Stimulant and depressant effects of beta-adrenoceptor blocking agents on isolated heart muscle. A positive inotropic effect not mediated through andrenoceptors

Abstract

The chronotropic and inotropic effects of fourteen beta-adrenoceptor blocking agents were studied in vitro on preparations of isolated heart muscle from kittens and guinea pigs. Most of the agents exert negative inotropic and chronotropic effects that increase rapidly with concentration above 10(-6) M. Exceptions are the closely related compounds practolol and atenolol, which have minimal depressant effects in concentrations as high as 2 X 10(-3) M. Dose-response relations for the depressant effects are similar for pacemaker frequency and for tension development in atrial and papillary muscle. The cardiodepressant effects of beta-blockers are non-stereospecific and are apparently unrelated to the actions of the drugs at beta-adrenoceptors. Many beta-blockers exert positive inotropic and chronotropic effects at concentrations lower than those that depress. The stimulant effects are slow in onset and do not fade. In most instances these effects are blocked by propranolol and may therefore be considered to be mediated throught beta-adrenoceptors; (-)-enantiomers are more potent than (+)-enantiomers as adrenoceptor stimulants. Adrenoceptor-mediated inotropic effects are usually more pronounced in atrial than in ventricular muscle. Certain beta-blockers, notably INPEA and sotalol, exert positive inotropic effects that are not blocked by propranolol or phenyoxybenzamine. The effects are very slow in onset and offset, and are accompanied by the development of contractions with a late tonic component which coincides with a greatly prolonged action potential. Unlike the adrenoceptor-mediated effect, the non-sympathomimetic inotropic effect is more pronounced in ventricular than in atrial muscle, and is not stereospecific. Pindolol also causes the development of a late tonic component, but the accompanying positive inotropic effect is overcome by the simultaneous development of the depressant action of the drug.