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Biomedical subjects

J L Reid

Publications and source records attributed to J L Reid.

At least 271 records · Page 15Linked to original sources
PubMed1987

Haemodynamic, metabolic, and lymphocyte beta 2-adrenoceptor changes following chronic beta-adrenoceptor antagonism.

We have examined the effects of 7 days treatment with beta adrenoceptor antagonists in 8 healthy volunteers in a placebo controlled, crossover study. We investigated three beta-adrenoceptor antagonists (atenolol, oxprenolol, and propranolol), which have differing profiles of selectivity and partial agonist properties (intrinsic sympathomimetic activity, ISA). We studied adrenaline-induced hypokalaemia, the vasodilator response to an infusion of adrenaline (0.06 micrograms X kg-1 X min-1 for 90 min), and lymphocyte beta 2-adrenoceptor number, determined by (-) [125I]-iodocyanopindolol binding, and measured these variables both before and after 7 days of treatment. The beta 2-mediated depressor response to adrenaline infusion was abolished by propranolol and oxprenolol but persisted after atenolol. In contrast, the hypokalaemia induced by adrenaline was abolished by all three beta-blockers. Lymphocyte beta 2-adrenoceptor number increased significantly following propranolol treatment, but not after oxprenolol for atenolol. We conclude that up-regulation of lymphocyte beta 2-adrenoceptors is dependent on beta 2-receptor blockade and is modified by ISA. The reversal of the hypokalaemic response by atenolol suggests that beta 1 receptors may contribute to the former effect. Alternatively, since different populations of beta 2-adrenoceptors differ in their susceptibility to antagonists there may also be differences in agonist coupling to beta 2-responses between tissues.

Adrenergic beta-Antagonists↗
PubMed1987

Age and the pharmacokinetics and pharmacodynamics of chronic enalapril treatment.

Enalapril clearance after single doses is reduced in the elderly. The influence of age on the pharmacokinetics and pharmacodynamics of chronic enalapril treatment was examined in six young (22 to 31 years) and six elderly (65 to 78 years) healthy subjects who took enalapril, 10 mg, daily for 8 days. The blood pressure fall was greater in the elderly even with chronic administration. Plasma angiotensin-converting enzyme inhibition was similar in both groups. Steady-state serum enalaprilat concentrations were achieved more slowly in the elderly subjects and were correspondingly higher for all subjects. Clearance/bioavailability and volume of distribution/bioavailability diminished with repeated administration. Repeated exposure also led to a reduction in sensitivity of plasma angiotensin-converting enzyme to the inhibitor. Prolonged inhibition probably induces synthesis of new angiotensin-converting enzyme.

Adult↗
PubMed1987

Adrenergic control of plasma magnesium in man.

Regulation of magnesium balance is poorly understood. However, hypomagnesaemia has been reported in patients in clinical situations where circulating catecholamines are raised including myocardial infarction, cardiac surgery and insulin-induced hypoglycaemia stress tests. The effects of L-adrenaline infusions, sufficient to achieve pathophysiological levels of adrenaline, and of therapeutic intravenous infusions of salbutamol, a beta 2-agonist, on plasma magnesium, plasma potassium, plasma glucose and plasma insulin levels were studied in a placebo-controlled design in eight normal subjects. Plasma magnesium levels fell significantly during the adrenaline infusion and also during the salbutamol infusion, though more slowly. In a 1 h period of observation after cessation of the infusions no recovery of plasma magnesium levels was seen. Significant falls in plasma potassium levels were also observed during both infusions with spontaneous recovery within 30 min after the infusions. No significant changes in plasma insulin levels occurred with either salbutamol or L-adrenaline compared with control. Plasma glucose levels rose significantly during the adrenaline infusion. The study suggests that both L-adrenaline and salbutamol cause shifts in plasma magnesium which are not mediated by insulin. We propose that intracellular shifts of magnesium occur as a result of beta-adrenergic stimulation.

Adult↗
PubMed1987

Effects of intravenous S-9780, an angiotensin-converting enzyme inhibitor, in normotensive subjects.

S-9780 is the active diacid metabolite of the new angiotensin-converting enzyme (ACE) inhibitor perindopril. In a double-blind, randomised, crossover study, the effects of 1, 2, and 4 mg of S-9780 administered intravenously (i.v.) were compared with placebo in eight normotensive subjects. All active doses caused immediate, maximal, and similar inhibition of plasma ACE with 40% inhibition persisting after 48 h. Plasma renin activity was elevated 4 and 8 h after dosing, but no effect on plasma aldosterone, adrenaline or noradrenaline levels was detected. Diastolic blood pressure was lowered by 4 mg of S-9780 until 24 h after dosing. Heart rate did not change. The pharmacokinetics of S-9780 fitted a three-compartment model with a terminal half-life (t1/2) of 31 h. Inhibition of plasma ACE was closely related to observed drug concentration, with 1.8 +/- 0.9 ng/ml (mean +/- S.D.) producing 50% inhibition of the enzyme. S-9780 caused predictable effects on the cardiovascular and renin angiotensin systems.

