1 The possible existence of a b 3 -adrenergic receptor (b 3 -AR) in the human detrusor muscle was investigated by in vitro functional studies and analysis of mRNA expression. 2 Isoprenaline, noradrenaline and adrenaline each produced a concentration-dependent relaxation of the human detrusor. The rank order for their relaxing potencies was isoprenaline (pD 2 6.37+0.07) 5 noradrenaline (pD 2 6.07+0.12) 5 adrenaline (pD 2 5.88+0.11). 3 Neither dobutamine (b 1 -and b 2 -AR agonist) nor procaterol (b 2 -AR agonist) produced any signi®cant relaxation at concentrations up to 10 75 M. BRL37344A, CL316243 and CGP-12177A (b 3 -AR agonists), relaxed the preparations signi®cantly at concentrations higher than 10 76 M. The pD 2 values for BRL37344A, CL316243 and CGP-12177A were 6.42+0.25, 5.53+0.09 and 5.74+0.14, respectively. 4 CGP-20712A (10 77 ± 10 75 M), a b 1 -AR antagonist, did not a ect the isoprenaline-induced relaxation. On the other hand, ICI-118,551, a b 2 -AR antagonist, produced a rightward parallel shift of the concentration-relaxation curve for isoprenaline only at the highest concentration used (10 75 M) and its pK B value was 5.71+0.19. Moreover, SR58894A (10 77 ± 10 75 M), a b 3 -AR antagonist, caused a rightward shift of the concentration-relaxation curve for isoprenaline in a concentration-dependent manner. The pA 2 value and slope obtained from Schild plots were 6.24+0.20 and 0.68+0.31. 5 The b 1 -, b 2 -and b 3 -AR mRNAs were all positively expressed in detrusor smooth muscle preparations in a reverse transcription polymerase chain reaction assay. 6 In conclusion, the present results provide the ®rst evidence for the existence of the b 3 -AR subtype in the human detrusor. They also suggest that the relaxation induced by adrenergic stimulation of the human detrusor is mediated mainly through b 3 -AR activation.

Involvement of p38 mitogen-activated protein (MAP) kinase in interleukin (IL)-6 gene expression of human fibroblast-like synoviocytes (FLSs) was assessed. p38 MAP kinase was constitutively expressed in human FLSs and activated in response to IL-1␤. A pyridinylimidazole compound, SB203580, inhibited p38 MAP kinase activity in vivo, since the activity of MAPKAP kinase-2 (a substrate of p38 MAP kinase) in IL-1␤-stimulated FLSs was totally suppressed by it. SB203580 concentrationdependently inhibited protein production and gene expression of IL-6 by human FLSs. The effect of SB203580 was dependent on de novo protein synthesis. SB203580 significantly reduced the stability of IL-6 mRNA without affecting the rate of IL-6 gene transcription. Here, we provide evidence that p38 MAP kinase is activated in response to IL-1␤ in human FLSs and is involved in IL-6 synthesis by stabilizing IL-6 mRNA.

1 The b-adrenoceptor (b-AR) subtypes mediating relaxation of the rabbit, rat and canine detrusors were subjected to functional investigation using selective b-AR agonists and antagonists. 2 In all three species, isoprenaline, noradrenaline and adrenaline each produced a concentrationdependent relaxation of the detrusor. The rank order for their relaxing potency was isoprenaline4 adrenaline4noradrenaline in rabbits and rats, but isoprenaline4noradrenaline4adrenaline in dogs. 3 Dobutamine did not produce relaxation of the detrusors at concentrations that are selective for b 1 -AR. The selective b 2 -AR agonist, procaterol, had a more potent relaxing e ect on rabbit and rat detrusors than on the canine detrusor. CGP-12177A, a selective b 3 -AR agonist, was more e ective in the rabbit than in the other two species. On the other hand, the relaxing e ect of another b 3 -AR agonist, CL316243, was more pronounced in dogs and rats than in rabbits. 4 CGP-20712A (10 79 to 10 77 M), a selective b 1 -AR antagonist, caused a slight rightward shift of the concentration-relaxation response curve for isoprenaline in the canine detrusor (pA 2 9.41), but not in the rabbit and rat detrusors. ICI-118,551, a selective b 2 -AR antagonist, antagonized the isoprenaline-induced relaxation in rabbits (pA 2 9.45) and rats (pA 2 9.05), but not in dogs. Bupranolol, a non-selective b-AR antagonist, caused a rightward shift of the concentration-relaxation curve for isoprenaline in the rabbit (pA 2 9.32) and rat (pA 2 8.98). However, higher concentrations (3610 78 to 10 75 M) were needed to induce a rightward shift of the curve for isoprenaline in the dog (pA 2 8.19) than in the other two species. 5. We have con®rmed that the distribution of b-AR subtypes in the detrusor muscle varies signi®cantly from species to species and we provide here the ®rst evidence of the presence of b 3 -AR in the detrusor. It is suggested that the relaxation induced by adrenoceptor agonists in urinary bladder smooth muscle may be mediated mainly via b 2 -AR in rabbits, via both b 2 -and b 3 -AR in rats, but mainly via b 3 -AR in dogs.

No abstract

beta-adrenoceptor stimulation is an effective way of relaxing the human detrusor and the effect is similar in normal and neurogenic bladders. A major portion of the relaxant effect of isoproterenol is mediated via beta3-adrenoceptor stimulation. Clinical trials may reveal whether this method is useful for treating bladder overactivity.