Biomedical subjects

J L Reid

Publications and source records attributed to J L Reid.

At least 199 records · Page 11Linked to original sources

PubMed1989

Regulation of beta 1- and beta 2-adrenoceptors following chronic treatment with beta-adrenoceptor antagonists.

The effect of chronic pretreatment of guinea pigs with various beta-adrenoceptor antagonists on the binding characteristics of the radioligand 125I-cyanopindolol (ICYP) and responsiveness of adenylate cyclase to isoprenaline in the gastrocnemius muscle (beta 2-adrenoceptors) and the left ventricle (beta 1-adrenoceptors) were compared. Pretreatment of guinea pigs with propranolol or ICI 118,551 for one week significantly increased the density of the beta 2-adrenoceptors in the gastrocnemius muscle. Atenolol pretreatment for one week did not affect the density of the receptors. Pretreatment of the animals with pindolol for one week reduced the density of beta 2-adrenoceptors in skeletal muscle. In the left ventricle pretreatment of the guinea pigs with any of the antagonists did not alter either the density or the KD of beta 1-adrenoceptors. The responsiveness of adenylate cyclase to isoprenaline (10(-4) M) in the left ventricle or skeletal muscle was not affected when the guinea pigs were pretreated with propranolol. Pretreatment of the guinea pigs with reserpine (0.5 mg.kg-1) intraperitoneally for one week, to deplete catecholamines did not affect beta-adrenoceptor density or KD in the left ventricle or skeletal muscle. We conclude that the regulation of beta-adrenoceptors by the antagonist may not be caused by the prevention of the access of endogenous agonists to beta-adrenoceptors and it is dependent on the selectivity of the antagonist and on the susceptibility of the receptors to regulation.

Adenylyl Cyclases↗

PubMed1989

Effects of short-term exposure to noradrenaline and adrenaline on adrenoceptor responses.

Adrenaline (0.05 and 1.5 mumol/kg per h) and noradrenaline (0.09 and 0.5 mumol/kg per h) were infused i.v. into conscious rabbits. Pressor responses to bolus doses of phenylephrine, alpha-methylnoradrenaline and chronotropic responses to isoprenaline were studied before and during infusion. Plasma adrenaline levels rose from 1.4 +/- 0.5 to 13 +/- 2 and 31 +/- 9 nM during the 0.05 and 1.5 mumol/kg per h infusions respectively while noradrenaline levels rose from 2.0 +/- 0.9 to 16 +/- 7 and 29 +/- 11 nM during the 0.09 and 0.5 mumol/kg per h noradrenaline infusions. Pressor responses to alpha-methylnoradrenaline were attenuated within 2.5 and 60 min during the higher and lower rates of adrenaline infusion respectively. Attenuation occurred within 10 min with the higher rate infusion of noradrenaline but no change was seen during the lower noradrenaline infusion. Chronotropic responses to isoprenaline were also reduced during the adrenaline infusions but not during noradrenaline infusion. In contrast no change was observed in phenylephrine pressor responses. These results suggest that short-term elevation in the levels of the endogenous catecholamines, noradrenaline and adrenaline, can cause desensitisation of alpha 2- and beta-adrenoceptors but not of alpha 1-adrenoceptors.

Animals↗

PubMed1989

First-line and combination treatment for hypertension.

Conventional stepped-care approaches for the control of high blood pressure based on the use of diuretics and beta-blockers have had a disappointing impact on coronary heart disease, the major cause of death in hypertension. Drug therapy for blood pressure should be complementary to attempts to control other risk factors and should not adversely affect other factors. A range of drugs, including calcium antagonists, angiotensin-converting enzyme inhibitors, and alpha-blockers, can be considered as possible first-line treatment. The choice of drug therapy should be individualized and the minimal number of drugs used in the simplest rational regimen. Simple demographic factors and associated diseases, risk factors, and activities should be used to select the most appropriate agents. New combinations offer alternatives for patients who do not receive adequate control with monotherapy.

Adrenergic beta-Antagonists↗

PubMed1989

Pharmacokinetics of an ACE inhibitor, S-9780, in man: evidence of tissue binding.

