Plasma Dihydroxyphenylglycol Levels Research Articles

Effect of endothelin receptor antagonists on ventricular susceptibility in postinfarcted rats

This study investigated whether selective endothelin (ET) type A (ET(A)) or nonselective ET(A)/ET(B) receptor blockade exerted antiarrhythmic effects through attenuated sympathetic reinnervation after infarction. Twenty-four hours after ligation of the left anterior descending artery, male Wistar rats received either vehicle, ABT-627 (selective ET(A) receptor antagonist), bosentan (nonselective ET(A)/ET(B) receptor antagonist), or hydralazine for 4 wk. The measurement of myocardial ET-1 levels at the remote zone revealed a significant increase in vehicle-treated infarcted rats compared with sham-operated rats, consistent with increased activities of ET-1 after infarction. Sympathetic nerve function changes assessed by the norepinephrine content of myocardium and the dialysate and plasma dihydroxyphenylglycol levels were parallel to ET-1 levels. Immunohistochemical analysis for tyrosine hydroxylase, growth-associated protein 43, and neurofilament also confirmed the change of nerve function. This was accompanied with a significant upregulation of nerve growth factor protein expression and mRNA in the vehicle-treated infarcted rats, which reduced after the administration of either ET(A) or ET(A)/ET(B) blockade to a similar extent. The beneficial effects of ET receptor antagonists on sympathetic nerve function and structures were dissociated from their blood pressure-lowering effect because ET receptor antagonists and hydralazine reduced arterial pressure similarly. Arrhythmic severity during programmed stimulation in ET receptor antagonists-treated rats was significantly lower than that in vehicle-treated infarcted rats. Our data indicate that the ET system, especially via ET(A) receptors, plays an important role in attenuating sympathetic reinnervation after infarction. Independent of their hemodynamic effects, a chronic use of either ET(A) or ET(A)/ET(B) antagonists may modify the arrhythmogenic response to programmed electrical stimulation.

Pharmacodynamics and Pharmacokinetics of Two Dose Regimens of Befloxatone, a New Reversible and Selective Monoamine Oxidase Inhibitor, at Steady State in Healthy Volunteers

The pharmacodynamic equipotency of 2 dose regimens (5 mg twice daily versus 10 mg once daily) of befloxatone, a new reversible and selective monoamine oxidase A (MAO-A) inhibitor, after single and multiple doses for 6 days was examined in a randomized, double-blind, three-way crossover, placebo-controlled trial of 12 healthy volunteers. Plasma levels of the deaminated metabolite 3-4 dihydroxyphenylglycol (DHPG), as measured by high-performance liquid chromatography (HPLC) with coulometric electrochemical detection, were used as an index of MAO inhibition. A single dose of befloxatone produced a significant dose-related reduction in plasma DHPG levels, as shown by the decrease in the 24-hour area under the concentration-time curve (AUC0-24) of DHPG, which peaked 2 hours after administration and persisted over 24 hours. Both dose regimens provided equipotent extent and duration of MAO-A inhibition at steady state, suggesting a once daily dosage should be sufficient for most patients. The pharmacokinetic bioavailability at steady state of both dose regimens was also similar. The concentration-time effect curve after a single dose revealed a hysteresis corresponding to the delay necessary to elicit MAO inhibition and/or elimination of DHPG. The relationship between plasma levels of DHPG and/or elimination of plasma concentrations of DHPG and befloxatone after a single dose can be modeled using the Emax model with a mean EC50 of 4.75 ng/mL, and suggests the presence of a maximal response from the single dose. This model permits prediction of steady-state levels of DHPG.

Plasma noradrenaline and its deaminated metabolites in essential hypertension and pheochromocytoma.

Dihydroxyphenylglycol (DOPEG) is a metabolite of noradrenaline (NA) in the sympathetic nerve endings, and dihydroxymandelic acid (DOMA) is one in the extraneuronal tissues. The measurement of plasma DOPEG and DOMA were evaluated with NA as one of the clinical indices of sympathetic nerve activity. These were measured in essential hypertension and also applied for diagnosis of pheochromocytoma. Plasma DOPEG levels were correlated with NA. Plasma NA and DOPEG were decreased after oral administration of clonidine (150 micrograms) and plasma DOPEG levels were slowly increased after standing. Therefore, plasma DOPEG seemed to be useful as one of the rather stable indices of the sympathetic nerve activity. Plasma NA and DOPEG levels in WHO stage I essential hypertension were higher than those in normotensive controls. Observed normal plasma noradrenaline and DOPEG levels in stage II reflect the normalized sympathetic tone in this stage. The elevation of plasma NA and DOMA levels in stage III seemed to be at least partly explained by renal function disturbance. In patients with pheochromocytoma, despite of the marked elevation of plasma NA and DOMA, plasma DOPEG showed only three-fold elevation and the ratio DOPEG/NA was reduced. The simultaneous measurement of plasma NA, DOPEG and DOMA is useful to evaluate sympathetic nerve activity in essential hypertension and to differentiate pheochromocytoma in hypertension.