brl-37344 and Hypertension

beta-Adrenoceptors mediate urinary bladder relaxation, and gender, age and hypertension have been linked to bladder dysfunction. Therefore, we have studied whether any of these factors affects the ability of beta-adrenoceptor agonists to relax rat bladder detrusor muscle in vitro. For this purpose we have compared male and female Wistar rats, young and old male Wistar rats, and male normotensive and spontaneously hypertensive rats (SHR). Comparisons were done using KCl-precontracted bladder strips (length about 15-20 mm) and the endogenous agonist noradrenaline, the synthetic non-subtype-selective agonist isoprenaline, and the prototypical beta(3)-adrenoceptor agonists BRL 37,344 and CGP 12,177. While all agonists yielded numerically weaker relaxation in female as compared to male rats (for example for noradrenaline E(max) 40+/-4% vs 53+/-6% relaxation, pEC(50) 5.41+/-0.13 vs 5.60+/-0.14), this difference reached statistical significance only for the weak partial agonist CGP 12,177. Responses to all agonists were attenuated in old as compared to young rats, largely due to a reduced maximum effect, although the difference did not reach statistical significance for isoprenaline. The maximum relaxation responses to noradrenaline and isoprenaline were significantly lower in SHR than in normotensive rats, but both strains exhibited similar responses to the partial agonist BRL 37,344. We conclude that factors associated with bladder dysfunction, such as gender, age and hypertension, can be associated with impaired beta-adrenoceptor-mediated bladder relaxation. However, these alterations are not always consistent across various agonists, and the extent of the differences can be small. Therefore, we propose that beta-adrenoceptor dysfunction may contribute to the pathophysiology of such conditions, but is unlikely to be the only or even the major factor in this regard. We speculate that beta-adrenoceptor agonists may be effective in the treatment of bladder dysfunction under all of these conditions.

Topics: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Age Factors; Animals; Ethanolamines; Female; Hypertension; In Vitro Techniques; Isoproterenol; Male; Muscle Relaxation; Muscle, Smooth; Norepinephrine; Propanolamines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Receptors, Adrenergic, beta; Sex Factors; Urinary Bladder; Urinary Incontinence

1. In oesophageal smooth muscle strips from spontaneously hypertensive rats (SHR) of 8-10 and 22-24 weeks of age, respectively, beta-adrenoceptor-mediated relaxation was investigated, by use of the beta-agonists, (-)-isoprenaline and fenoterol (both in the absence and presence of the beta 2-selective antagonist ICI 118,551) and the selective beta 3-agonist, BRL 37,344. 2. In preparations from 8-10 week SHR, (-)-isoprenaline- and fenoterol-induced concentration-response curves (CRCs) were hardly antagonized by ICI 118,551 at concentrations up to 1 microM, indicating only a minor contribution of beta 2-adrenoceptors. pA2-values for ICI 118,551 of 5.30 ((-)-isoprenaline as agonist) and 5.46 (fenoterol as agonist), estimated from the shifts at the highest (10-100 microM) antagonist concentrations, are consistent with affinity at a beta 3-adrenoceptor, similar to that in Wistar rat oesophageal smooth muscle. 3. In 8-10 week SHR, adrenodemedullated at 4 weeks of age (SHR-ADM4) the potency of fenoterol was markedly increased and CRCs were shallow. In addition, ICI 118,551 (0.1 microM) now produced a clear rightward shift accompanied by a steepening of the CRC. A marked further shift was observed only at 100 microM of the antagonist. The data are compatible with the involvement of both beta 2- and beta 3-adrenoceptors. 4. In 22-24 week animals, the same differences between SHR and SHR-ADM4 were observed with fenoterol as in 8-10 week animals, though beta-adrenoceptor responsiveness was slightly decreased. The potency of ICI 118,551 at beta 3-adrenoceptors (pA2 = 5.11) was significantly different from the pA2 value of 5.46 obtained with the younger animals. 5. Responses to the beta 3-adrenoceptor agonist, BRL 37,344, were similar in Wistar rat and SHR preparations. In 8-10 week SHR, a small decrease in the maximal response was observed, which in animals of 22-24 weeks of age was accompanied by a small decrease in the pEC50 value as well. 6. The results clearly indicate that beta 2-adrenoceptors in SHR oesophageal muscularis mucosae are desensitized, whereas beta 3-adrenoceptor-mediated responses are unaffected and similar to the responses observed in the Wistar rat oesophagus. The functional presence of beta 2-adrenoceptor-responses in SHR-ADM4 suggests a major role for adrenal-derived adrenaline in the desensitization of the beta 2-adrenoceptor-population.

Topics: Adrenal Medulla; Adrenalectomy; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Esophagus; Ethanolamines; Fenoterol; Hypertension; In Vitro Techniques; Isoproterenol; Male; Muscle Relaxation; Muscle, Smooth; Propanolamines; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-2; Receptors, Adrenergic, beta-3