In vivo pharmacodynamic interactions between two drugs used in orthostatic hypotension--midodrine and dihydroergotamine.

A combination of midodrine and dihydroergotamine (DHE) is frequently used clinically in patients suffering from severe orthostatic hypotension (OH). Whereas midodrine acts as a selective, peripheral alpha1-receptor agonist, DHE displays complex pharmacology and can behave as an alpha-adrenergic receptor agonist or antagonist. Surprisingly, the consequences of such a combination on blood pressure have never been investigated. The present study was performed in order to evaluate the pressor effects induced by the administration of both midodrine and DHE in old conscious dogs (n = 6) in experimental condition reproducing autonomic failure-related baroreflex dysfunction (atropine 0.1 mg/kg). For this purpose, we first studied the relative potency and intrinsic activity of each agonist and noradrenaline (NA) for the alpha1-adrenergic receptor. The orders of potency obtained in our study were 0.35, 11 and 400 microg/kg for NA, DHE and midodrine, and intrinsic activity: NA > midodrine > DHE. These results strongly suggest that DHE really acts in vivo as an alpha1-adrenoceptor partial agonist. Afterwards, the pressor effects of coadministration of midodrine (0.4 mg/kg) and DHE (15 microg/kg) were investigated: in one setting, midodrine was first administered, followed by DHE; in another, DHE was first administered, followed by midodrine. Our results show that in conscious dogs, the combination of midodrine and DHE leads to near-complete abolition of the pressor effect induced by the first administered drug. This in vivo proof of such antagonistic effects on blood pressure could explain clinical observations of worsening of OH in humans administered midodrine plus DHE. Although in vivo results obtained in conscious healthy dogs need to be experimentally and clinically confirmed in humans suffering from OH, these results strongly suggest that a midodrine-DHE combined treatment should be avoided in clinical practice.

Blood pressure and heart rate variability in patients with essential hyperhidrosis.

INTRODUCTION: Essential hyperhidrosis (EH) is often considered to be related to an increased activity of sympathetic nervous system (SNS). However, there is a lack of studies comparing autonomic nervous system (ANS) activity in controls and in EH patients. The aim of the present study was to simultaneously investigate in patients with severe EH, blood pressure, heart rate variability and plasma catecholamine levels in comparison with controls. METHODS: 19 EH patients and 20 controls with normal ANS function assessed by clinical testing were included. Blood pressure (BP) and heart rate (HR) were measured using a Finapres beat-to-beat monitor. BP and HR variabilities (Fast Fourier transformation) and plasma catecholamine levels (HPLC) were obtained at rest and during a 15 min 70 degrees head-up tilt test. RESULTS: At rest, a significantly higher relative energy of low frequency band (LF) of systolic BP was observed in EH in comparison with controls contrasting with the lack of difference in BP, HR, plasma catecholamine levels and in other spectral parameters. During tilt, all changes were comparable in EH and in control subjects excepting relative energy of LF of SBP which remained unchanged when compared to the resting condition in EH group. CONCLUSIONS: In EH, SNS is not over-reactive even if resting overactivity cannot be excluded.

In vivo effects of fenoldopam on autonomic nervous system after inhibition or activation of ganglionic transmission.

The study investigated the effects of dopamine D1-like receptor stimulation on the autonomic nervous system. Fenoldopam (20 microg/kg) was injected i.v. in conscious sinoaortic denervated dogs, that is, surgically deprived of baroreflex pathways. In barodenervated dogs, fenoldopam (20 microg/kg) induced arterial hypotension as well as bradycardia and reduced noradrenaline plasma levels. Pentolinium (0.1 mg/kg i.v.), used to induce partial blockade of nicotinic ganglionic receptors, suppressed the fenoldopam-induced decrease in sympathetic tone, suggesting a ganglionic location for the dopamine D1-like receptor. Moreover, the inability of fenoldopam to reduce the nicotine-induced increase in sympathetic tone suggests that a postsynaptic ganglionic location can be excluded for the dopamine D1-like receptor. The results of these "in vivo" experiments strongly suggest a presynaptic location for the ganglionic dopamine D1-like receptor, stimulation of which results in a reduction of sympathetic tone.

Alpha2 -adrenoceptor function in arterial hypertension associated with obesity in dogs fed a high-fat diet.

OBJECTIVE: To investigate the status of alpha2-adrenoceptors in a model of obesity-related arterial hypertension. DESIGN: A parallel study in dogs randomly assigned to a high-fat diet (HFD group, n = 6) or normal canine food (controls, n = 6) for 9 weeks. METHODS: Postsynaptic vascular alpha2-adrenoceptors were assessed through analysis of dose-pressor responses to clonidine [2.5, 5.0 and 15.0 microg/kg intravenously (i.v.)] after muscarinic, beta- and alpha1-adrenergic receptor blockade. Presynaptic and central alpha2-adrenoceptors were studied through measurement of changes in plasma concentrations of catecholamine induced by yohimbine (0.05 mg/kg i.v.). The number of platelet alpha2-adrenoceptors (expressed as fmol/mg protein) and the percentage in a state of high affinity were measured using [3H]RX821002. RESULTS: Clonidine, when administered to dogs that were under autonomic blockade, elicited a dose-dependent increase in blood pressure. The doses of clonidine required to induce a 50% maximum increase in systolic and diastolic blood pressures remained unchanged after 9 weeks of a high-fat diet (systolic: 6.0 +/- 0.3 microg/kg at baseline and 5.6 +/- 0.2 microg/kg after 9 weeks; diastolic: 4.2 +/- 0.2 microg/kg at baseline and 3.9 +/- 0.2 microg/kg after 9 weeks). After 9 weeks of the regimen, plasma concentrations of noradrenaline were significantly greater in the HFD group than in controls (337 +/- 22 pg/ml compared with 212 +/- 37 pg/ml). The increment in plasma concentrations of noradrenaline elicited by yohimbine after 9 weeks was smaller in the HFD group than in controls (93 +/- 44% compared with 181 +/- 46%; P = 0.024). In the HFD group, the number of platelet alpha2-adrenoceptors and the percentage that were in a state of high affinity were significantly lower after 9 weeks, compared with baseline (number: 239 +/- 21 fmol/mg protein at baseline and 95 +/- 7 fmol/mg protein after 9 weeks; high-affinity: 30 +/- 3% at baseline and 21 +/- 4% after 9 weeks; P < 0.05). CONCLUSIONS: These results suggest that presynaptic or central alpha2-adrenoceptor function, or both, is specifically impaired after 9 weeks of a high-fat diet. These modifications may account for the development of arterial hypertension in this model.