Effect of catechol-O-methyl-transferase (COMT) inhibition on the vascular and metabolic responses to noradrenaline, isoprenaline and sympathetic nerve stimulation in canine subcutaneous adipose tissue.

Abstract

The effect of COMT-inhibitors (U-0521, H 22/54) on lipolysis and on vascular responses induced by noradrenaline, isoprenaline and nerve stimulation in canine adipose tissue in situ has been studied. COMT inhibition, before or after β-adrenoceptor blockade, did not influence the α-adrenoceptor mediated vasoconstriction due to nerve stimulation (2–5 Hz). Vasoconstriction due to close i.a. noradrenaline was unaffected at a dose of 2×10−10 moles but at a dose of 10−9 moles the peak vasoconstriction was enhanced but the duration of the response was not changed. Prior β-adrenoceptor blockade did not alter the responses to U-0521. After α-adrenoceptor blockade with Hydergine (120–300 μg i.a.) a vasodilatation was induced by noradrenaline 2×10−10 mole. This response and that produced by isoprenaline (2×10−11 or 10−10 moles) were enhanced after U-0521-treatment, but the vasodilating response to nerve stimulation (2 Hz) after α-adrenoceptor blockade was unaffected. Lipolysis induced by nerve stimulation or noradrenaline in vivo was increased 50% and that induced by isoprenaline was increased 100% by COMT inhibition. U-0521 did not alter basal lipolysis in vitro but enhanced lipolysis induced by 0.1 μM noradrenaline significantly, both in the presence and in the absence of theophylline. The present results shows that COMT influences the effective concentration of isoprenaline more than that of noradrenaline. In the vasculature the effects of exogenous noradrenaline is influenced to a larger degree than those induced by nerve stimulation. However, COMT blockade increased lipolysis induced by equieffective doses of exogenous noradrenaline and nerve stimulation to an equal extent. These results are in agreement with the idea that COMT is of physiological importance mainly at receptor sites that are not in close contact with sympathetic nerve endings and supports the idea that vascular α-adrenoceptors are innervated receptors. Vascular β-adrenoceptors on the other hand seem to be humoral receptors unrelated to sympathetic nerve endings and preferentially stimulated by circulating noradrenaline. The β-adrenoceptors on the fat cells may be of both types, i.e. innervated and humoral.