Role of the b3-Adrenoceptor in Urine Storage in the Rat: Comparison between the Selective b3-Adrenoceptor Agonist, CL316,243, and Various Smooth Muscle Relaxants

The objective of this study was to compare the effects of a b3-adrenoceptor (b3-AR) agonist on bladder function and cardiovascular parameters in rats with those of several drugs that act on smooth muscle. CL316,243 (b3-AR agonist), isoproterenol (nonselective b-AR agonist), procaterol (b2-AR agonist), verapamil (Ca antagonist), and papaverine (antispastic drug) each evoked a concentration-dependent relaxation of the detrusor in vitro. They also reduced bladder pressure in anesthetized rats, the b-AR agonists apparently being more potent than the other drugs. Atropine (muscarinic antagonist) neither relaxed detrusor strips nor reduced bladder pressure. In anesthetized rats, CL316,243 and atropine each had only a slight influence on blood pressure and heart rate, but isoproterenol, procaterol, verapamil, and papaverine significantly affected cardiovascular function at the same dose range as that required to reduce bladder pressure. In cystometry experiments, CL316,243 (10 mg/kg i.v.), verapamil (1 mg/kg i.v.), and papaverine (1 mg/kg i.v.) all significantly prolonged micturition interval and increased bladder capacity, but did not change the residual urine volume after a micturition contraction. Procaterol (100 mg/kg i.v.) prolonged the micturition interval and increased both bladder capacity and residual urine volume (all significantly). Atropine (100 mg/kg i.v.) reduced micturition pressure and increased residual urine volume (both significantly). Because the human detrusor, like the rat detrusor, relaxes on b3-AR stimulation, we conclude that this b3-AR agonist may have potential in pollakiuria (frequent urination) as a therapeutic agent without cardiovascular side effects. Urinary bladder function is controlled by both the parasympathetic and sympathetic nervous systems, their activation mediating bladder contraction and relaxation, respectively (Andersson, 1993). It is considered that pathophysiologic conditions such as pollakiuria, urgency, and incontinence arise from disturbances of this dual control mechanism (Andersson, 1988). Consequently, drugs such as muscarinic antagonists (Boman and von Garrelts, 1973; Blaivas et al., 1980), Ca antagonists (Palmer et al., 1981), and antispastic drugs (Stanton, 1973; Delaere et al., 1977) are considered useful for the treatment of patients with pollakiuria caused by a hyperactive bladder. However, because they have little or no selectivity for the detrusor, such drugs often produce adverse systemic effects. In the bladder, the b-adrenoceptor (b-AR) subtypes mediating sympathetic relaxation of the detrusor differ substantially from species to species. For example, relaxation of the detrusor in cats (Nergårdh et al., 1977) and guinea pigs (Li et al., 1992) is mediated mainly via b1-AR, whereas in rabbits (Anderson and Marks, 1984; Levin et al., 1988; Yamazaki et al., 1998) it is said to be mediated entirely via b2-AR. Moreover, the rat detrusor relaxes through not only b2-AR, but also b3-AR (Yamazaki et al., 1998) even though all three b-AR subtype mRNAs are expressed in the detrusor in this species (Seguchi et al., 1998). We recently confirmed that although all three b-AR subtype mRNAs are positively expressed in the human detrusor, the major b-AR subtype responsible for its relaxation is neither the b1nor the b2-AR, but the b3-AR (Igawa et al., 1997, 1998, 1999). In this study, we used rats to investigate the usefulness of a selective b3-AR agonist on aspects of bladder function closely related to urine storage, and we compared its effects with those of other drugs expected to be useful clinically for the treatment of such bladder dysfunctions as pollakiuria and urinary incontinence. Materials and Methods