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Biomedical subjects

M Esler

Publications and source records attributed to M Esler.

At least 91 records · Page 5Linked to original sources
PubMed1981

Low oral bioavailability of dihydroergotamine and first-pass extraction in patients with orthostatic hypotension.

The relative importance of the effect of absorption and first-pass extraction in bioavailability and clinical effectiveness of oraldihydroergotamine (DHE) was examined in six subjects with orthostatic hypotension. Maximum increases in systolic blood pressure of standing subjects occurred within 15 min of intravenous administration (10 micrograms/kg); after 30 min pressure declined linearly with respect to time over the ensuing 3 hr. Plasma DHE concentrations declined biexponentially with respect to time. Mean plasma half-life was 2.15 hr and plasma clearance averaged 862 ml/min. There was no rise in "standing" systolic blood pressure on oral administration (200 to 600 micrograms/kg). Peak plasma concentrations ranged from less than 0.1 to 2 ng/ml. Apparent oral absorption for DHE ranged from 19.5% to 53.3% while systemic bioavailability varied from less than 0.1% to 1.5%. when glyceryl trinitrate was taken orally with DHE, the bioavailability of the latter increased between 56% and 370% over the 0.1% to 1.5% without any apparent alteration in DHE absorption. Standing systolic blood pressure increased 27% (P less than 0.05) 2 hr after the same doses of DHE with glyceryl trinitrate. These findings suggest that the extent of first-pass extraction by the liver is the prime determinant of DHE bioavailability after oral administration and that factors that alter gastrointestinal and portal vein flow to the liver affect its bioavailability.

Absorption↗
PubMed1981

Effect of norepinephrine uptake blockers on norepinephrine kinetics.

We studied the effect of a single oral dose of the neuronal norepinephrine uptake blocker, desipramine 125 mg, on norepinephrine kinetics. Desipramine reduced the plasma norepinephrine clearance by approximately 20%, from 1.33 +/- 0.22 to 1.08 +/- 0.19 l/m2/min (p less than 0.01). Similarly, plasma norepinephrine clearance was slowed in patients with sympathetic nerves damaged by disease (idiopathic peripheral autonomic insufficiency). Desipramine also reduced the rate of spillover of norepinephrine to plasma, 0.27 +/- 0.07 to 0.15 +/- 0.04 micrograms/m2/min, leaving the plasma norepinephrine concentration unchanged. Disappearance of tritiated norepinephrine from plasma, after infusion to steady state, was biexponential, with half-time of the rapid-removal phase (t1 1/2) = 2.0 +/- 0.4 min and half-time of the second exponential (t2 1/2) = 34 +/- 10 min. The rapid-removal phase was sensitive to disturbances in the neuronal uptake of norepinephrine, the t1 1/2 being prolonged by desipramine and lengthened in the patients with peripheral autonomic insufficiency. In contrast, the selective extraneuronal norepinephrine uptake blocker, cortisol, 500 mg intravenously, had no effect in normal subjects on either plasma norepinephrine clearance or the t1 1/2 value. Neuronal uptake of norepinephrine contributes to the overall removal of norepinephrine from plasma. Extraneuronal uptake of norepinephrine could not be demonstrated at existing plasma norepinephrine concentrations.

Adult↗
PubMed1981

Age-dependence of noradrenaline kinetics in normal subjects.

1. The influence of age on the rate of spillover of noradrenaline into plasma, clearance of noradrenaline from plasma, and plasma noradrenaline concentration at rest was studied in 34 healthy subjects aged 20--69 years. 2. The plasma concentration of noradrenaline was dependent on age, values being higher in older subjects. 3. This age-dependence of plasma noradrenaline concentration was due principally to a reduced clearance of noradrenaline from the circulation in older subjects. 4. The rate of spillover of noradrenaline into plasma was little influenced by age. The higher plasma noradrenaline values found in older subjects do not seem to be due to an increase in sympathetic nervous system tone with aging.

Adult↗
PubMed1981

Effect of propranolol on noradrenaline kinetics in patients with essential hypertension.

1 The rates of noradrenaline spillover to, and removal from, plasma were measured in ten patients with essential hypertension treated with propranolol, to ascertain if long-term administration of this drug reduces sympathetic nervous system tone. 2 The plasma clearance of noradrenaline fell with propranolol, leading to a small rise in the mean plasma noradrenaline concentration. Sympathetic nervous activity in treated patients cannot be reliably gauged from plasma noradrenaline values because these are distorted by the reduction in noradrenaline clearance. 3 There was no consistent effect on noradrenaline spillover rates, which fell in six patients, but rose in the remaining four. The magnitude of the antihypertensive response was unrelated to these changes in noradrenaline release. During propranolol treatment, noradrenaline spillover rates were in every case within the normal range, much higher than in patients treated with the known sympathetic nervous systems suppressant, clonidine. 4 The principal mode of antihypertensive action of propranolol is something often than central suppression of sympathetic tone or pre-synaptic inhibition of noradrenaline release.

