Simultaneous assessment of membrane-stabilizing and β-adrenoceptor blocking activity of drugs with the rat isolated left atria

Abstract

Three consecutive challenges of the rat isolated left atria with electrical stimulation and then electrical stimulation and isoprenaline were made. The responses to electrical stimulation decreased and the responses to isoprenaline increased with consecutive challenges such that the maximal combined response to electrical stimulation and isoprenaline remained constant. The sensitivity (pD 2) to isoprenaline decreased with successive challenges. Thus, in studies of the effects of drugs on the responses to electrical stimulation and isoprenaline, it is necessary to perform parallel experiments with untreated atria to monitor changes in the responses unrelated to the addition of drug. Analysis of the effects of procaine, metoprolol, and propranolol on the responses to electrical stimulation and/or isoprenaline demonstrated distinct contractile manifestations of β-adrenoceptor blocking and membrane stabilizing activity. The β-adrenoceptor blocking activity of metroprolol at 10 −7 M and propranolol (3 × 10 −9−10 −6 M) consisted of parallel rightward shifts of the concentration-response curves to isoprenaline alone. There were three components to the membrane-stabilizing action of drugs: first, there was a decrease in the responses to electrical stimulation alone, which was observed with procaine at ⩾ 10 −4 M and propranolol at ⩾ 3 × 10 −9 M, second, there was a small parallel rightward shift of concentration-response curve to isoprenaline alone with metoprolol at 10 −6 M and propranolol at 3 × 10 −6 M (that the inhibitory effects of metoprolol at 10 −6 M or propranolol at 3 × 10 −6 M are greater than can be explained by β-adrenoceptor blockade only may be detected either by determining pA 2 values from the formula pA 2 = pA x + log (x − 1) or by Schild analysis); third, the highest concentrations of procaine (3 × 10 −4 M) and propranolol (10 −5 M) tested decreased the maximal combined response to electrical stimulation and isoprenaline.