Biomedical subjects
Publications and source records attributed to P Vermey.
Phenytoin-parahydroxylation capacity was determined in 24 patients with Parkinson's disease (PD) and 17 controls. Different function of the phenytoin-metabolizing cytochrome P450 subsystem was found in 6 patients, but in none of the controls. These results add to previous studies suggesting a relation between the pathogenesis of PD and the function of cytochrome P450 subsystems.
131 patients with osteolytic metastases from breast cancer were randomised to receive long-term oral treatment with aminohydroxy-propylidene-bisphosphonate (APD), 300 mg daily (n = 70), or to act as controls (n = 61) in a multicentre trial. Specific antitumour therapy was at the discretion of the clinician and variable. An interim analysis was made after a median follow-up of 13 months in the APD group and 14 months in the controls. There was a significant reduction in pathological fractures and severe bone pain in the APD group, and hypercalcaemia was prevented. Consequently the necessity for radiotherapy for skeletal complications was more than halved; the number of systemic therapy changes was also reduced. Gastrointestinal side-effects of APD led to a drop-out of 8% of patients. Oral supportive APD therapy is simple and convenient, and significantly reduced skeletal morbidity in advanced breast cancer.
The influence of treatment with the calcium entry blockers PY 108-068 (PY) and PN 200-110 (PN) on alpha 1- and alpha 2-adrenoceptor mediated vasoconstriction has been investigated in the forearms of hypertensive patients. Changes in forearm vascular resistance (FVR) in response to the intra-arterial infusion of drugs were determined at the end of a placebo period and after 2-4 weeks of treatment with PY or PN. The drugs used were the selective agonists methoxamine (alpha 1) and B-HT 933 (alpha 2). During placebo, basal FVR was dose-dependently increased by methoxamine and B-HT 933. Basal blood pressure was lowered during PN but not during PY. Treatment with the calcium entry blockers did not influence the effect of methoxamine, but the vasoconstriction induced by B-HT 933 was attenuated by both of the calcium entry blockers. These results confirm the findings in animal studies that calcium entry blockers preferentially inhibit the alpha 2-adrenoceptor mediated vasoconstriction induced by selective agonists.
The existence of a functional presynaptic alpha 2-adrenoceptor that modulates noradrenaline release was studied in 15 volunteers. Noradrenaline spillover was measured in the forearm under basal conditions, during single intraarterial infusions of the alpha-adrenoceptor antagonists yohimbine (alpha 2, 1.0 micrograms/kg/min) and doxazosin (alpha 1, 0.1 microgram/kg/min), and during intraarterial infusion of tyramine (1.25 microgram/kg/min) alone and in combination with either and both alpha-adrenoceptor antagonists. Forearm blood flow (FBF) was measured by plethysmography. Noradrenaline spillover was calculated as the product of FBF and the difference in arterial and venous plasma noradrenaline. The various infusions did not induce systemic hemodynamic effects. Tyramine induced a dose-dependent decrease in FBF (p less than 0.001) which was reduced by yohimbine (p less than 0.01), as well as by doxazosin (p less than 0.01), and abolished by the combination of both alpha-adrenoceptor antagonists (p less than 0.001). During basal conditions noradrenaline spillover was virtually zero, and this was not changed by yohimbine or doxazosin. Local infusion of tyramine increased noradrenaline spillover (p less than 0.05). This tyramine-induced noradrenaline spillover was further increased by yohimbine (p less than 0.01) and by the combination of yohimbine and doxazosin (p less than 0.001). The single infusion of doxazosin only enhanced the tyramine-induced noradrenaline spillover significantly when it was preceded by yohimbine. The present investigation supports the concept of a presynaptic alpha 2-adrenoceptor modulating noradrenaline release from sympathetic nerve endings via a negative feedback mechanism in humans. Stimulation of noradrenaline release might help to reveal this mechanism.