Adult↗
PubMed1980

Determination of noradrenaline uptake, spillover to plasma and plasma concentration in patients with essential hypertension.

1. The rates of entry of noradrenaline to plasma and of removal of noradrenaline from plasma, and plasma noradrenaline concentration, were determined in normal subjects and in patients with essential hypertension. Neuronal uptake of noradrenaline was assessed from the plasma tritiated noradrenaline disappearance curve, after infusion to steady state. 2. Noradrenaline disappearance was biexponential. Rapid removal was dependent on neuronal uptake, being slowed if neuronal noradrenaline uptake was reduced, either by desipramine in normal subjects, or in patients with sympathetic nerve dysfunction (autonomic insufficiency). 3. In 10 of 41 hypertensive patients the t 1 1/2 similarly was prolonged, presumptive evidence of a defect in neuronal noradrenaline uptake. Endogenous noradrenaline escaping uptake after release, and spilling over into plasma, and plasma noradrenaline concentration, were increased in these patients. 4. Defective neuronal uptake of noradrenaline, by exposing adrenoreceptors to high local transmitter concentration, may be important in the pathogenesis of essential hypertension in some patients.

Adult↗
PubMed1980

Study of noradrenaline uptake and spillover to plasma in normal subjects and patients with essential hypertension.

Noradrenaline uptake was studied in normal subjects, and in patients with essential hypertension. Uptake of noradrenaline by blood platelets was low-affinity in type. Platelets do not provide a satisfactory in vitro model of neuronal noradrenaline uptake. Study of disappearance of tritiated noradrenaline from the circulation was more helpful. Plasma disappearance was biexponential. The rapid removal component was slowed if neuronal noradrenaline uptake was reduced, either by desipramine in normal subjects, or in patients with idiopathic peripheral autonomic insufficiency, who have sympathetic nerve dysfunction. The t1 1/2 similarly was prolonged in a proportion of patients with essential hypertension, providing presumptive evidence of a defect in neuronal noradrenaline uptake. Spillover of endogenous noradrenaline to plasma, of transmitter escaping uptake after release, and plasma noradrenaline concentration, were increased in these patients. Defective neuronal uptake of noradrenaline, by exposing adrenergic receptors to high local transmitter concentration, may be important in the pathogenesis of essential hypertension in some patients.

Biological Transport, Active↗
PubMed1980

Norepinephrine kinetics in patients with idiopathic autonomic insufficiency.

The rates of norepinephrine release into plasma and removal from plasma were studied in patients with idiopathic peripheral autonomic insufficiency (sympathetic neuronal dysfunction), as it was thought that plasma norepinephrine concentration alone inadequately quantifies the degree of sympathetic nervous underactivity in this disorder. In four patients with autonomic insufficiency, clearance of norepinephrine from the circulation was slowed, 1.69 +/- 0.44 liters/min, compared with 2.80 +/- 0.73 liters/min in 10 normal subjects (P less than 0.05). As a consequence, despite a 60% lower norepinephrine apparent secretion rate, 0.19 +/- 0.12 microgram/m2 per min vs. 0.54 +/- 0.20 microgram/m2 per min, the plasma norepinephrine concentration was near normal. The plasma concentration of neurotransmitter does not provide a valid index of sympathetic nervous tone in this disorder in which removal of norepinephrine from the circulation is slowed.

Dysautonomia, Familial↗
PubMed1978

The determinants of plasma-renin activity in essential hypertension.

Plasma-renin activity was studied, under different conditions of sitmulation, in normal subjects and patients with essential hypertension. In normal subjects, three components of renin release, "basal," "neural," and "sodium-sensitive," could be delineated. Among the hypertensive patients, abnormal patterns of renin release were noted. The categorization of patients according to "plasma-renin status," however, differed with the conditions of testing, being dependent both on the pathophysiology of the essential hypertension and the character of the renin-releasing stimulus, specifically whether this stimulus elevated plasma-renin activity through a predominantly neural (upright posture) or non-neural mechanism (dietary sodium deprivation). Abnormal plasma-renin activity in essential hypertension resulted in part from disordered sympathetic nervous system function. Patients with mild hypertension and elevated plasma-renin activity exhibited increased neural stimulation of renin release, whereas in patients with low plasma-renin values, all three components of renin release, including the neural element, were diminished.

