piperidines and Cystitis

In nine separate clinical trials, 382 patients having symptoms of either prostatitis, acute cystitis, urethritis, and/or trigonitis were randomly assigned to treatment with flavoxate or phenazopyridine. Over-all response was evaluated in 384 patients after five days of therapy. In patients having prostatitis, response was satisfactory in 66 per cent treated with flavoxate and 31 per cent treated with phenazopyridine. In all other patients, satisfactory responses were reported in 80 per cent on flavoxate compared with 56 per cent on phenazopyridine. Similarly, symptom-severity evaluations at two and five days of therapy showed most symptoms improved in more of the patients on flavoxate therapy than on phenazopyridine therapy. Although more adverse effects were reported in patients treated with phenazopyridine than with flavoxate, the difference between medications was not statistically significant.

Topics: Acute Disease; Adolescent; Adult; Aged; Child; Clinical Trials as Topic; Cystitis; Female; Flavonoids; Humans; Male; Middle Aged; Parasympatholytics; Phenazopyridine; Piperidines; Prostatitis; Pyridines; Urethritis; Urinary Tract Infections

Topics: Bacteriuria; Clinical Trials as Topic; Colic; Cystitis; Female; Flavonoids; Humans; Kidney Diseases; Male; Parasympatholytics; Piperidines; Placebos; Sympatholytics; Time Factors; Urethritis; Urinary Bladder

Functional studies have shown altered cholinergic mechanisms in the inflamed bladder, which partly depend on muscarinic receptor-induced release of nitric oxide (NO). The current study aimed to characterize which muscarinic receptor subtypes that are involved in the regulation of the nitrergic effects in the bladder cholinergic response during cystitis. For this purpose, in vitro examinations of carbachol-evoked contractions of inflamed and normal bladder preparations were performed. The effects of antagonists with different selectivity for the receptor subtypes were assessed on intact and urothelium-denuded bladder preparations. In preparations from cyclophosphamide (CYP; in order to induce cystitis) pre-treated rats, the response to carbachol was about 75% of that of normal preparations. Removal of the urothelium or administration of a nitric oxide synthase inhibitor re-established the responses in the inflamed preparations. Administration of 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) inhibited the carbachol-induced contractile responses of preparations from CYP pre-treated rats less potently than controls. Pirenzepine and p-fluoro-hexahydro-sila-diphenidol (pFHHSiD) affected the carbachol-induced contractile responses to similar extents in preparations of CYP pre-treated and control rats. However, the Schild slopes for the three antagonists were all significantly different from unity in the preparations from CYP pre-treated rats. Again, L-NNA or removal of the urothelium eliminated any difference compared to normal preparations. This study confirms that muscarinic receptor stimulation in the inflamed rat urinary bladder induces urothelial release of NO, which counteracts detrusor contraction.

Topics: Animals; Carbachol; Cyclophosphamide; Cystitis; Dose-Response Relationship, Drug; Enzyme Inhibitors; Male; Muscarinic Antagonists; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Nitric Oxide Synthase; Nitroarginine; Piperidines; Pirenzepine; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Urinary Bladder; Urothelium

