A theoretical model of the effects of a saturable removal mechanism for an antagonist diffusing into the receptor compartment of a tissue is used to calculate expected deviations in Schild regressions. At concentrations of antagonist which do not saturate the removal mechanism, there can be a deficit of antagonist in the receptor compartment as compared to the concentration of antagonist bathing the tissue. This results in a shift to the right of the Schild regression and a corresponding underestimation of antagonist potency. The model predicts that as the concentration of antagonist exceeds the Km for removal (saturation of the removal process), this concentration deficit is eliminated, resulting in a proportionate increase in antagonist concentration at the receptor and a concomitant increase in receptor antagonism. This results in a steepening of the Schild regression; the slope in the region of saturation is greater than one. Experimental evidence in support of this model was found in studies of the antagonism of responses to bethanechol by atropine in rabbit ileum; this species is known to have an atropinesterase capable of hydrolyzing atropine. The Schild regression for atropine was curvilinear with an overall slope of 1.42 (1.34-1.5) and pKB = 8.5 (8.36-8.8); in the ileum from guinea pigs, a species which does not possess this enzyme, the Schild regression for atropine was linear, had a slope not significantly different from unity (1.1; 0.95-1.2) and a pKb of 9.0 (8.9-9.2). The slope of the regression in rabbit ileum was corrected to unity by the addition of an excess concentration of methylbutyrate, an alternate substrate for atropinesterase.(ABSTRACT TRUNCATED AT 250 WORDS)

Isoprenaline, but not prenalterol, produced positive inotropy in guinea-pig papillary muscle. Prenalterol was a competitive antagonist of responses to isoprenaline in this tissue with a pKB of 7.24, as estimated by a Schild regression. Guinea-pig papillary muscles pretreated with the phosphodiesterase inhibitor, isobutylmethylxanthine (IMX), were 10 times more sensitive than controls to isoprenaline. In these tissues, prenalterol was a partial agonist producing 68% of the maximal response to isoprenaline. Schild regressions with atenolol indicated no change in beta-adrenoreceptors with IMX treatment and also that isoprenaline and prenalterol activated the same receptor in this tissue. The relative efficacy of isoprenaline and prenalterol was measured by using the KB estimated by Schild analysis for prenalterol and a Kd for isoprenaline from published binding studies. The relative efficacy of these drugs (epsilon ISO/epsilon PREN) was 242 +/- 29. The general method of potentiation of responses to weak agonists to estimate relative efficacy is discussed.

Kenakin, T.P., D. Beek:The activity of nifedipine, diltiazern, veraparnil, and lidoflazine in isolated tissues: An approach to the determination of calcium channel blocking activity. Drug Dev. Res. 5:347-358, 1985. A characteristic profile of activity was obtained in six isolated tissues for the calcium channel antagonists nifedipine, diltiazern, veraparnil, and lidoflazine. All drugs produced relaxation of K+ depolarized guinea pig ileal longitudinal muscle strips and K+ depolarized canine coronary artery, depression of electrically stimulated basal contractions of guinea pig left atria, and depression of guinea pig right atrial rate. Also, all drugs produced parallel dextral displacement of concentration-response curves to calcium in guinea pig depolarized taenia caeci. The potency for this effect was quantified by Schild analysis yielding the following pA2 estimates: nifedipine 9.5, diltiazem 7.65, veraparnil 7.8, and lidoflazine 7.0.Nifedipine, diltiazem, and lidoflazine produced no relaxation of methoxamine-contracted rabbit aortae while weak effects were observed with veraparnil at concentrations 100 times greater than those required to reverse calcium effects in other tissues. In general, nifedipine and diltiazern displayed selectivity for smooth muscle over cardiac muscle while verapamil showed the least selectivity in this regard.

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