Noradrenaline inhibits autonomous activity in the isolated guinea pig bladder

OBJECTIVE: To investigate the actions of noradrenaline and the specific alpha-adrenergic agonists cirazoline (alpha1) and UK14304 (alpha2), and beta-receptor agonists formoterol (beta2) and BRL37344 (beta3) on the phasic activity induced by muscarinic stimulation on the isolated guinea pig bladder, as the physiological significance of this activity is unknown but it may underlie non-micturition contractions (NMCs, which can be inhibited by sympathetic nerve stimulation) and the generation of bladder sensations. MATERIALS AND METHODS: All experiments were conducted using whole isolated bladders from female guinea pigs (270-300 g). Bladders were cannulated via the urethra and suspended in a heated chamber containing oxygenated Tyrode's solution at 33-35 degrees C and the intravesical pressure recorded. All drugs were added to the solution bathing the abluminal surface. RESULTS: Exposure to noradrenaline reduced the amplitude and frequency of the phasic activity. When noradrenaline was washed off there was a transient increase in frequency. There was marked desensitization with repeated applications of noradrenaline. Applying the specific beta3-agonist BRL37344 reduced the amplitude of the phasic activity while formoterol, a specific beta2-agonist, had no effect. Cirazoline, a specific alpha1-agonist, reduced the amplitude of the responses and significantly reduced the frequency of the phasic activity. UK14304, a specific alpha2-agonist, had no effect. Stimulation of the hypogastric nerve to the guinea pig bladder generates contractions. Prolonged nerve stimulation at low frequency (6.5 Hz) generated phasic rises in intravesical pressure which were inhibited by noradrenaline. Using short (5 s) periods of stimulation noradrenaline inhibited nerve-mediated contractions at all frequencies but was more effective at <10 Hz. CONCLUSION: These experiments show that sympathomimetic stimulation in the isolated whole bladder results primarily in an inhibition of phasic activity, but also a stimulation. Two receptor subtypes appear to be involved in the inhibition, alpha1 and beta3, suggesting that there may be many sites of action. These results are discussed in terms of the possible physiological significance of phasic activity and the potential importance of its inhibition, in the context of the causes of pathological changes in the bladder, particularly those associated with bladder overactivity, and the pharmacological approach to the alleviation of clinical symptoms.