In cyclophosphamide-induced cystitis in the rat, detrusor function is impaired and the expression and effects of muscarinic receptors altered. Whether or not the neuronal transmission may be affected by cystitis was presently investigated. Responses of urinary strip preparations from control and cyclophosphamide-pretreated rats to electrical field stimulation and to agonists were assessed in the absence and presence of muscarinic, adrenergic and purinergic receptor antagonists. Generally, atropine reduced contractions, but in contrast to controls, it also reduced responses to low electrical field stimulation intensity (1-5 Hz) in inflamed preparations. In both types, purinoceptor desensitization with alpha,beta-methylene adenosine-5'-triphosphate (alpha,beta-meATP) caused further reductions at low frequencies (<10 Hz). The muscarinic receptor antagonists atropine, 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) ('M(1)/M(3)/M(5)-selective'), methoctramine ('M(2)-selective') and pirenzepine ('M(1)-selective') antagonized the tonic component of the electrical field stimulation-evoked contractile response more potently than the phasic component. 4-DAMP inhibited the tonic contractions in controls more potently than methoctramine and pirenzepine. In inflamed preparations, the muscarinic receptor antagonism on the phasic component of the electrical field stimulation-evoked contraction was decreased and the pirenzepine and 4-DAMP antagonism on the tonic component was much less efficient than in controls. In contrast to controls, methoctramine increased -- instead of decreased -- the tonic responses at high frequencies. While contractions to carbachol and ATP were the same in inflamed and in control strips when related to a reference potassium response, isoprenaline-induced relaxations were smaller in inflamed strips. Thus, in cystitis substantial changes of the efferent functional responses occur. While postjunctional beta-adrenoceptor-mediated relaxations are reduced, effects by prejunctional inhibitory muscarinic receptors may be increased.

Topics: Adenosine Triphosphate; Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Animals; Cyclophosphamide; Cystitis; Diamines; Electric Stimulation; In Vitro Techniques; Male; Muscarinic Antagonists; Muscle Contraction; Parasympatholytics; Phentolamine; Piperidines; Pirenzepine; Propranolol; Purinergic P2 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Suramin; Sympatholytics; Urinary Bladder

The role of neurokinin 1 (NK(1)) receptor and possible interaction between NK(1) and N-methyl-D-aspartic acid (NMDA) glutamatergic receptors were investigated on spinal c-fos expression after lower urinary tract irritation with acetic acid infusion in rats. At both levels of the first (L(1)) and sixth lumbar (L(6)) spinal cord, where most of hypogastric nerve and pelvic nerve afferent terminals project, respectively, the selective NK(1) receptor antagonist CP-99,994 dose dependently reduced the total number of c-fos protein (Fos)-positive cells. However, CP-100,263, the enantiomer of CP-99,994 with a very low affinity for NK(1) receptor, did not have any effect on the total number of Fos-positive cells. Coadministration of a low dose (1 mg/kg) of CP-99,994 and NMDA receptor antagonist (MK-801), either of which alone did not affect c-fos expression, significantly inhibited c-fos expression at both levels of the spinal cord. Regarding regional differences, the number of Fos-positive cells decreased significantly at all regions of the L(6) level, but only at the dorsal horn of the L(1) level. These results indicate that NK(1) receptor is involved in spinal c-fos expression after lower urinary tract irritation and that NK(1) and NMDA receptors have a synergistic interaction in the spinal processing of nociceptive input from the lower urinary tract.

Topics: Acetic Acid; Animals; Cystitis; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Irritants; Nociceptors; Piperidines; Proto-Oncogene Proteins c-fos; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurokinin-1; Spinal Cord; Urinary Bladder

The present study was conducted to investigate the role of NK(1) receptors and of nitric oxide (NO) on the pathogenesis of cyclophosphamide-induced cystitis, in rats. This bladder toxicity was characterized by marked increases in protein plasma extravasation, urothelial damage, edema, white blood cell infiltrates, and vascular congestion. These changes were associated with appearance of Ca(2+)-independent NO-synthase (NOS) activity [characteristic of inducible NOS (iNOS)] in the bladder and with increases in urinary NO metabolites. GR205171, a selective NK(1) antagonist (10-20 mg/kg, i.p.) reduced cyclophosphamide-induced increases in protein plasma extravasation and in the urinary excretion of NO metabolites. N(G)-Nitro-L-arginine (L-NNA) (10 mg/kg, i.p.), a NOS inhibitor, reduced basal and cyclophosphamide-induced increases in NO metabolites and protected against cyclophosphamide-induced protein plasma extravasation. GR205171 had no effect, whereas L-NNA reduced basal NO metabolite excretion. Combined treatment with the NK(1) antagonist and the NO-synthesis inhibitor produced comparable reduction in protein plasma extravasation than that achieved with each drug given separately. Combined drug treatment ameliorated cyclophosphamideinduced urothelial damage, and the extent of edema, vascular congestion, and white blood cell infiltrates in the bladder. In summary, NK(1) receptors and iNOS play a role in NO formation and on cyclophosphamide-induced cystitis. Activation of NK(1) receptors mainly acts through the formation of NO. It is proposed that cyclophosphamide and/or its metabolites would stimulate primary afferent capsaicin-sensitive fibers in the bladder, releasing neuropeptides, which would activate NK(1) receptors. However, additional mechanisms are involved, because neither the NK(1) receptor antagonist nor the NO synthesis inhibitor, either alone or in combination, were able to completely prevent the toxicity.

