THE INFLUENCE OF ACIDOSIS ON THE CHRONOTROPIC EFFECTS OF TYRAMINE IN GUINEA-PIG ATRIA: RELATION TO TYRAMINE UPTAKE AND METABOLISM

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

It has been reported that acidosis depressed the chronotropic effects of tyramine. Spontaneously beating right guinea-pig atria were placed in 10 ml of Krebs-Henseleit solution at 35°C, pH 7.0 or 7.6 with oxygenation by 95% O₂-5% CO₂. After equilibration, chronotropic effects were obtained with tyramine at pH 7.6 or 7.0, isoproterenol at pH 7.6 or 7.0, tyramine + diethyldithiocarbamate, pH 7.6, tyramine + cocaine, pH 7.6, and tyramine + phenoxybenzamine, pH 7.6. Cocaine, phenoxybenzamine, diethyldithiocarbamate and acidosis were also studied for effects on the uptake and metabolism of ¹⁴C-tyramine. ¹⁴C-tyramine and its metabolites (¹⁴C-octopamine, ¹⁴C-p-hydroxyphenylacetic acid and ¹⁴C-p-hydroxymandelic acid) were isolated via thin-layer chromatography and quantified by liquid scintillation spectrometry. Cocaine and phenoxybenzamine blocked the chronotropic effects of tyramine and decreased atrial ¹⁴C-tyramine and the levels of all three metabolites of tyramine. Diethyldithiocarbamate, an inhibitor of dopamine--hydroxylase, potentiated chronotropic effects of tyramine and markedly decreased atrial levels of ¹⁴C-octopamine and ¹⁴C-p-hydroxymandelic acid. This agent also reduced ¹⁴C-tyramine levels but had no effect on ¹⁴C-p-hydroxyphenylacetic acid levels. Acidosis caused a decrease in the chronotropic effects of ¹⁴C-tyramine and markedly increased -hydroxylated and deaminated metabolites of tyramine in the atria. The data suggest that acidosis alters the storage capacity or binding affinity for amines in the adrenergic neuron.