C. A. Maggi

Cystometric Evidence that Capsaicin-Sensitive Nerves Modulate the Afferent Branch of Micturition Reflex in Humans

Intravesical instillation of capsaicin (0.1 to 10 microM) in six patients (five with hypersensitive disorders of the lower urinary tract, one with benign prostatic hyperplasia) produced a concentration-related reduction of the first desire to void, bladder capacity and pressure threshold for micturition. At a threshold concentration of one microM, capsaicin also produced a warm to burning sensation referred to the suprapubic area during the collecting phase and to the urethra during micturition. All the patients with hypersensitive disorders of the lower urinary tract reported disappearance or marked attenuation of their symptoms for a few days after capsaicin application. In three other patients with hypersensitive disorders of the lower urinary tract, intravesical instillation of capsaicins vehicle (0.1% ethanol in saline) did not produce significant cystometric changes nor modify the symptomatology. These observations provide the first indication that capsaicin-sensitive structures (nerves?) may be present in the human urinary bladder as they have been shown to occur in various other species.

Intravesical Capsaicin for Treatment of Severe Bladder Pain: A Randomized Placebo Controlled Study

PURPOSE Present therapeutic approaches to control bladder pain are clinically and scientifically unsatisfactory, and pain in the lower urinary tract remains a challenge even to the skilled urologist. A randomized placebo controlled study was done to evaluate intravesical capsaicin for severe bladder pain. Followup was 6 months. MATERIALS AND METHODS A total of 36 patients was prospectively randomized into those receiving 10 microM. intravesical capsaicin twice weekly for 1 month (group 1) or placebo (group 2). All patients had pelvic pain for at least 6 months, and had no urinary tract infection within the last 3 months, functional disorders of the lower urinary tract, or other vesical or urethral pathology. Pretreatment voiding pattern and pain score were recorded. Patients were evaluated immediately at the end of treatment (primary end point) and 6 months later (secondary end point). RESULTS Both groups were adequately homogeneous with regard to age, sex ratio, duration of disease, voiding pattern and pain score. At both end points group 1 had significant improvement in frequency and nocturia but no improvement in urgency. No change was noted in group 2. A significant decrease in pain score was found in group 1 at the primary (mean plus or minus standard deviation 3.22 +/- 0.42, p < 0.01) and secondary (3.83 +/- 0.47, p < 0.01) end points compared to before treatment (5.61 +/- 0.40, chi-square with 2 degrees of freedom 29.25, p < 0.0001). A significant improvement was also observed in the placebo group, in which the pretreatment pain score (5.47 +/- 0.37) was decreased at the primary (4.47 +/- 0.36, p < 0.01) and secondary (4.48 +/- 0.34, p < 0.01, chi-square with 2 degrees of freedom 12.71, p < 0.002) end points. There were no statistically significant differences between the 2 groups. CONCLUSIONS We confirmed the beneficial effect of intravesical instillation of capsaicin on voiding pattern in patients with hypersensitive disorders (frequency and nocturia). We could not confirm improvement in pain score after capsaicin treatment compared to placebo. Possibly a larger dose of capsaicin would be more effective in controlling pain and neurological disease of the bladder.

Tachykinin antagonists inhibit nerve-mediated contractions in the circular muscle of the human ileum: Involvement of neurokinin-2 receptors