Adolescent↗
PubMed1987

An evaluation of the pharmacodynamics and pharmacokinetics of nicardipine combined with enalapril in essential hypertension.

Recent observations suggest that calcium antagonists may enhance the antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors. Twelve essential hypertensives who had blood pressures greater than 160/90 after a minimum of 6 weeks of monotherapy with the ACE inhibitor enalapril 20 mg daily received additional treatment with nicardipine 30 mg t.i.d. and placebo, each for 2 weeks, in a double-blind crossover study. The combination of nicardipine with enalapril was well tolerated. The addition of the first dose of nicardipine was associated with significant reductions (p less than 0.05) in blood pressure during the first 4 h: from a baseline of 165/99 to 128/80 (supine) at 2 h after nicardipine as compared with 167/101-146/90 following placebo. Two weeks of combined treatment with nicardipine and enalapril significantly reduced the predosing blood pressure, 12 h after the last dose of nicardipine (158/96 as compared with 172/106 with placebo), and there were further significant reductions in blood pressure during the subsequent dosage interval. The profile of plasma ACE inhibition and the pharmacokinetics of enalaprilat were unaffected by the addition of nicardipine. These results suggest that nicardipine and enalapril are an effective and well-tolerated antihypertensive combination.

Adult↗
PubMed1987

The mechanism of salbutamol-induced hypokalaemia.

The following four intravenous treatments were administered in a balanced, randomized Latin square design to eight healthy volunteers: (-)-adrenaline (0.06 microgram kg-1 min-1 for 90 min) + vehicle control (+)-glucose infusion (60 min), salbutamol (120 ng kg-1 min-1 for 30 min) + vehicle control (+)-glucose infusion (90 min), (-)-adrenaline (0.06 microgram kg-1 min-1 for 90 min) + salbutamol (120 ng kg-1 min-1 for 30 min) and two vehicle control infusions of (+)-glucose. All active solutions were preceded by a 1 h control infusion and the control infusion was continued for 1 h following the active solutions. Both the active solutions, (-)-adrenaline and salbutamol were increased stepwise to the above doses. Heart rate and blood pressure were recorded at frequent intervals throughout and venous blood was taken for the estimation of potassium, insulin, glucose, catecholamine and salbutamol levels. Adrenaline levels similar to those seen in acute illness were achieved using this infusion protocol. Salbutamol levels rose throughout the period of the salbutamol infusions and steady-state was not achieved. Potassium levels were unchanged on the control + control study day and fell on all active treatments (0.45 mmol l-1 following (-)-adrenaline + control; 0.48 mmol l-1 following salbutamol + control; 0.93 mmol l-1 following (-)-adrenaline + salbutamol). Insulin levels rose insignificantly after salbutamol alone and fell slightly on all other treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Haemodynamic and humoral effects of oral perindopril, an angiotensin converting enzyme inhibitor, in man.

The tolerance to and dynamic effects of 1 week's oral treatment with the angiotensin converting enzyme inhibitor, perindopril, were assessed in a placebo controlled, parallel group study in 36 normotensive males. The daily dose of perindopril was 1, 2, 4, 8 or 16 mg. The drug was well tolerated and produced no change in routine haematology or serum biochemistry tests. Dose related inhibition of plasma angiotensin converting enzyme was observed. Perindopril 16 mg produced 90% inhibition 4 h after dosing and 60% after 24 h. A dose related rise in plasma renin activity followed doses of 4 mg and over. The renin remained above the normal range for 24 h. Perindopril caused a modest lowering of plasma aldosterone levels but had no effect on plasma adrenaline or noradrenaline levels. Standing diastolic blood pressure was lowered, particularly with 16 mg daily of perindopril but only a slight rise in heart rate occurred. Perindopril appears to be a well tolerated inhibitor of plasma angiotensin converting enzyme, with predictable effects on the renin angiotensin system and blood pressure. An appropriate dose range for further study would appear to be 4 to 16 mg daily.

Adolescent↗
PubMed1987

A pragmatic approach to the pressor dose-response as an index of vascular reactivity and adrenoceptor function in man.