The relative efficacy of epinephrine and norepinephrine on vascular alpha 1- and alpha 2-adrenoceptors and also the difference in vasoconstriction induced by exogenous norepinephrine as opposed to neuronally released norepinephrine were studied in the forearm of healthy volunteers. Intra-arterial cumulative dose infusions of epinephrine and norepinephrine (0.6, 1.6 and 4.0 ng kg-1 min-1) were given in the presence of saline, the selective alpha 1-antagonist doxazosin (0.1 microgram kg min-1) the selective alpha 2-antagonist yohimbine (1.0 microgram kg min-1) and the combination of both antagonists. beta-Adrenoceptor-mediated effects were prevented by a concomitant i.a. infusion of propranolol (1.0 microgram kg-1 min-1). Forearm blood flow (FBF) was measured before each infusion and at the end of each dose step. Neuronal norepinephrine was released by i.a. infusion of tyramine in three cumulative doses (0.25, 0.50 and 1.25 micrograms kg-1 min-1) and by lower body negative pressure (LBNP, -40 mmHg for 5 min). Changes in FBF were measured without and with concomitant i.a. infusions of the aforementioned doses of doxazosin and yohimbine. In the LBNP experiment the opposite arm was used as a control. Forearm blood flow was measured by plethysmography. Epinephrine and norepinephrine induced an equal and dose-dependent vasoconstriction, which was significantly inhibited by doxazosin as well as yohimbine and to a greater extent by the combination of the antagonists. No differences were found between epinephrine and norepinephrine in this respect.(ABSTRACT TRUNCATED AT 250 WORDS)
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Adrenaline and noradrenaline were infused in cumulative doses into the brachial artery of six healthy volunteers and changes in forearm blood flow (FBF) were measured by plethysmography. The catecholamines were infused together with saline, yohimbine and doxazosin, in that order. All infusions were given in the presence of intra-arterial propranolol to prevent beta-adrenoceptor-mediated effects. Adrenaline and noradrenaline reduced FBF significantly. This decrease in FBF was significantly attenuated by doxazosin as well as by yohimbine. No differences were found between adrenaline and noradrenaline. It is concluded that postjunctional alpha 1- and alpha 2-adrenoceptors are involved in the vasoconstriction caused by exogenous adrenaline and noradrenaline in man. The relevance of circulating adrenaline for the alpha 2-adrenoceptor-mediated contribution to basal vascular tone remains to be established.
Effects of exogenous and endogenous noradrenaline, released by tyramine and lower body negative pressure (LBNP), on vascular post-synaptic alpha 1- and alpha 2-adrenoceptors have been compared in healthy volunteers. Intra-arterial (i.a.) infusions of noradrenaline and tyramine into the forearm were given in the presence of saline, of yohimbine and of doxazosin, and changes in forearm blood flow (FBF) were measured. Lower body negative pressure of -40 mmHg was applied without and with a continuous i.a. infusion of yohimbine and of doxazosin, and changes in FBF in both forearms were compared. Forearm blood flow was measured by venous occlusion plethysmography. Noradrenaline and tyramine reduced FBF dose-dependently and to the same extent. Both these vasoconstrictions were significantly reduced by yohimbine (P < 0.001 for both) as well as by doxazosin (P < 0.05 for noradrenaline and P < 0.001 for tyramine). The tyramine-induced vasoconstriction was more effectively reduced by doxazosin, whereas yohimbine reduced the noradrenaline-induced vasoconstriction more effectively. Lower body negative pressure reduced FBF in both forearms to the same extent. Doxazosin effectively inhibited the LBNP induced decrease in FBF (P < 0.05) whereas yohimbine had no effect (P > 0.05). These results are in accordance with a predominant intrasynaptic location of post-synaptic alpha 1-adrenoceptors and a predominant extrasynaptic location of post-synaptic alpha 2-adrenoceptors in human blood vessels.
