The effect of varying carbachol concentration on the slope of Schild plots of selective beta-adrenoceptor antagonists in the carbachol-contracted guinea-pig trachea.

Abstract

The effect of varying the level of smooth muscle tone induced by carbachol on the Schild analysis of atenolol (beta 1-selective) and ICI 118,551 (beta 2-selective) with salbutamol as agonist, on the guinea-pig tracheal preparation has been examined. When 10(-6) M carbachol was used to induce near-maximal smooth muscle tone, Schild plot slopes for atenolol and ICI 118,551 were less than 1. Slopes of Schild plots for both drugs were equivalent to 1 when 10(-7) M carbachol was used to produce approximately half-maximal smooth muscle tone. Depletion of neuronal noradrenaline by prior treatment with reserpine had no effect on the Schild analysis. Salbutamol produced maximal relaxation and was more potent when tone was induced with 10(-7) M carbachol, but was less effective at 10(-6) M carbachol. Pretreatment with reserpine increased the potency of salbutamol at each concentration of carbachol. The results suggest that either the level of smooth muscle tone or an unknown effect associated with a high level of smooth muscle tone induced by carbachol may contribute to low slope values of Schild plots of selective beta-adrenoceptor antagonists in the carbachol-contracted guinea-pig trachea. The carbachol-contracted guinea-pig trachea can be used to determine theoretically valid pA2 values for selective beta-adrenoceptor antagonists as long as substantially less than a maximal level of smooth muscle tone is induced by carbachol.