Chronic clorgyline treatment enhances release of norepinephrine following sympathetic stimulation in the rat

Summary Plasma catecholamine levels were determined in pithed rats during electrical stimulation of the entire sympathetic nervous system. In animals treated chronically with clorgyline (1 mg/kg daily for 21 days) the increment in plasma norepinephrine concentration during stimulation was greather than in control animals, whereas a single dose of clorgyline (2 mg/kg 2 h before pithing), which produced the same degree of inhibition of arterial MAO type A and a similar increase in arterial norepinephrine content, had no effect on the plasma norepinephrine response to stimulation. Injection of yohimbine (1 mg/kg) produced the same degree of enhancement of plasma norepinephrine response to stimulation in chronically treated and control animals, showing that the overall gain of the ₂-adrenoceptor inhibitory loop in vascular sympathetic nerves was not affected. Plasma epinephrine concentration during electrical stimulation was also increased by chronic but not by acute clorgyline treatment. Chronic clorgyline treatment did not significantly affect the total systemic metabolic clearance rate of infused norepinephrine, thus the increased plasma norepinephrine response to stimulation reflects an increased release rate from sympathetic neurons.In rats treated chronically with clorgyline, the pressor response to norepinephrine in the presence of yohimbine (0.3 mg/kg) was significantly reduced, whereas the pressor response to guanabenz was unchanged. There was also no change in the guanabenz-induced inhibition of the tachycardic response to electrical stimulation. These results show that the enhanced norepinephrine release produced by chronic clorgyline treatment leads to down-regulation of post-synaptic ₁-adrenoreceptors with no change in post-synaptic ₂-adrenoceptors or in cardiac presynaptic ₂-adrenoreceptors, and are in agreement with an intrasynaptic location of ₁-adrenoceptors and an extra-synaptic location of ₂-adrenoceptors in the rat vasculature.