Effects of catechol-O-methyltransferase inhibition on the plasma clearance of noradrenaline and the formation of 3,4-dihydroxyphenylglycol in the rabbit

Summary The purpose of this study was to elucidate the finding of Friedgen et al. (1993b) that catechol-O-methyltransferase (COMT) inhibition is much more effective in increasing the plasma concentration of endogenous dihydroxyphenylglycol (DOPED) than in increasing the plasma concentration of infused DOPED. To this end, reserpine-pretreated rabbits were anaesthetized and infused with noradrenaline and/or DOPED, and the plasma clearances of infused noradrenaline (Cl_NA) and DOPED (Cl_DOPEG) as well as the plasma DOPED response to noradrenaline infusion [as reflected by the ratio of the steady-state increase in plasma DOPED (DOPEG) to that in plasma noradrenaline (NA)] were determined before and after blockade of neuronal uptake by desipramine. Experiments were carried out either under control conditions or after COMT inhibition by i.v. administration of 3,4-dihydroxy-4-methyl-5-nitrobenzophenone (Ro 40-7592). On the assumption that rates of neuronal noradrenaline uptake equal steady-state rates of neuronal DOPED formation, the desipramine-sensitive components of Cl_NA and DOPEG/NA were used to estimate the apparent plasma clearance of DOPED formed intraneuronally (Cl_f-DOPEG) in response to noradrenaline infusion.Cl_NA was 83.6 ml kg-^–1 min^–1 in the absence and 48.1 ml kg ^–1min^–1 in the presence of desipramine. Neither the former nor the latter value was altered after COMT inhibition. However, the COMT inhibitor reduced Cl_DOPEG from 47.6 to 28.5 ml kg ^–1 min^–1 (indicating a 1.7-fold increase in the plasma DOPED response to DOPED infusion) and Cl_f-DOPEG from 106.2 to 43.3 ml kg^–1 min^–1 (indicating a 2.5-fold increase in the neuronal component of the plasma DOPED response to noradrenaline infusion). DOPEG/NA increased following treatment with Ro 40-7592 from 0.381 to 1.294 in the absence and from 0.036 to 0.391 in the presence of desipramine. These increases were more pronounced than the Ro 40-7592-induced change in Cl_f-DOPEG would predict. Therefore, the values of Cl_f-DOPEG were used to calculate rates of DOPED formation. The results show that the increases in DOPEG/NA induced by COMT inhibition were not due only to the block of O-methylation of DOPED, but also to a pronounced increase in the extraneuronal DOPED formation.Hence, COMT inhibition affects neither the neuronal nor the extraneuronal removal of circulating noradrenaline from plasma. By contrast, COMT inhibition reduces the clearance of infused DOPED by about 40% and that of neuronally formed DOPEG by about 60%. The observation of Ro 40-7592 being more effective in increasing the plasma DOPEG response to noradrenaline infusion than in increasing the plasma DOPED response to DOPEG infusion is due to the fact that newly formed DOPEG is O-methylated not only while being removed from plasma, but also on the way to plasma, and that COMT inhibition increases the DOPEG formation at extraneuronal sites.This study was supported by the Deutsche Forschungsgemeinschaft (Gr 490/5). A preliminary account of the results was presented to the German Society for Pharmacology and Toxicology (Halbrügge et al. 1992)Correspondence to K. H. Graefe at the above address