The effects of some newly developed tachykinin antagonists that are selective for the neurokinin (NK)-1 (L 668,169) or the NK-2 (MEN 10,207, L 659,877 and R 396) tachykinin receptor on the cholinergic and noncholinergic contraction and on the nonadrenergic noncholinergic relaxation produced by electrical field stimulation (50 Hz) were investigated in mucosa-free circular strips of the human ileum. The strips were contracted by substance P and neurokinin A as well as by selective NK-2-receptor ligands, [beta Ala8]neurokinin A(4-10), and MDL 28,564, the latter peptide being capable of discriminating between NK-2-receptor subtypes. The selectivity of the antagonists for NK-1 or NK-2 receptors was confirmed in pharmacological experiments using substance P, neurokinin A, and [beta Ala8]neurokinin A(4-10) as stimulants. Among the NK-2-selective antagonists, MEN 10,207 displayed the highest affinity, followed by L 659,877 and R 396. The antagonists MEN 10,207 and L 659,877 inhibited the noncholinergic contraction to electrical stimulation in a concentration-dependent manner; L 668,169 and R 396 were poorly effective. Thus the potency of antagonists toward the noncholinergic response closely paralleled their rank order of potency at NK-2 receptors. The cholinergic contraction and nonadrenergic noncholinergic relaxation were not inhibited by the antagonists. Both substance P- and neurokinin A-like immunoreactivities were detected in extracts of the human ileum, and the identity of the corresponding peptides was confirmed by reverse-phase high-performance liquid chromatography. It was concluded that in addition to NK-1 receptors, the circular muscle of the human ileum also contains NK-2 receptors. Activation of the latter is chiefly responsible for the noncholinergic contraction to nerve stimulation.

Anti-ulcer activity of calcitonin gene-related peptide in rats

Calcitonin gene-related peptide (CGRP, 5-10 micrograms/kg s.c.). reduced both incidence and degree of indomethacin- or acetylsalicylic acid (ASA) plus HCl-induced gastric as well as cysteamine-induced duodenal ulcers in rats. CGRP had no effect on ethanol-induced gastric lesions. The anti-ulcer activity of CGRP is most likely ascribable to its potent antisecretory properties.

EFFECT OF TACHYKININ NK2 RECEPTOR BLOCKADE ON DETRUSOR HYPERREFLEXIA INDUCED BY BACTERIAL TOXIN IN RATS

PURPOSE To see whether a recently characterized model of bacterial toxin-induced urinary bladder inflammation (Stein et al., J. Urol. 155, 1133-1138, 1996) is associated with detrusor hyperreflexia, and whether endogenous tachykinins acting through NK2 or NK1 receptors were involved in this model. MATERIALS AND METHODS The bladder of urethane-anesthetized male Wistar rats was cannulated through the dome. Intravesical administration of protamine sulfate (PS, 10 mg./ml./rat) or vehicle for 1 hour was followed by the intravesical administration of E. coli lipopolysaccharide (LPS, 1 mg./ml./rat) or vehicle for 1 hour. Cystometries (50 microl./min.) were performed 3.5 hours after the exposure to LPS. MEN 11,420, a peptide tachykinin NK2 receptor antagonist, was administered before cystometries or, in a separate group of animals, during cystometries. The effect of SR 140,333, a non-peptide NK1 receptor antagonist, was also assessed in the presence or absence of MEN 11,420. The urodynamic effects of PS + LPS were also tested in capsaicin-pretreated rats. RESULTS Unlike PS or LPS alone, the intravesical administration of PS + LPS induced detrusor hyperreflexia. In PS + LPS treated animals during nonstop cystometries, the intermicturition interval was decreased by about 50% as compared to vehicle-pretreated rats. A quantitatively similar reduction in the bladder capacity was also observed. MEN 11,420 (100 nmol./kg., i.v.) restored the intermicturition interval in PS + LPS-pretreated rats at the level of controls by increasing the bladder capacity, whereas it had no effect in vehicle-pretreated rats. SR 140,333 (1 micromol./kg., i.v.) neither modified urodynamic parameters in controls and in PS + LPS-treated rats nor altered the effect of MEN 11,420 in these groups. Capsaicin pretreatment (164 micromol./kg., s.c., 4-5 days before) induced a two-fold increase of the bladder capacity in control rats and prevented PS + LPS-induced bladder hyperreflexia. CONCLUSIONS The intravesical administration of PS + LPS produces the activation of capsaicin-sensitive afferents. Endogenous tachykinins released from these fibers act through NK2 receptors to induce detrusor hyperreflexia.

Specific motor effects of capsaicin on human jejunum

Capsaicin (1 microM) produced a biphasic effect on the motility of longitudinal muscle strips from human jejunum e.g. an initial inhibitory effect on nerve-mediated contractions followed by a delayed increase in motility. Neither effect was observed upon a second application of the drug, indicating desensitization, a proposed marker of the action of capsaicin on sensory nerves. Both substance P and neurokinin A produced a contraction of isolated human jejunum, while calcitonin gene-related peptide had a small and inconsistent inhibitory effect.

