Physiological Role of Endogenous Amines in the Modulation of Ventricular Automaticity in the Guinea-pig

1. Current-clamp experiments were carried out with guinea-pig papillary muscles to determine the dependence of depolarization-induced automaticity on endogenous catecholamines. 2. Catecholamine depletion was produced by pre-treatment of animals with 6-hydroxydopamine and confirmed by fluorimetric assay of right ventricular tissue. Papillary muscles from depleted animals demonstrated a marked suppression of depolarization-induced automaticity for maximum diastolic potentials less negative than -55 mV. This suppression was completely reversed by noradrenaline but not by tyramine. 3. In normal tissue, noradrenaline and tyramine had much smaller effects on automaticity arising from maximum diastolic potentials negative to -55 mV than on repetitive activity arising positive to this level. 4. L-propranolol in concentrations of 2-3 x 10(-7) M reduced repetitive activity in the less negative range of maximum diastolic potential. No evidence of direct membrane depression was observed at these doses and the effect was reversed by application of noradrenaline. 5. D-propranolol, the isomer with much lower beta-receptor blocking potency, required twentyfold higher concentrations to depress automaticity and this was accompanied by evidence of direct membrane depression, i.e. reduction of upstroke velocity of action potentials. 6. These results show that automaticity induced in guinea-pig papillary muscles by depolarization positive to -55 mV is strongly dependent upon endogenous catecholamines. 7. The hypothesis that endogenous catecholamines facilitate depolarization-induced automaticity through an increase in calcium conductance was modelled using numerical techniques. It was found that changes in calcium conductance caused changes in the model which closely parallelled the experimental effects of catecholamine depletion and beta-blockade. The effects of changes in delayed rectification in the model did not accurately reproduce the experimental results.