The determination of presynaptic pA2 values of yohimbine and phentolamine on the perfused rat heart under conditions of negligible autoinhibition

Abstract

Rat isolated perfused hearts with the right sympathetic nerves attached were loaded with [3H]‐(—)‐noradrenaline. The nerves were stimulated with up to 40 trains of 10 pulses every min at 1 Hz, and the evoked increases of [3H]‐noradrenaline overflow into the perfusate, of right atrial tension development and ventricular beating frequency were measured. Oxymetazoline inhibited the evoked transmitter overflow (IC50: 10 nM) and decreased the postsynaptic responses in a concentration‐dependent manner. It behaved as a full agonist in abolishing the evoked transmitter overflow. Yohimbine up to 1 μM neither enhanced the evoked [3H]‐noradrenaline overflow nor the postsynaptic parameters. Phentolamine (1 μM) caused a transient, minor (<30%) increase in [3H]‐noradrenaline overflow. Yohimbine (0.03–1.0 μM) and phentolamine (0.1–5.0 μM) shifted to the right the concentration‐response curve of oxymetazoline for the inhibition of [3H]‐noradrenaline overflow in response to nerve stimulation without depressing the maxima. The pA2 values were 7.82 and 7.52, respectively. Yohimbine (0.1 μM) also antagonized the decrease induced by oxymetazoline in the postsynaptic responses to nerve stimulation. The results confirm the existence of presynaptic inhibitory α2‐adrenoceptors at the adrenergic nerve fibres of the rat heart in vitro. Under the stimulation and perfusion conditions selected, the released endogenous transmitter apparently does not activate a negative feedback mechanism, thus permitting the determination of pA2 values. 1983 British Pharmacological Society