effect of oxyhemoglobin was reduced or abolished by L-arginine (200 mg./kg.-1), given intra-arterially near the bladder, and was enhanced by the guanylate cyclase inhibitor, ODQ (0.5 and 1 mg./kg.-1). The K+ channel opener, ZD6169 100 ng.ml. -1, given intravesically for 1 hour prior to instillation of oxyhemoglobin, reduced or completely prevented the bladder activity induced by oxyhemoglobin. CONCLUSIONS Intravesical oxyhemoglobin induces bladder overactivity, probably by interfering with nitric oxide (NO) generated in the urothelium or suburothelially. NO may be involved in the regulation of the threshold for afferent firing in the bladder.

Pharmacological characterization of a novel investigational antimuscarinic drug, fesoterodine, in vitro and in vivo

To investigate the primary pharmacology of fesoterodine (a novel antimuscarinic drug developed for treating overactive bladder) and SPM 7605 (its active metabolite, considered to be the main pharmacologically active principle of fesoterodine in man) against human muscarinic receptor subtypes, and to investigate in vitro and in vivo functional activity of these agents on the rat bladder compared with existing standard agents.

Actions of tramadol on micturition in awake, freely moving rats.

(±)‐Tramadol, a widely used analgesic, is a racemate stimulating opioid receptors and inhibiting reuptake of noradrenaline and serotonin, that is, pharmacological principles previously shown to influence rat micturition. We studied both (±)‐tramadol and its enantiomers in conscious Sprague–Dawley rats undergoing continuous cystometry. The effects of these agents were compared to those of morphine (μ‐opioid receptor agonist) and tested after pretreatment with naloxone (μ‐opioid receptor antagonist). Cystometries were evaluated before and after intravenous (i.v.), intraperitoneal (i.p.) and intrathecal (i.t.) drug administrations. The most conspicuous effects of i.v. (±)‐tramadol (0.1–10 mg kg−1) was an increase in threshold pressure and an increase in micturition volume. These effects were mimicked by (+)‐tramadol (0.1–5 mg kg−1 i.v.), whereas (−)‐tramadol (5 mg kg−1 i.v.) did not influence threshold pressure and micturition volume. The effects of (±)‐tramadol 5 mg kg−1 on micturition volume were blocked by pretreatment with naloxone 0.3 mg kg−1. Morphine (0.3–10 mg kg−1 i.p.) increased threshold pressure but did not significantly increase micturition volume in doses not resulting in overflow incontinence. (±)‐Tramadol 10 mg kg−1 increased urine production, an effect blocked by desmopressin 25 ng kg−1. (±)‐Tramadol effectively inhibits micturition in conscious rats by stimulating μ‐opioid receptors. A synergy between opioid receptor stimulation and monoamine reuptake inhibition may contribute to the micturition effects.

Capsaicin-induced bladder overactivity and nociceptive behaviour in conscious rats: Involvement of spinal nitric oxide

To investigate the role of nitric oxide (NO) in spinal regulation of lower urinary tract function and bladder nociceptive behaviour, cystometry was performed in conscious rats. The effects of intra-arterial and intrathecal administration of the NO synthase (NOS)-inhibitor, L-NG-nitroarginine methyl ester (L-NAME), were studied on volume- and capsaicin-induced micturitions. The incidence of nociceptive behaviour after intravesical capsaicin was investigated in the absence and presence of L-NAME. Intrathecal L-NAME (0.5 mg) had no effect on the normal, volume-induced micturition. Intravesical capsaicin (30 microM) increased the micturition pressure (p < 0.01), the basal pressure (p < 0.01) and decreased the bladder capacity (p < 0.01) and the micturition volume (p < 0.01). Administration of L-NAME intrathecally (0.5 mg) or intra-arterially (25 mg/kg) had no effects on the capsaicin-induced bladder activity. During capsaicin-infusion, the rats showed signs of distress such as licking and head-turning directed toward the abdomen. This nociceptive behaviour was shown during 31 +/- 3% (n = 6) of the observation period. The capsaicin-induced nociceptive behaviour was markedly reduced by intrathecal and to a less extent by intra-arterial, administration of L-NAME. The percentage time spent licking and head-turning was reduced to 11 +/- 2%, n = 6 (p < 0.001) and 18 +/- 3%, n = 6 (p < 0.05) in rats treated with intrathecal and intra-arterial L-NAME, respectively. The results suggest that NO is not involved in the spinal regulation of the volume- or capsaicin-induced micturition. In contrast, the nociceptive behaviour evoked by intravesical capsaicin seems to involve spinal NO.

