Autoinhibition of noradrenaline release from the rat heart as a function of the biophase concentration. Effects of exogenous alpha-adrenoceptor agonists, cocaine, and perfusion rate.

Rat isolated perfused hearts with the right sympathetic nerves intact were loaded with 3H-(-)-noradrenaline. The nerves were stimulated with trains of 180 pulses at 3 Hz and at 10 min intervals. The overflow of 3H-noradrenaline and 3H-metabolites was determined by liquid scintillation spectrometry. Clonidine (IC50 17 nM), oxymetazoline (IC50 63 nM), and alpha-methylnoradrenaline (apparent IC50 35 nM, determined in the presence of cocaine and propranolol) decreased the stimulation-evoked overflow of 3H-noradrenaline by 26, 49, and 78%, respectively, but not methoxamine up to 100 microM (propranolol present). Oxymetazoline and alpha-methyl-noradrenaline did not cause desensitization of the presynaptic adrenoceptors when present at their IC80 for 33 min. At a perfusion rate of 7 ml/min, yohimbine 1 microM enhanced the stimulation-evoked 3H-noradrenaline overflow by 26% in the absence, and by 58% in the presence of cocaine. Phentolamine 1 microM increased it by 69% when the neuronal reuptake was blocked. The increase by the antagonists faded with successive period of nerve stimulations, and was positively correlated with the biophase concentration of noradrenaline as reflected by the amount of 3H-noradrenaline released into the perfusate per nerve stimulation. At a perfusion rate of 1.8 ml/min (neuronal reuptake blocked), yohimbine 1 microM increased the overflow by 127%. The results indicate that the alpha 2-adrenoceptor-mediated autoinhibition in the rat perfused heart depends on the clearance of transmitter from the biophase via neuronal reuptake and diffusion into the vascular space. Reduction of either elimination pathway enhances the biophase concentration of noradrenaline, thus increasing the autoinhibition of release.