Assessment of two in vitro methods for determination of the apparent affinities of β-sympathomimetics on myocardial contractility

Abstract

As long ago as 1871 it was reported by Bowditch that changes in heart frequency influences the degree of contractility of isolated myocardial preparations. This was subsequently confirmed by Koch-Weser & Blinks (1963). It has recently been shown that quantitative differences exist between structure-activity relation for chronotropic and inotropic effects of 8-adrenoceptor stimulants and 8-sympatholytics and it was postulated that the cardiac &adrenoceptors could probably be subdivided into two groups (Dreyer & Offermeier, 1975). For quantitative in vitro assessments of apparent affinity values on the inotropic j,-receptors it would be preferable to employ methods which could exclude, as far as possible, factors which may influence the results in one way or another.The purpose of this investigation was to determine whether changes in frequency of contraction would influence the apparent affinities of different j3-sympathomimetic drugs for the inotropic 8-receptors to the same extent. To demonstrate that frequency of contraction does in fact influence the force of contraction, isolated left atrial strips from guinea-pigs were mounted in an organ bath perfused by a modified Locke solution at 37" gassed with 5 % C 0 2 in oxygen. A driving stimulus was applied through a pair of silver electrodes in contact with the left atrial strip. The strips were stimulated at different frequencies by squarewave pulses of 5 ms duration. Stimulus intensity was kept constant at approximately 50 % above threshold. Fig. 1 indicates that an increase in frequency of stimulation leads to an increase in the force of contraction up to a certain limit. Frequencies between 0.5 and 5 stimuli s-l may be regarded as the physiological range.To determine to what extent frequency of contraction influences the apparent affinities of j3-sympathomimetic l ' , f

Cardiac Adrenoreceptors

“…In some species increases in frequency exert negative inotropic effects, whereas in others the reverse occurs (Koch-Weser & Blinks, 1963). Indeed, the inotropic potency of agonists has been shown to differ between spontaneously beating and paced guinea-pig atria (Offermeier, Smit & Dreyer, 1976). Therefore positive inotropic responses should only be examined in cardiac preparations where the rate is kept constant by electrical pacing.…”