EFFECTS OF INTRAVESICAL ADMINISTRATION OF THE K+ CHANNEL OPENER, ZD6169, IN CONSCIOUS RATS WITH AND WITHOUT BLADDER OUTFLOW OBSTRUCTION

PURPOSE To investigate the urodynamic effects of the new K(ATP) channel opener, ZD6169, given intravesically, in rats with and without bladder outflow obstruction. MATERIALS AND METHODS Female, conscious Sprague-Dawley rats, normal or with bladder hypertrophy and overactivity secondary to bladder outflow obstruction, were given ZD6169 intravesically (10 or 100 ng./ml.), and intra-arterially (1 mg./kg.). Continuous cystometry was performed. RESULTS In normal and obstructed rats, intravesical ZD6169 had similar, dose-dependent effects on bladder function. In obstructed rats, ZD6169 (100 ng./ml.) significantly decreased micturition pressure (17%), and increased bladder capacity (32%), micturition volume (18%), residual volume (145%), and inter-contraction interval (71%). There was a marked decrease in both frequency (40%) and amplitude (43%) of the spontaneous bladder activity. When given intra-arterially in obstructed rats ZD6169 increased bladder capacity (19%) and residual volume (47%) and decreased amplitude (51%), but not frequency, of the spontaneous bladder activity. CONCLUSIONS In both normal and obstructed rats, intravesical ZD6169, at the investigated doses, significantly affected bladder function. In obstructed rats, the drug markedly reduced bladder overactivity. If the results have clinical validity, intravesical ZD6169 may offer an alternative way of treating bladder overactivity in selected patients.

EFFECTS OF THE K+ CHANNEL OPENER, ZD6169, ON VOLUME AND PGE2-STIMULATED BLADDER ACTIVITY IN CONSCIOUS RATS

PURPOSE To investigate the effects of the new K(ATP) channel opener, ZD6169, shown to have an in vivo selectivity for the bladder, on bladder activity in rats. MATERIALS AND METHODS ZD6169 was given intra-arterially (i.a., 0.1 and 1 mg./kg.) or orally (3 mg./kg.) to conscious Sprague-Dawley rats undergoing continuous cystometry. Investigations were also performed before and after stimulation of bladder activity by intravesical prostaglandin (PG) E2. RESULTS Intra-arterial ZD6169 increased residual volume, but caused no changes in other cystometric parameters. In rats receiving oral ZD6169, cystometric parameters were compared (every hour up to five hours) to those recorded in rats receiving oral vehicle. No differences were found, except in threshold pressure, which was significantly increased. Intravesical PGE2 20 microM increased micturition and basal pressures, and decreased bladder capacity and micturition volume. ZD6169 1 mg./kg., given i.a., reduced or completely prevented the activity induced by intravesical PGE2. Three hours after orally administered ZD6169 (3 mg./kg.), intravesical PGE2 20 microM had no effect. Three hours after oral administration of vehicle, the effects of PGE2 were attenuated, but still statistically significant. CONCLUSIONS ZD6169, given i.a. or orally, increased threshold pressure, but had otherwise little effect on volume-induced micturition. However, the drug markedly reduced or prevented PGE2-induced bladder activity when given i.a.; it was also effective when given orally. If ZD6169 has inhibiting effects on bladder contraction in man without any cardiovascular actions, the drug may represent a novel, promising way of treating bladder overactivity.

Testosterone-induced prostatic growth in the rat causes bladder overactivity unrelated to detrusor hypertrophy

Testosterone treatment of rats produces prostatic hypertrophy and detrusor overactivity. Whether or not the detrusor overactivity can be related to an increase in the responsiveness of lower urinary tract smooth muscles is not known.