In clinical pharmacological studies, where it is not possible to describe the full dose-response curve, the construction of dose-response relationships ideally depends upon achieving a reproducible and readily measurable response for each dose administered. This study investigates in normotensive males the technique of dose-response analysis for the blood pressure and heart rate increases with constant infusions of incremental doses of vasoactive drugs, particularly catecholamines. Steady state responses could be adequately obtained using 5 min infusion periods (at each dose level) for noradrenaline and alpha-methyl noradrenaline. At least 7 min was required for phenylephrine and 8 min for isoprenaline. There was an approximate correlation between the time to achieve the steady state response and the half-life of the offset of the agonist effect. For interindividual comparisons it is desirable to compare steady state responses and so the time at each dose level will vary according to which agonist is being used. For intraindividual comparisons it may not be essential that steady state responses are achieved. For example, assessment of the effect of prazosin on the responses to phenylephrine, by calculation of dose ratios, indicated that 5 min dose intervals were adequate.

Adult↗
PubMed1987

Adimolol, a long acting beta-adrenoceptor blocker in man.

A comparative study in eight healthy normotensive males of the effects on blood pressure, heart rate and beta-adrenoceptor function following single oral doses of adimolol (600 mg), propranolol (240 mg) and placebo. Both active treatments produced small but significant reductions in blood pressure and heart rate, supine and erect. These effects persisted for up to 7 days after adimolol. The heart rate increases following both dynamic exercise and intravenous isoprenaline were attenuated by both propranolol and adimolol. With adimolol evidence of functional beta-adrenoceptor antagonism was sustained for up to 7 days. Lymphocyte beta-adrenoceptor binding studies showed that both adimolol and propranolol significantly reduced affinity for beta-adrenoceptors. In addition, adimolol significantly reduced receptor number and even by 3 days after dosing Bmax had only returned to half the control value. In a small sub-group of subjects there was no evidence to suggest that adimolol had additional alpha-adrenoceptor antagonist properties. Adimolol was detected in plasma for up to 3 days after dosing. The mean terminal elimination half-life was 14 h, compared to 3 h for propranolol. This study confirms that adimolol has prolonged beta-adrenoceptor antagonist activity with effects persisting for up to 7 days after a single dose. The reduction in beta-adrenoceptor number following adimolol suggests that this prolonged effect may not be solely due to competitive antagonism but may additionally depend upon non-competitive antagonism at beta-adrenoceptors.

Adrenergic beta-Antagonists↗
PubMed1987

Acute and chronic ketanserin in essential hypertension: antihypertensive mechanisms and pharmacokinetics.

1. In nine patients with essential hypertension, following single and multiple doses of ketanserin, assessments were made of blood pressure and heart rate, QT interval, and pressor responses to phenylephrine and angiotensin II. 2. Significant reductions in blood pressure occurred for 6 h after the first dose, on average 23/14 mm Hg supine, and there was a comparable antihypertensive effect after 1 month's treatment. 3. There were small but significant rightward shifts (1.5 to 2-fold) in the phenylephrine pressor-response curves but no changes in the responsiveness to angiotensin II. 4. The QT interval (QTc) was significantly increased after 1 month's treatment: at 1 h after dosing 334 +/- 32 ms after 1 month of ketanserin compared with 302 +/- 31 ms after placebo. 5. The elimination half-life and AUC for ketanserin were both significantly increased at steady state compared with the first dose: respectively 13.4 vs 4.3 h for half-life and 830 vs 437 ng ml-1 h for AUC. 6. Ketanserin had no significant effects on baroreflex function, plasma renin activity, aldosterone, catecholamines and 24 h urinary excretion.

Adult↗
PubMed1987

Enalapril in essential hypertension: the comparative effects of additional placebo, nicardipine and chlorthalidone.

The effect of adding placebo, a calcium antagonist, nicardipine and a thiazide diuretic, chlorthalidone, each for 2 weeks, to ongoing treatment with the ACE inhibitor, enalapril was evaluated in seven patients with essential hypertension. Compared with placebo, nicardipine and chlorthalidone both significantly enhanced the antihypertensive effect of enalapril: average blood pressure reductions over 8 h were respectively 26/16 and 33/17 mm Hg (supine) but the time-course of these augmented effects was significantly different. In particular, blood pressure control with the addition of nicardipine, despite apparently being at steady state, was significantly attenuated during the latter part of the dosage interval and therefore was less well sustained at 24 h. In contrast, an effect throughout 24 h appeared possible with the chlorthalidone-enalapril combination.

Acetylcholinesterase↗
PubMed1987

The effects of calcium antagonists on blood pressure and responses to alpha-adrenoceptor agonists in hypertensive rabbits.