Topics: Animals; Blood Proteins; Capillary Permeability; Cyclophosphamide; Cystitis; Drug Interactions; Enzyme Inhibitors; Evans Blue; Extravasation of Diagnostic and Therapeutic Materials; Male; Neurokinin-1 Receptor Antagonists; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; Nitroarginine; Piperidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Tetrazoles; Urinary Bladder

The intraperitoneal administration of cyclophosphamide (150 mg/kg, 48 h before cystometry) induced detrusor hyperreflexia in urethane-anaesthetized rats. Intrathecal administration of the selective tachykinin NK1 receptor antagonist, GR 82,334 ([D-Pro9(spiro-gamma-lactam)Leu10,Trp11]physalaemin-(1-11)) (1 nmol/rat i.t.) had no significant effect on micturition in normal rats but increased the volume threshold In cyclophosphamide-treated rats. Another tachykinin NK1 receptor antagonist, RP 67,580 ((3aR,7aR)-7,7-diphenyl-2-[1-imino-2(2-methoxyphenyl)ethyl]+ ++perhydroisoindol -4-one) (10 nmol/rat i.t.) increased the volume threshold to a similar extent in both vehicle- and cyclophosphamide-treated animals. The tachykinin NK2 receptor antagonist, SR 48,968 (S7-N-methyl-N[4-(acetylamino-4-phenylpiperidino)-2-(3,4- dichlorophenyl)butyl]benzamide hydrochloride (10 nmol/rat i.t.) did not modify micturition parameters in normal rats but antagonized bladder hyperreflexia in cyclophosphamide-treated animals; SR 48,968 restored the volume threshold for the micturition reflex to values close to control values. SR 48,965 (R7-N-methyl-N[4-(acetylamino-4-phenylpiperidino)-2-(3,4- dichlorophenyl)butyl]benzamide hydrochloride) (10 nmol/rat i.t.), the enantiomer of SR 48,968 devoid of affinity for tachykinin NK2 receptors, was inactive. 2-Amino-5-phosphonovaleric acid (25 and 250 nmol/rat i.t.), a selective antagonist of NMDA receptors, augmented the volume threshold both in controls and in rats with detrusor hyperreflexia; after administration of this antagonist, however, the volume threshold in cyclophosphamide-treated animals was still lower than in controls. Intravenous administration of SR 48,968, RP 67,580, or the combined administration of SR 48,968 and RP 67,580 had no effect on cystometry variables either in rats with detrusor hyperreflexia or in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2-Amino-5-phosphonovalerate; Animals; Benzamides; Cyclophosphamide; Cystitis; Indoles; Injections, Intravenous; Injections, Spinal; Isoindoles; Male; Neurokinin-1 Receptor Antagonists; Physalaemin; Piperidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Spinal Cord; Urinary Incontinence; Urination

Topics: Administration, Oral; Adult; Analgesics; Cystitis; Dioxoles; Female; Hemorrhage; Humans; Hydronephrosis; Kidney Calculi; Male; Middle Aged; Piperidines; Prostatitis; Tuberculosis, Urogenital; Ureteral Diseases; Urologic Diseases