Evidence against beta 3-adrenoceptors or low affinity state of beta 1-adrenoceptors mediating relaxation in rat isolated aorta

Abstract

1 The presence of beta(3)-adrenoceptors and the low affinity state of the beta(1)-adrenoceptor (formerly "putative beta(4)-adrenoceptor") was investigated in ring preparations of rat isolated aorta preconstricted with phenylephrine or prostaglandin F(2alpha) (PGF(2alpha)). Relaxant responses to isoprenaline, selective beta(3)-adrenoceptor agonists (BRL 37344, SR 58611A, CL 316243) and non-conventional partial agonists (CGP 12177A, cyanopindolol, pindolol) were obtained. 2 In phenylephrine-constricted, but not PGF(2alpha)-constricted rings, relaxations to isoprenaline showed a propranolol-resistant component. 3 In phenylephrine-constricted rings, relaxations to BRL 37344 (pEC(50), 4.64) and SR 58611A (pEC(50), 4.94) were not antagonized by the selective beta(3)-adrenoceptor antagonist SR 59230A (< or =1 microM). CL 316243 (< or =100 microM) failed to produce relaxation. In PGF(2alpha)-constricted rings only SR 58611A produced relaxation, which was not affected by SR 59230A (< or =3 microM). 4 Non-conventional partial agonists produced relaxation in phenylephrine-constricted but not PGF(2alpha)-constricted rings. The relaxation to CGP 12177A was unaffected by SR 59230A (< or =1 microM) or by CGP 20712A (10 microM), reported to block the low affinity state of the beta(1)-adrenoceptor. 5 beta-adrenoceptor antagonists also produced relaxation in phenylephrine-constricted rings with an order of potency of (pEC(50) values): bupranolol (5.5) approximately 38;SR 59230A (5.47) approximately 38;cyanopindolol (5.47)>pindolol (5.30)>alprenolol (5.10)>propranolol (4.83)>ICI 118551 (4.60)>CGP 12177A (4.38) approximately 38;CGP 20712A (4.35). Bupranolol (100 microM), alprenolol (30 microM), propranolol (100 microM) and SR 59230A (10 microM) produced no relaxation in PGF(2alpha)-constricted rings. 6 These results provide no evidence for the presence of functional beta(3)-adrenoceptors or the low affinity state of the beta(1)-adrenoceptor in rat aorta.

Figure 1

(a) Effect of propranolol on relaxations induced by (−)-isoprenaline in rat thoracic aorta preconstricted with phenylephrine (0.6 μM). Results are expressed as percentage reduction of tone induced by phenylephrine. Values are mean±s.e.mean of eight observations for each curve. (b) Schild plot for propranolol against isoprenaline with slope of 0.42 (95% C.L. 0.24 to 0.60), significantly different from unity (P<0.05, n=24).

Figure 2

Relaxant effect of (a) β₃-adrenoceptor agonists, (b) non-conventional partial agonists and (c) β-adrenoceptor antagonists in rat thoracic aortae preconstricted with phenylephrine (0.6 μM). Results are expressed as percentage reduction of tone induced by phenylephrine. Values are mean±s.e.mean of 3–14 observations.

Figure 3

(a) Effect of SR 59230A (1 μM) on relaxation to BRL 37344 in rat distal colon preconstricted with KCl (30 mM). Values are mean±s.e.mean of six observations. (b) Effect of SR 59230A (1 μM) and propranolol (0.3 μM) on relaxation to CL 316243 in rat distal colon preconstricted with KCl (30 mM). Values are mean±s.e.mean of five observations.