Pharmacological characterization of the β-adrenoceptor that mediates the relaxant response to noradrenaline in guinea-pig tracheal smooth muscle

Pharmacological characteristics of β-adrenoceptors (β-ARs) mediating noradrenaline-induced relaxation were investigated in guinea-pig tracheal smooth muscle. The inhibitory effects of several types of β-AR antagonists on noradrenaline-induced relaxation against histamine contraction were scrutinized with Schild plot analysis. The concentration-response curve for noradrenaline obtained in the absence of phentolamine and uptake inhibitors was competitively antagonized by all of the β-AR antagonists used in this study (propranolol, bupranolol, atenolol, butoxamine and ICI-118,551). However, their pA2 values were markedly less than the expected values for β1-AR and β2-AR. On the other hand, pA2 values of ICI-118,551 (6.85) determined in the presence of phentolamine suggested a contribution of a β1-AR rather than β2-AR. In the presence of phentolamine and uptake inhibitors (desipramine and deoxycorticosterone), the Schild plot for atenolol was a better fit, with two distinct straight lines. The pA2 values of atenolol provided by the regression were: ≈7.0, which corresponds to the expected β1-AR value, and ≈6.5, which was 3 times less than the expected value for β1-AR, and thus the possible presence of two classes of β1-AR (β1(Low) and β1(High)) was suggested. This view was also supported by Schild plot analysis for propranolol, which fit two straight lines each with a slope of 1.0. The present findings indicate that β1-ARs contributing to noradrenaline-elicited relaxation in guinea-pig tracheal smooth muscle exhibit diverse pharmacological characteristics and may be subdivided into at least two classes with distinct affinities for atenolol. Under physiological conditions, β1(Low) rather than β1(High) seems to play a more significant role in noradrenaline-regulated airway smooth muscle tone.