Isoprenaline is known to produce vascular relaxation through activation of β-adrenoceptors. In recent years, β-adrenoceptor-activated vascular relaxation has been the focus of pharmacological study in terms of both the receptor subtypes and the intracellular signaling mechanisms which trigger smooth muscle mechanical functions. In addition, the possible contribution of the endothelium to β-adrenoceptor-activated relaxation of vascular beds has provoked considerable discussion, with consensus still to be established. In the present study, we examined the effects of isoprenaline on isolated mouse aortic smooth muscles to determine whether the presence of the endothelium plays a substantial role in the relaxation it produces. A possible role for nitric oxide (NO) as a primary endothelium-derived factor released in response to isoprenaline was also elucidated pharmaco-mechanically. In isolated thoracic and abdominal aortae precontracted with phenylephrine (3 × 10 -7 -10 -6 M), isoprenaline elicited relaxation in a concentration-dependent fashion (10 -9 -10 -5 M). In endothelium-denuded preparations, isoprenaline-elicited relaxation was reduced to 40~50% of the response obtained in endothelium-intact preparations. In the preparations treated with N G -nitro-L-arginine methyl ester (L-NAME, 3 × 10 -4 M; an NO synthase inhibitor) or 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ, 10 -5 M; a soluble guanylyl cyclase inhibitor), isoprenalineelicited relaxation was attenuated almost to the same degree as the response in endothelium-denuded preparations. The degree of endothelium-dependency in isoprenaline-elicited relaxation was largely diminished when treated with propranolol (3 × 10 -6 M). The present findings indicate that isoprenaline substantially relaxes the mouse aorta with both endothelium-dependent and -independent mechanisms. The endothelium-dependent component seems to correspond to about 50% of the isoprenaline-elicited relaxation, and is almost entirely due to endothelium-derived NO. Activation of propranolol (3 × 10 -6 M)-inhibitable β-adrenoceptors seems to be primarily responsible for the NO-mediated endothelium-dependent pathway in isoprenaline-elicited Correspondence to:

Fenoterol, a β2-adrenoceptor selective agonist, belongs to the arylethanolamine class. To understand the receptor subtypes responsible for β-adrenoceptor-mediated relaxation of guinea pig taenia caecum, we investigated the effect of fenoterol. Fenoterol caused concentration-dependent relaxation of the guinea pig taenia caecum. Propranolol, bupranolol and butoxamine produced shifts of the concentration-response curve for fenoterol. Schild regression analyses carried out for propranolol, butoxamine and bupranolol against fenoterol gave pA2 values of 8.41, 6.33 and 8.44, respectively. However, in the presence of 3 × 10 -4 M atenolol, 10 -4 M butoxamine and 10 -6 M phentolamine to block the β1-, β2-and α-adrenoceptor effects, respectively, Schild regression analysis carried out for bupranolol against fenoterol gave pA2 values of 5.80. These results suggest that the relaxant response to fenoterol in the guinea pig taenia caecum is mediated by both the β2-and the β3-adrenoceptors.

The mechanisms of the β-adrenoceptor-mediated relaxation induced by dopamine in guinea pig taenia caecum were examined. The relaxant response to dopamine was unaffected by propranolol (10 -8 -10 -5 M) or phentolamine (10 -8 -10 -5 M). Atenolol (3 × 10 -7 -3 × 10 -4 M), butoxamine (10 -7 -10 -4 M), prazosin (10 -8 -10 -5 M), yohimbine (10 -8 -10-5 M), SCH 23390 (10 -8 -10 -5 M) and haloperidol (10 -8 -10 -5 M) had no effect on the potency of dopamine. The response to dopamine was antagonized in a concentrationdependent manner by bupranolol (3 × 10 -6 -3 × 10 -5 M), and Schild plot of the data revealed the pA2 value of 5.55 and the slope of the regression line was 1.13. These results suggest that the relaxant response to dopamine in the guinea pig taenia caecum is mainly mediated by the β3-adrenoceptors.