Pharmacokinetic data from 20-min constant rate infusions of the ACE inhibitor S-9780 1 mg to 16 subjects were studied for evidence of nonlinearity. A hierarchy of standard compartmental models and of nonlinear binding models was fitted to the data by least squares nonlinear regression and the most appropriate model was chosen on the basis of F-ratio tests, Schwarz criteria, and residual plots. A one-compartment model which included saturable tissue and plasma binding components allowed the best overall description of the data. Median parameter estimates from this model suggest that approximately 308 nmol of plasma binding sites and 572 nmol of tissue binding sites were present and that the total plasma concentration of S-9780 at 50% saturation of binding sites was 16.5 nmol L-1. The elimination half-life for free drug in plasma was only 30 min. This model describes the discrepancy previously noted between accumulation and apparent elimination half-lives for long-acting ACE inhibitors and offers a noninvasive method for assessment of tissue-bound ACE inhibitor in vivo.

Adult↗

PubMed1989

Angiotensin-converting enzyme inhibitors in the elderly.

Although early studies suggested little role for angiotensin-converting enzyme (ACE) inhibitors in older hypertensive patients, more careful evaluation has confirmed their efficacy and good tolerability. Although the elderly tend to have low plasma renin levels, the fall in blood pressure after ACE inhibitors is at least as great (and in several studies greater) than in younger age groups. Because several ACE inhibitors, including captopril and enalaprilat, are eliminated by the kidneys, there are predictable age-related effects on pharmacokinetics. Reduced renal clearance will contribute, at least in part, to the enhanced intensity and duration of action seen in elderly patients. However, not all the effects of age on the kinetics and dynamics of ACE inhibitors are predictable. Studies with perindopril and benazepril in the elderly confirm the efficacy of this group of drugs but highlight other pharmacokinetic differences. ACE inhibitors are effective in reducing blood pressure and can be considered for wider use in elderly hypertensives.

Aged↗

PubMed1989

Comparison of enalapril and atenolol in mild to moderate hypertension.

PURPOSE: Short-term therapy with angiotensin converting enzyme (ACE) inhibitors for hypertension is effective and well tolerated, and compared with beta blockers, may cause fewer adverse reactions. Furthermore, enalapril has been observed to have a greater effect on systolic blood pressure than beta blockers. We therefore decided to compare the ACE inhibitor enalapril and the beta blocker atenolol as monotherapy in a double-blind study of patients with mild to moderate hypertension. PATIENTS AND METHODS: After a four-week placebo run-in period, 162 patients were allocated randomly to receive atenolol (50 to 100 mg daily) or enalapril (20 to 40 mg daily) for 12 weeks. To assess the influence of these drugs on quality of life, a series of psychologic tests was performed, and a subset of patients also underwent treadmill exercise and pulmonary function tests. RESULTS: In 147 patients who completed the study, enalapril reduced supine blood pressure by 19/12 mm Hg, compared with 9/7 mm Hg for atenolol (p less than 0.001/p less than 0.005). The modest blood pressure response to atenolol was not due to poor compliance. A target blood pressure of 140/90 mm Hg or less was achieved by 35 percent of enalapril-treated atenolol (p less than 0.01). The frequency and severity of adverse effects with the two drugs were similar, and few important differences emerged from the quality-of-life assessments. CONCLUSION: At the doses used, enalapril induced a greater short-term blood pressure response than atenolol; long-term studies of its safety and efficacy are required.

Adolescent↗

PubMed1989

Predictability of antihypertensive responsiveness and alpha-adrenoceptor antagonism during prazosin treatment.

This study investigates concentration-effect relationships in nine patients who had essential hypertension treated with prazosin. Antihypertensive responsiveness was determined for each individual patient in terms of millimeters of mercury of blood pressure reduction per nanogram per milliliter of plasma prazosin concentration. The principal findings were that there was significant attenuation of antihypertensive responsiveness, from 11.5 mm Hg per nanogram per milliter after the first dose to 8.7 mm Hg per ng/ml after 1 week of treatment with prazosin. Correspondingly, there was significant attenuation of the degree of alpha 1-antagonism as assessed by the pressor response to intravenous phenylephrine. However, there was no significant further attenuation of either assessment during continued treatment for up to 3 months. These findings suggest that after an early adaptation, which occurs within the first week of treatment, there is no long-term attenuation of the antihypertensive effect of prazosin. Despite this initial adaptive change, the magnitude of the long-term antihypertensive effect of prazosin was predictable from the first dose response in individual patients.