Adolescent↗
PubMed1978

Determinants of baroreflex sensitivity in man.

To determine the relationship of BRS to age, ACI, TPRI, and MBP, 61 male subjects, 19 to 65 years of age, whose MBP ranged from 77 to 134 mm Hg, were investigated. Partial correlative analysis was used to hold individual variables constant so that the effect of each on a given BRS relationship could be observed. An independent and significant relationship was observed between BRS and age; BRS and ACI correlated significantly through the influence of age, TPRI, and MBP; BRS and TPRI did not correlate; a significant BRS-MBP relationship existed through the influence of ACI. It was concluded that TPRI was not directly related to BRS and that the relationship of MBP to BRS was dependent on the influence of ACI whereas age was independently related to BRS.

Adult↗
PubMed1977

Mild high-renin essential hypertension. Neurogenic human hypertension?

To determine whether the elevated plasma renin activity in some cases of mild essential hypertension expresses sympathetic-nervous-system over-activity, we compared indexes of sympathetic activity in 16 patients with mild high-renin essential hypertension, 15 hypertensive patients with normal plasma renin activity and 20 normal subjects. Patients with elevated activity exhibited a raised plasma norepinephrine concentration (P less than 0.05), a greater fall in cardiac output with cardiac beta-adrenergic blockade by intravenous propranolol (P less than 0.01), reduction in total peripheral vascular resistance with alpha-adrenergic blockade produced by intravenous phentolamine (P less than 0.01), and reduction to normal of blood pressure by "total" autonomic blockade (atropine, propranolol and phentolamine). On psychometric testing, patients with high-renin hypertension, but not those with normal plasma renin activity, exhibited suppressed hostility (P less than 0.01), a behavioral pattern linked to increased sympathetic activity. The hypertension in these patients with high renin activity is neurogenic and possibly psychosomatic in origin.

Adolescent↗
PubMed1977

Pathophysiologic and pharmacokinetic determinants of the antihypertensive response to propranolol.

The tendency for patients with essential hypertension to differ markedly in antihypertensive response to propranolol could arise from pathophysiologic or pharmacokinetic differences between them. This possibility was investigated in 23 men with mild to moderately severe essential hypertension. At each of three propranolol doses, 40 mg, 80 mg, and 320 mg daily, approximately a 20-fold range in steady-state plasma propranolol concentrations was observed. Clinical response however was unrelated to plasma propranolol: oral dose ratio, since patients with higher plasma levels were less sensitive to the existing plasma drug concentration. When falls in blood pressure and plasma propranolol concentration were compared overall, a biphasic dose-response relationship was noted, with a first component at plasma propranolol concentrations of 3 to 30 ng/ml and a second at concentrations above 30 ng/ml. Only patients with increased sympathetic nervous system activity and high plasma renin activity (PRA) had substantial falls in pressure at propranolol levels of 3 to 30 ng/ml. Cardiac beta adrenergic receptor blockade, not suppression of PRA, seemed to be the antihypertensive mechanism. This relation of pretreatment sympathetic nervous activity and PRA to antihypertensive response existed only at lower plasma propranolol concentrations. With a propranolol dose of 320 mg daily, both plasma norepinephrine concentration and PRA were unrelated to the clinical response.

Adolescent↗
PubMed1977

Blood pressure, renin activity and heart rate changes during propranolol therapy of hypertension.

To investigate the importance of plasma renin activity in determining the antihypertensive action of propranolol and of heart rate in guiding propranolol therapy, the effect of a graded oral dose of propranolol on blood pressure, plasma renin and heart rate was studied in 24 men with essential hypertension and differing initial levels of renin activity. Although plasma renin decreased substantially in patients with normal and high renin levels tasking a small dose of propranolol (40 mg/day), blood pressure was unchanged in the normal renin group, and a small decrease in systolic pressure alone was noted in those with high plasma levels of renin. Patients with low renin levels had no reduction in blood pressure with small doses of propranolol, but as a group they responded well to a dose of 320 mg/day. Standing heart rate decreased maximally at plasma propranolol concentrations greater than 25 ng/ml, and did not exceed 72 beats/min with plasma concentrations above that level. Overall, the observed responses for plasma renin and heart were more pronounced at lower plasma propranolol concentrations than those for blood pressure.

Adult↗