ACTION OF A BETA ADRENERGIC RECEPTOR BLOCKING AGENT ON THE POSITIVE CHRONOTROPIC RESPONSE AND UPTAKE OF NOREPINEPHRINE IN THE PERFUSED GUINEA-PIG HEART

¹ Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia

The influence of varying concentrations of the beta adrenergic receptor blocking agent, MJ 1998, in antagonizing the positive chronotropic response of the perfused guinea-pig heart to norepinephrine (NE) and the amount of NE taken up by the adrenergic nerves of this organ have been studied. All three concentrations of MJ 1998 (10^-5, 3 x 10^-5 and 10^-4 M) significantly reduced the increase in heart rate which resulted from a 20-min perfusion of NE (50 ng/ml, at a rate of 7 ml/min) in a dose-dependent fashion when the blocking agent was continuously perfused 30 min prior to and during the NE treatment. MJ 1998 blocked the increase in tissue NE and increased the content measured in the perfusate effluent. Therefore, it is concluded that MJ 1998 can antagonize NE uptake. The highest concentration of MJ 1998 (10^-4 M) did not influence the positive chronotropic action of CaCl₂, which suggests that blockade of NE uptake is not a result of myocardial depression but is probably a specific effect. The blockade of NE uptake correlates reasonably well with the receptor-blocking properties of this drug. Experiments utilizing reserpine and the monoamine oxidase inhibitor, nialamide, seem to indicate that MJ 1998 is antagonizing the uptake of NE into the axonal membrane rather than the transport and/or binding in intraneuronal storage vesicles.