Alpha 1- and alpha 2-adrenoceptor mediated vasoconstriction were compared between 13 patients with essential hypertension and 13 normotensive controls, matched for age and sex. For this purpose changes in forearm blood flow induced by infusion of the selective alpha 1-adrenoceptor agonist methoxamine, the selective alpha 2-adrenoceptor agonist B-HT 933, the catecholamines adrenaline and noradrenaline and the alpha 2-adrenoceptor antagonist yohimbine were measured in both study groups. The catecholamines were infused together with propranolol to avoid beta-adrenergic effects. Forearm blood flow was measured by plethysmography. All agonists produced a dose-dependent vasoconstriction which was more pronounced in the hypertensive subjects but no preference was found for either the alpha 1- or alpha 2-adrenoceptor mediated vasoconstriction. Yohimbine induced a greater vasodilatation in the normotensive subjects. The greater vasoconstriction in the hypertensive patients could be explained by structural vascular changes. No evidence was found for an important role of alpha 2-adrenoceptor mediated vasoconstriction in essential hypertension.
We studied postsynaptic alpha-adrenoceptors in human blood vessels by measuring the influence on forearm blood flow induced by intra-arterial infusions of selective alpha 1- and alpha 2-adrenoceptor agonists (methoxamine, B-HT 933, clonidine and guanfacine) and antagonists (doxazosin and yohimbine). The studies were done in healthy volunteers, and forearm blood flow was measured by plethysmography. All agonists produced a significant and dose-dependent vasoconstriction. The effect of B-HT 933 was completely abolished by the concomitant infusion of yohimbine, whereas it was hardly influenced by doxazosin. The effect of methoxamine was prevented by doxazosin and little influenced by yohimbine. The vasoconstriction by clonidine and guanfacine was partially prevented by both doxazosin and yohimbine. The single intra-arterial infusion of yohimbine, as well as doxazosin, resulted in vasodilation. These findings provide strong evidence for the existence of postsynaptic alpha 1- as well as alpha 2-adrenoceptors, both mediating vasoconstriction and contributing to basal vascular tone. The (patho-)physiological significance of this subdivision of alpha-adrenoceptors remains to be elucidated.
The effects of adrenaline and noradrenaline on vascular postsynaptic alpha 1- and alpha 2-adrenoceptors were investigated in six healthy volunteers. The catecholamines were infused intra-arterially, in three cumulative doses, together with a continuous infusion of saline, doxazosin (alpha 1-selective antagonist), yohimbine (alpha 2-selective antagonist) or the combination of the two antagonists, and changes in forearm blood flow were measured by plethysmography. beta-adrenoceptor mediated effects of the catecholamines were prevented by concomitant intra-arterial infusion of propranolol. Adrenaline and noradrenaline reduced forearm blood flow dose-dependently and to the same extent. The vasoconstrictive effect of adrenaline and of noradrenaline was significantly reduced by doxazosin and by yohimbine, and, to a greater extent, by the combination of doxazosin and yohimbine. The magnitude of these reductions were approximately the same for adrenaline and noradrenaline. No changes in heart rate or blood pressure were observed during the infusions. It is concluded that exogenous adrenaline and noradrenaline produce vasoconstriction in the vasculature of the human forearm by stimulation of both postsynaptic alpha 1- and alpha 2-adrenoceptors.
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alpha 1- And alpha 2-adrenoceptor mediated vasoconstriction were studied in 13 patients with essential hypertension and 13 age-matched normotensive controls. This was done by comparing the changes in forearm blood flow induced by intra-arterial infusion of the selective alpha 1- and alpha 2-adrenoceptor agonists methoxamine and B-HT 933, the catecholamines adrenaline and noradrenaline, and the selective alpha 2-adrenoceptor antagonist yohimbine in both study groups. The catecholamines were infused in the presence of propranolol in order to prevent beta-adrenergic effects. Forearm blood flow was measured by plethysmography. All agonists produced a dose-dependent vasoconstriction which was more pronounced in the hypertensive patients, although the difference was significant only for the infusion of the catecholamines and for the combined effects of methoxamine and B-HT 933. No preference was found for either the alpha 1- or alpha 2-adrenoceptor mediated vasoconstriction in the greater response of the hypertensive patients. These results could well be explained by structural vascular changes, secondary to the elevated blood pressure. No evidence was found for increased alpha 2-adrenoceptor mediated basal vascular tone in patients with essential hypertension, since yohimbine tended to induce a greater vasodilatation in the normotensive subjects.