Dual, but not selective, COX-1 and COX-2 inhibitors, attenuate acetic acid-evoked bladder irritation in the anaesthetised female cat.

Non-selective cyclooxygenase (COX) inhibitors exert effects on lower urinary tract function in several species. The exact contributions of COX-1 and COX-2 isozymes have not been studied much. The present studies investigated the effects of non- and selective COX inhibitors on bladder irritation in the cat.Chloralose-anaesthetised female cats were catheterised through the bladder dome for cystometric evaluation of bladder responses to intravesical infusion of saline or acetic acid. Bladder capacity, voiding efficiency, threshold pressure, and reflex-evoked bladder contraction amplitude and duration were measured. The cat COX selectivity of the doses of inhibitors examined was determined using an in vitro whole-blood assay and analysis of plasma levels. Pretreatment with indomethacin or ketoprofen (non-selective COX inhibitors; 0.3 mg kg(-1) i.v.) inhibited acetic acid-evoked irritation (characterised by a decrease in bladder capacity in vehicle pretreated animals). FR-122047 (selective COX-1 inhibitor), NS-398 and nimesulide (selective COX-2 inhibitors; 1 and 3 mg kg(-1) i.v.) had no effects on bladder irritation. Analysis of plasma levels of the doses examined and determination of COX-1 and COX-2 inhibition in cat whole blood confirmed the reported selectivity of these compounds in this species. The present studies suggest that dual COX inhibition is required to attenuate acetic acid-evoked bladder irritation in the cat.

Urotensin-II: a novel systemic hypertensive factor in the cat.

Urotensin-II, a potent mammalian vasoconstrictor, may play a role in the etiology of essential hypertension. However, a species suitable for assessing such a role, one where a "classical" systemic hypertensive response (increase in mean blood pressure and systemic vascular resistance) is observed following bolus i.v. urotensin-II administration, has yet to be identified. The present study demonstrates that the cat may represent such a species since urotensin-II potently (pEC(50)s 9.68+/-0.24-8.73+/-0.08) and efficaciously (E(max) 73+/-15%-205+/-21% KCl) constricts all feline isolated arteries studied (aortae, renal, femoral, carotid, and mesenteric conduit/resistance). Accordingly, exogenous urotensin-II (1 nmol/kg, i.v.) effectively doubles both mean blood pressure (from 99+/-14 to 183+/-15 mmHg) and systemic vascular resistance (from 0.36+/-0.12 to 0.86+/-0.20 mmHg/ml/min) in the anaesthetized cat (without altering heart rate or stroke volume). Thus, in view of these profound contractile effects, the cat could be suitable for determining the effects of urotensin-II receptor antagonism on cardiovascular homeostasis in both normal and diseased states.

Expression and functional role of Rho-kinase in rat urinary bladder smooth muscle.

(1) The involvement of Rho-kinase (ROCK) in the contractile mechanisms mediating smooth muscle contraction of the rat urinary bladder was investigated using expression studies and the ROCK inhibitor Y-27632. (2) Both isoforms of ROCK (ROCK I and ROCK II) were detected in high levels in rat urinary bladder. (3) Y-27632 (10 micro M) significantly attenuated contractions of rat urinary bladder strips evoked by the G-protein coupled receptor agonists carbachol (58.1+/-10.5% at 0.3 micro M) and neurokinin A (68.6+/-12.7% at 1 micro M) without affecting contractions to potassium chloride (10-100 mM). In addition, basal tone was reduced by 47.8+/-2.0% by 10 micro M Y-27632 in the absence of stimulation. (4) Contractions of urinary bladder strips evoked by the P2X receptor agonist alpha,beta-methylene ATP (alpha,beta-mATP; 10 micro M) were also attenuated by Y-27632 (30.0+/-7.2% at 10 micro M). (5) Y-27632 (10 micro M) significantly attenuated contractions evoked by electrical field stimulation (2-16 Hz). The effect of Y-27632 on the tonic portion of the neurogenic response (4-16 Hz) was not significantly different from the effect of atropine (1 micro M) alone. (6) While the mechanism underlying the ability of Y-27632 to inhibit alpha,beta-mATP-evoked contractions remains undetermined, the results of the present study clearly demonstrate a role for ROCK in the regulation of rat urinary bladder smooth muscle contraction and tone.

An investigation of the effects of zaprinast, a PDE inhibitor, on the nitrergic control of the urethra in anaesthetized female rats.

1. The effects of L-NAME and zaprinast were investigated (i.v.) on reflex-evoked changes in bladder and urethral pressures in urethane-anaesthetized female rats. 2. L-NAME attenuated reflex-evoked urethral relaxations (65+/-10%), while zaprinast potentiated these responses (68+/-24%). L-NAME and zaprinast also increased baseline urethral pressure and urethral striated muscle (EUS-EMG) activity. These drugs had little effect on the bladder. 3. Following pre-treatment with alpha-bungarotoxin (i.v.) to block urethral striated muscle, L-NAME and zaprinast failed to increase baseline urethral pressure. Further zaprinast failed to alter the size of reflex-evoked urethral relaxations. 4. Intra-urethral zaprinast caused a significant increase while sodium nitroprusside (SNP) and isoprenaline caused decreases in urethral pressure (+14+/-3%, -25+/-5%, -29+/-7%, respectively). These changes were associated with increases in EUS-EMG activity. After chlorisondamine (i.v.), zaprinast caused a significant fall in urethral pressure, while the decrease in urethral pressure caused by SNP and isoprenaline was potentiated. No changes in EUS-EMG activity occurred. 5. These results indicate that a nitrergic pathway mediates reflex-evoked urethral smooth muscle relaxations. The data also indicates that there is a background release of NO, which reduces sphincter skeletal muscle activity. Further, the ability of zaprinast to potentiate nitrergic evoked urethral relaxations involves an increase in striated muscle tone. This appears to be an indirect result of smooth muscle relaxation and is mediated, at least in part, by a chlorisondamine-sensitive mechanism.