AIMS OF STUDY 

It is well known that excitation of the sympathetic nerves relaxes the bladder via activation of b-adrenoceptors during filling phase. We have demonstrated using an in vitro  functional study that the subtypes of b-adrenoceptors that contribute to the detrusor relaxation are b2- and b3-adrenoceptors in the rat (1). A rat model of detrusor hyperreflexia associated with cerebral infarction has been recently developed (2). In the present study, we investigated whether selective b2- and b3-adrenoceptor agonists could suppress detrusor hyperreflexia in conscious cerebral-infarcted rats.

METHODS 

Female Sprague-Dawley rats weighing 210-260 g (n=132) were used. Under general anesthesia with ketamine and xylazine, a catheter was implanted into the bladder through the dome and a separate catheter into the right jugular vein for drug administration. Three or four days after the operation, cystometric investigations were performed without any anesthesia as a base-line study. Then, these rats were anesthetized again with halothane and left carotid artery was exposed. Left middle cerebral artery was occuluded with a 4-0 monofilament nylon thread introduced from carotid bifurcation by 17 mm in cerebral-infarcted (CI) group. In sham-operated animals, left carotid artery was exposed, but no further procedures were performed. Two hours after the operation, cystometric investigations were repeated without any anesthesia. Then, effects of intravenous (i.v.) administration of saline (1 ml/kg: vehicle) and CL316243 (0.1-100 mg/kg), a selective b3-adrenoceptor agonist, or procaterol (0.1-100 mg/kg), a selective b2-adrenoceptor agonist on the cystometric parameters were evaluated.

RESULTS 

In the cerebral-infarcted animals, a significant (p<0.01) decrease in the bladder capacity and a significant (p<0.01) increase in the amplitude of voiding contractions were observed after occulusion of middle cerebral artery. On the other hand, the sham-operated animals did not show any changes of cystometric parameters after the operation (Fig.1A, 1B).  I.v. administration of saline (vehicle) did not affect any cystometric parameters in the CI or sham-operated group. In the CI group, CL 316243 (0.1-100 mg/kg given i.v.) increased the bladder capacity in a dose-dependent manner (Fig. 2A) without affecting the amplitude of voiding contractions and residual volumes. In the sham-operated group, no significant changes were observed after i.v. administration of CL 316243 (0.1-100 mg/kg: Fig. 2A). Procaterol, administered i.v. at 10 mg/kg, significantly (p<0.01) increased the bladder capacity in the CI group (Fig. 2B). Procaterol at 10 and 100 mg/kg also tended to increase residual volumes in the CI group, but the increase was not statistically significant. In the sham-operated group, no significant changes in the cystometric parameters were observed after i.v. administration of procaterol (0.1-100 mg/kg: Fig. 2B).

 

CONCLUSIONS 

Although neither b2- nor b3-adrenoceptor agonists affected micturition in neurologically intact rats, both the selective agonists for b2- and b3-adrenoceptor, CL 316243 and procaterol, could suppress detrusor hyperreflexia without affecting voiding efficacy in rats with cerebral infarction. Thus, selective agonists for b2- or b3-adrenoceptor might be promising drugs in the treatment of detrusor hyperreflexia associated with cerebral infarction. 

REFERENCES

1 .Br. J. Pharmacol., 124, 593, 1998

2. J. Urol., 159 577, 1998