The effects of the calcium antagonists verapamil and nifedipine on mean arterial blood pressure, heart rate and pressor responses to a range of alpha-adrenoceptor agonists were examined in male normotensive New Zealand white rabbits and in rabbits with perinephritis hypertension. Verapamil and nifedipine caused a greater fall in mean arterial pressure in hypertensive compared to normotensive rabbits both when the fall was expressed as an absolute and as a percentage change. Effects on heart rate were similar in normotensive and hypertensive animals. Pressor responses to phenylephrine were attenuated by nifedipine and verapamil in normotensive and hypertensive rabbits. Pressor responses to alphamethyl noradrenaline were also attenuated by nifedipine, but pressor responses to BHT 920 were not significantly altered by either calcium antagonist in normotensive or hypertensive rabbits at the dose used. Thus the calcium antagonists had a greater effect on alpha 1 - than alpha 2-adrenoceptor mediated responses in both normotensive and hypertensive rabbits. Hypertensive animals showed an increased responsiveness to phenylephrine and alphamethyl noradrenaline but not BHT 920 compared to normotensives. This difference remained after treatment with both the calcium antagonists.

Adrenergic alpha-Agonists↗
PubMed1987

Perindopril, a new angiotensin converting enzyme inhibitor--clinical pharmacological studies in healthy subjects.

Perindopril is a new angiotensin converting enzyme (ACE) inhibitor which is activated after hydrolysis in vivo to a diacid (S9780). Oral administration of perindopril (1-16 mg) to groups of 6 healthy males led to a long lasting and dose-elated inhibition of plasma ACE and rises in plasma renin activity with no evidence of accumulation of drug or effect. At higher doses there was a modest fall in blood pressure. S9780 given intravenously in doses of 1,2 or 4 mg caused an immediate inhibition of plasma ACE. The concentration of S9780 in plasma which led to 50% inhibition of plasma ACE was 1.55 +/- 1.14 ng/ml (mean +/- S.D.). Clinical trials with 2-8 mg once daily in essential hypertension are currently in progress.

Administration, Oral↗
PubMed1987

A clinical pharmacological study of nifedipine and lisinopril alone and in combination.

A double-blind, randomised, placebo-controlled, latin square design study of nifedipine, 20 mg, and lisinopril, 20 mg, alone and in combination was performed in 12 healthy male volunteers. Blood pressure, heart rate, lisinopril and nifedipine levels, plasma catecholamines, renin, aldosterone, and angiotensin converting enzyme activity were measured for 96 h after each acute dose. Both drugs lowered blood pressure (p less than 0.001), but the combination showed only additive effects. Heart rate rose over the first 4 h following the combination. Side effects were also additive. There was no effect of nifedipine on plasma ACE, renin, or aldosterone and no effect of either drug on plasma catecholamines. The pharmacokinetics of both drugs were unaltered in combination. Thus, nifedipine and lisinopril have additive dynamic effects with no pharmacokinetic interaction.

Adult↗
PubMed1987

Verapamil and prazosin in essential hypertension: evidence of a synergistic combination?

An enhanced hypotensive effect has been observed in short-term studies of the combination of an alpha-adrenoceptor antagonist and a calcium channel blocker. This study further evaluates combined treatment with prazosin and verapamil in 12 essential hypertensives who had not responded satisfactorily to standard beta-blocker and thiazide diuretic regimens. After placebo treatment, patients received monotherapy with either prazosin or verapamil. The appropriate second drug was then added, and combination treatment was continued for 4 weeks. A series of 8 h study days was undertaken at the end of each treatment phase to assess blood pressure, heart rate, and pharmacokinetics. Both monotherapies caused significant reductions in blood pressure. For the prazosin group the average blood pressure on monotherapy was 146/81 mm Hg (supine) and 151/88 mm Hg (erect), and for the verapamil group the corresponding figures were 149/81 and 156/92 mm Hg. In both groups significant further reductions in blood pressure were observed during combination treatment: on average, 133/74 mm Hg (supine) and 130/77 mm Hg (erect) for the prazosin group and, respectively, 137/75 and 141/85 mm Hg for the verapamil group. The pharmacokinetics of verapamil were not altered by the coadministration of prazosin, but there were changes in the pharmacokinetics of prazosin, with significant increases in peak plasma concentrations and bioavailability. Prazosin and verapamil form a useful antihypertensive drug combination. The overall effect is partly due to an increase in the apparent bioavailability of prazosin but may also reflect a synergistic effect on reducing peripheral vascular resistance.

Adult↗