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1. Experiments were done to determine the influence of gender and the oestrous cycle on rat urinary bladder contractility in response to cholinergic stimulation. 2. Bladder strips from female rats responded to high frequency stimulation with smaller contractile responses than did strips from males, and to low concentrations of carbachol with greater responses. The decreased responsiveness of bladder strips from female rats to electrical field stimulation can be primarily attributed to the rats in the oestrous stage of the oestrous cycle. 3. Bladder strips from female rats in all stages of the oestrous cycle were more sensitive to carbachol than those from males, but there were no differences in sensitivity to electrical field stimulation. 4. The contractile responses of strips from both male and female rats to carbachol were antagonized by muscarinic antagonists with the following rank order of affinity (pA(2)) estimates: 4-DAMP>>pirenzepine>methoctramine, suggesting that the receptor mediating contraction was the M3 subtype. There were no differences in pA(2) values between bladder strips from male and female rats. 5. The data indicate that responsiveness of bladder strips to electrical field stimulation and carbachol is altered in female rats in the oestrous stage of the oestrous cycle. Furthermore, gender influences the sensitivity of rat bladder to muscarinic stimulation.

1. Isoproterenol relaxed KCl-precontracted rat bladder strips with a pD2 of 7.21 leaving a residual contractile response of 3.2% after 30 microM. The selective beta1-agonist, T-0509 (pD2 : 6.24, 10.1% residual contraction after 100 microM), beta2-agonist, terbutaline (pD2 : 5.43, 13.7% residual contraction after 100 microM), and beta3-agonists, BRL 37344A (pD2 : 6.60, 17.3% residual contraction after 100 microM), and SR 58611A (pD2 : 5.15, 34.0% residual contraction after 100 microM), also relaxed bladder strips. 2. The relaxant response to isoproterenol was weakly but significantly antagonized by 1 microM propranolol which produced a 3 fold shift of the concentration-response curve to the right, and significantly antagonized by the beta1-selective antagonist, metoprolol (10 microM, 3 fold shift), and the beta2-selective antagonist, butoxamine (100 microM, 6 fold shift). A combination of 10 microM metoprolol and 100 microM butoxamine caused a 15 fold shift of the concentration-response curve for isoproterenol to the right. Incubation with the beta3-antagonist, SR 59230A (1 microM), caused a 6 fold shift of the concentration response curve for isoproterenol to the right. 3. The non-conventional partial agonist, CGP 12177A, weakly relaxed KCl-precontracted bladder strips (pD2 : 3.31, 51.3% residual contraction after 300 microM); the relaxation was resistant to blockade by 1 or 10 microM propranolol. 4. In the presence of 200 microM propranolol, CGP 12177A (20 microM) or SR 59230A (10 microM) antagonized surmountably the relaxant effects of BRL 37344A. 5. The data suggest that rat urinary bladder body contains beta1, beta2, and beta3-adrenoceptors, all of which mediate relaxation.

1. The effects of phosphodiesterase (PDE) inhibition and forskolin pretreatment on the contractile responses of guinea-pig urinary bladder strips to electrical field stimulation, carbachol, ATP and KCl were studied. 2. Inhibition of cyclic AMP-specific PDE4 isozymes by rolipram significantly reduced the contractile response of bladder strips to field stimulation. Rolipram also suppressed the contractile response to low concentrations of carbachol, but potentiated the response to high concentrations. The contractile response to ATP was significantly reduced by rolipram treatment, but that to KCl was unaltered. 3. Inhibition of cyclic GMP-specific PDE5 isozymes by zaprinast had no effects on the contractile response of bladder strips to field stimulation, ATP or KCl. Zaprinast suppressed the contractile responses to 1 microM carbachol and potentiated the response to high concentrations. 4. Contractile responses to field stimulation and to carbachol after pretreatment with the adenylyl cyclase activator, forskolin, were qualitatively similar to those caused by rolipram treatment. beta-Adrenoceptor blockade with propranolol partially reversed the inhibitory effects of rolipram on the response to field stimulation. 5. Rolipram significantly reduced the contractile response of bladder strips from sensitized guinea-pigs to ovalbumin challenge, but zaprinast was ineffective. PDE inhibition had similar effects on the responsiveness of control and of sensitized guinea-pig bladder strips to field stimulation, carbachol, ATP and KCl. 6. The data suggest that the contractile response of guinea-pig bladder strips can be modified by increases in cyclic AMP levels.