Multiple sites of action in the inhibitory effect of nociceptin on the micturition reflex

PURPOSE Nociceptin, the endogenous peptide ligand for the opioid receptor-like1 (ORL1) receptors, exerts a naloxone-resistant suppressant effect on micturition reflex after intravenous administration. This work aims to elucidate the mechanism and the site of action of the inhibitory effect of nociceptin on the micturition reflex. MATERIALS AND METHODS The bladder of urethane-anesthetized rats was cannulated through the dome (cystometries) or the urethra in isovolumetric conditions (distension-induced reflex contractions, DIRCs). In this latter model, the effect of the application of nociceptin onto the serosal surface of the urinary bladder was determined. The effect of intravenous, intrathecal and intracerebroventricular administration of nociceptin on ongoing cystometries at two different infusion rates (50 and 250 microL/min.) was assessed. The effect of the intravenous administration of nociceptin on cystometries was also studied in capsaicin-pretreated animals. RESULTS When cystometric recordings were obtained at a low infusion-rate (50 microL/min.), the intravenous administration of nociceptin (10 to 100 nmol./kg.) induced a dose-dependent reduction in the micturition frequency associated to an increase of the pressure threshold for activating the micturition reflex, whereas the amplitude of micturition contractions was unaffected. These effects faded within 60 minutes. The intracerebroventricular administration of nociceptin (0.3 nmol./rat) produced urodynamic changes similar to those observed after the intravenous route and, in addition, also reduced the amplitude of micturition contractions. The intrathecal administration of nociceptin up to 1 nmol./rat was ineffective. Capsaicin pretreatment (164 micromol./kg., s.c. 5 to 6 days before) significantly reduced the micturition frequency as compared with controls. In capsaicin pretreated animals intravenous nociceptin was ineffective. When cystometries were recorded at a high infusion-rate (250 microL/min.) either intravenous (100 nmol./kg.), i.t. (1 nmol./rat) nociceptin or capsaicin pretreatment had no effect. In contrast, intracerebroventricular nociceptin (0.3 and 1 nmol./rat) inhibited the micturition reflex by reducing both the frequency and the amplitude of micturition contractions: these effect were not modified by naloxone (0.5 micromol./kg., i.v.). The topical application of nociceptin (5 and 50 nmol./rat) caused a dose-dependent inhibition of DIRCs. CONCLUSION Nociceptin inhibits the micturition reflex at a peripheral and at a supraspinal site. The effects observed after the intravenous administration of nociceptin indicate that the functional integrity of capsaicin-sensitive bladder afferents is required for exerting its inhibitory activity at the peripheral level. In contrast, the supraspinal effect of nociceptin involves both the afferent and the efferent pathways of the micturition reflex, possibly through a direct effect on ORL1 receptors located in the pontine micturition center.

Contractile responses of the human urinary bladder, renal pelvis and renal artery to endothelins and sarafotoxin S6b

1. Endothelin-1 (ET-1), endothelin-3 (ET-3) and sarafotoxin S6b (SRFTX) produced a concentration-dependent tonic contraction of the human isolated urinary bladder, renal pelvis and renal artery with threshold at nM concentration. 2. In the bladder, the following order of potency was found: ET-1 greater than SRFTX greater than ET-3. In the renal pelvis, all peptides displayed similar affinity but, at high concentrations the maximal response was highest for SRFTX followed by ET-1 and ET-3. In the renal artery ET-1 and SRFTX were about equipotent and equieffective while ET-3 produced only a slight and inconsistent (2 out of 5 cases) vasoconstrictor response. 3. As shown previously for the human bladder muscle, the response to ET-1 in the renal pelvis was nifedipine (1 microM)-resistant while a consistent fraction of the response was blocked by nifedipine in the human renal artery. 4. These findings indicate that peptides of the endothelin family exert a potent contractile effect on various human smooth muscles. Participation of dihydropyridine- and voltage-sensitive calcium channels in the contractile response produced by these peptides may vary from one organ to another.