Bupranolol Hydrochloride

β-Adrenoceptors (β-ADRs) mediating the relaxation of rat superior mesenteric arteries (SMAs) were pharmacologically identified, and the effects of chemical sympathetic denervation on β-ADR-mediated relaxation were examined.

The tension changes of endothelium-denuded SMAs were isometrically recorded and the mRNA of endothelium-denuded SMA β-ADR was detected using RT-PCR.

In endothelium-denuded SMAs contracted with ≥10^-7 M phenylephrine (an α₁-ADR agonist), isoprenaline (a β-ADR agonist)-induced relaxation was competitively inhibited by 3 × 10^-9-10^-8 M propranolol (a β_1,2-ADR antagonist), but not further affected by ≥10^-8 M propranolol. Although isoprenaline-induced relaxation was not affected by ICI-118,551 (10^-9-10^-8 M; a β₂-ADR antagonist), it was competitively inhibited by atenolol (10^-7-3 × 10^-7 M; a β₁-ADR antagonist) in the presence of ICI-118,551. In the presence of 10^-7 M propranolol, isoprenaline- and CGP-12177A (a β₃-ADR partial agonist)-induced relaxation was competitively inhibited by high concentrations of bupranolol (a β_1,2,3-ADR antagonist), with pA₂ values of 6.49 and 5.76, respectively. We detected the mRNA of β₁- and β₃-ADRs in endothelium-denuded SMAs. Treatment with 6-hydroxydopamine (a catecholaminergic neurotoxin) reduced maximal isoprenaline-induced relaxation in the presence and absence of 10^-7 M propranolol, but not CGP-12177A-induced relaxation.

Isoprenaline-induced relaxation of rat SMAs is mediated by β₁- and β₃-ADRs. β-ADR-mediated relaxation of rat SMAs is shown to be attenuated by chemical sympathetic denervation. The differences in the effects of bupranolol and chemical sympathetic denervation on the responses to isoprenaline and CGP-12177A in rat SMAs might be explained by the possible presence of multiple β₃-ADRs with different pharmacological properties.

β-Adrenoceptors are subclassified into 3 subtypes (β₁-β₃). Among these, β₃-adrenoceptors are present in various types of smooth muscle and are believed to play a role in relaxation responses of these muscles. β₃-Adrenoceptors are also present in urinary bladder smooth muscle (UBSM), although their expression varies depending on the animal species. To date, there has been little information available about the endogenous ligand that stimulates β₃-adrenoceptors to produce relaxation responses in UBSM. In this study, to determine whether noradrenaline is a ligand of UBSM β₃-adrenoceptors, noradrenaline-induced relaxation was analyzed pharmacologically using rat UBSM. We also assessed whether noradrenaline metabolites were ligands in UBSM. In isolated rat urinary bladder tissues, mRNAs for β₁-, β₂-, and β₃-adrenoceptors were detected using RT-PCR. In UBSM preparations contracted with methacholine (3 × 10^-5 M), noradrenaline-induced relaxation was not inhibited by the following antagonists: atenolol (10^-6 M; selective β₁-adrenoceptor antagonist), ICI-118,551 (3 × 10^-8 M; selective β₂-adrenoceptor antagonist), propranolol (10^-7 M; non-selective β-adrenoceptor antagonist), and bupranolol (10^-7 M; non-selective β-adrenoceptor antagonist). In the presence of propranolol (10^-6 M), noradrenaline-induced relaxation was competitively inhibited by bupranolol (3 × 10^-7-3 × 10^-6 M) or SR59230A (10^-7-10^-6 M; selective β₃-adrenoceptor antagonist), with their pA₂ values calculated to be 6.64 and 7.27, respectively. None of the six noradrenaline metabolites produced significant relaxation of methacholine-contracted UBSM. These findings suggest that noradrenaline, but not its metabolites, is a ligand for β₃-adrenoceptors to produce relaxation responses of UBSM in rats.