1. Muscarinic receptors mediating contraction of the rat urinary bladder were characterized functionally in vitro by use of atropine, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP methiodide), 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride (4-DAMP mustard), hexahydro-sila-diphenidol hydrochloride (HHSiD), the p-fluoro analogue of hexahydro-sila-diphenidol hydrochloride (p-F-HHSiD), methoctramine, and pirenzepine. 2. (+)-cis-Dioxolane contracted bladder strips in a concentration-dependent manner with an EC50 of 0.169 +/- 0.018 microM and an Emax of 7.84 +/- 0.67 g. 3. Concentration-effect curves to (+)-cis-dioxolane were shifted to the right in the presence of the antagonists in a concentration-dependent manner. The rank order of antagonist affinities against the (+)-cis-dioxolane response was (pA2 values in the parentheses) atropine (9.28) > or = 4-DAMP methiodide (9.04) > HHSiD (8.01) > p-F-HHSiD (7.28) = pirenzepine (7.12) > or = methoctramine (6.77, 7.25). The profile resembles that associated with the M3 receptor subtype. 4. Atropine, 4-DAMP methiodide, pirenzepine, and methoctramine had no effects on the contractile response to 120 mM KCl. However, HHSiD and p-F-HHSiD decreased the response to KCl, and 4-DAMP mustard increased it. 5. Contractile responses to electrical field stimulation (1-32 Hz, 0.05 ms pulse duration) were biphasic in nature. The tonic response was suppressed more than the phasic response by all antagonists except methoctramine. The suppression was not always concentration-dependent, and did not seem to be related to antagonism of any one receptor subtype. 6. Our findings are consistent with the minority M3 receptors mediating the contractile response to muscarinic stimulation by (+)-cis-dioxolane in the rat bladder.

1. The responses of bladder strips from control, streptozotocin-diabetic, and sucrose-drinking rats to electrical field stimulation were investigated. Sucrose-drinking rats were included as additional controls because they have enlarged bladders as a result of non-diabetic diuresis. 2. Bladder strips from diabetic rats developed more spontaneous activity than those from the two control groups. Indomethacin reduced the amplitude and frequency of spontaneous contractions suggesting that they resulted from endogenous prostaglandin formation. Tetrodotoxin (TTX) had little effect, while alpha, beta-methylene ATP caused increases in spontaneous activity. 3. Bladder strips from diabetic rats responded to field stimulation with greater contractions than controls in the absence of antagonists as well as in the presence of atropine and alpha, beta-methylene ATP. Increasing TTX concentrations caused a step-wise depression of the contractile response to electrical stimulation which was not affected by preincubation with either atropine or alpha, beta-methylene ATP. 4. Atropine and indomethacin had no effect on strength-duration curves constructed to measure threshold contractile responses to five pulses stimulation. The curves were shifted to the right by both TTX and alpha, beta-methylene ATP, indicating that the responses were neurogenic in nature and at least partially, the result of stimulation of P2-purinoceptors. In the absence of drugs, bladder strips from diabetics responded at lower voltages and pulse widths than those of control and sucrose-drinking rats, suggesting that they were more excitable. 5. The response curve of bladder strips from diabetics to field stimulation at increasing voltage was shifted upwards and to the left compared to strips from control or sucrose-drinking rats. 6. Bladder strips from diabetics responded to stimulation at increasing pulse width with greater responses than those from control or sucrose-drinking rats. At 1.0 ms pulse width, the TTX-resistant response of strips from diabetic rats was still greater than that of the other groups, indicating that a myogenic component was also involved.7. The data suggest that bladder strips from diabetic rats are more excitable than those of control or sucrose-drinking rats. This may result from diabetes-induced decreases in bladder lipid or other membrane changes, and/or be a result of partial depolarization, perhaps related to diabetic neuropathy.

Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (65 mg kg-1). Rabbits were rendered diabetic by injecting alloxan (100 mg kg-1) into the lateral ear vein. Diabetes was confirmed by a significant elevation of serum glucose in both species 8 weeks after injection. The maximum contraction to noradrenaline (NA), 5-hydroxytryptamine (5-HT) and KCl was markedly diminished in thoracic aortic rings (AR) from diabetic rats with no change in the EC50 of the agonists. There were no differences in the contractile properties of AR from diabetic rabbits to NA, 5-HT or KCl. Diabetes did not alter the responsiveness of AR from the rat to angiotensin II (AII). However, AR from diabetic rabbits displayed a decreased maximal contraction and an increased EC50 to AII. The magnitude of the acetylcholine-induced relaxation to precontracted AR was not different between diabetic and control rats and rabbits. The contractile responses of AR to NA, 5-HT and KCl were depressed in diabetic rats, regardless of the control tissue to which they were compared. The decrease in maximal contraction to NA, 5-HT and KCl seen in diabetic animals was prevented by insulin replacement. The results demonstrated that while both rats and rabbits exhibited a similar degree of hyperglycemia after treatment with a diabetogenic agent, aortic preparations from the rabbit are not affected in the same way as the aorta from the diabetic rat when exposed to NA, 5-HT and KCl. This feature may be related to the marked differences between the extent of sympathetic innervation of the aorta in the rabbit and rat. Furthermore, the decrease in maximal contraction in rat aorta was non-specific with respect to agonists since it could also be demonstrated with KCl. Therefore, it follows that the diabetic state may affect processes responsible for contraction beyond the level of receptor activation.