Adrenergic alpha-Antagonists↗

PubMed1989

Prediction of response to antihypertensive therapy with enalapril and nifedipine.

We evaluated the usefulness of an integrated concentration-effect modelling technique in predicting the long-term response to antihypertensive therapy with enalapril and nifedipine. Two groups of essential hypertensives were given monotherapy with 20 mg nifedipine twice a day (n = 14) or 20 mg enalapril once a day (n = 13), and were studied following the administration of the drugs and after at least 6 weeks' treatment. For both drugs the predicted responses (predose and 4 h postdose) were in close agreement with the observed responses. With enalapril the observed and predicted profiles over a 12-h study period were well correlated in all subjects. In contrast, with nifedipine, although there was generally good agreement, the model over-predicted the profile of response in one patient and under-predicted the profile in one patient. Thus, there is evidence that application of concentration-effect analysis is useful in predicting the steady-state antihypertensive effect from the first dose-response to the drug.

Blood Pressure↗

PubMed1989

Hypercholesterolaemia in treated hypertensives: a controlled trial of intensive dietary advice.

We evaluated dietary counselling by dietitians in hypercholesterolaemic hypertensives over 6 months. A total of 141 patients were randomly assigned to intensive advice or usual care. Body weight fell significantly in the intervention group, but did not in the controls. There was a modest but significant fall in total cholesterol from 7.1 to 6.8 and 7.1 to 6.9 mmol/l in the diet and the control groups, respectively (4 and 3%). A similar pattern emerged from the triglyceride measurements. Low-density lipoprotein fell in both groups, but only achieved significance (P less than 0.05) in the intervention group. High-density lipoprotein did not change. There was a more marked change in cholesterol when serum levels during the study were compared with the previous annual review. These falls occurred after selection for the study but before random allocation to groups. They are unlikely to reflect regression to the mean as the lipids were stable for 2 or more years before the study, but may reflect spontaneous changes in diet after the patients were labelled hypercholesterolaemic. Dietary advice can lower total cholesterol but the magnitude of this decrease is small. Additional approaches are likely to be required to reduce plasma cholesterol to a normal range.

Antihypertensive Agents↗

PubMed1989

Twenty-four-hour intragastric acidity in duodenal ulcer patients during dosing with placebo, and 150 mg ranitidine twice or four times daily.

Twenty-four-hour intragastric acidity was measured in 10 patients with a past history of duodenal ulcer on the fourth day of dosing with placebo, and either 150 mg ranitidine given twice or four times daily. The order of the treatments was randomized and a double-blind design was employed. Ranitidine (150 mg) b.d. decreased median integrated 24-h intragastric acidity by 65.1%, nocturnal acidity by 89.1%, and daytime acidity by 54.6% (all P less than 0.01 compared to placebo). The corresponding decreases with 150 mg ranitidine q.d.s. were 62.3, 89.9 and 48.8%, respectively (all P less than 0.01) compared to placebo). There were no significant differences between the two dosage regimens of ranitidine (P greater than 0.05). This study shows that giving extra doses of 150 mg ranitidine during the day does not increase the degree of suppression of intragastric acidity.

Adult↗

PubMed1989

Effect of CGP 17/582, a selective beta-adrenoceptor antagonist, on the haemodynamic and hypokalaemic response to adrenaline.

1. CGP 17/582B is a new beta-adrenoceptor antagonist which on experimental studies appears to combine selective beta 1-adrenoceptor blockade with partial agonist activity (ISA). Assessing beta-adrenoceptor selectivity and the degree of partial agonist activity in vivo can be difficult. 2. In a double-blind placebo controlled crossover study we have compared the effect of oral pretreatment for 7 days with CGP (100 mg twice daily), with propranolol (non-selective beta-adrenoceptor blocker with no ISA) and metoprolol (selective beta-adrenoceptor blocker with no ISA) on resting heart rate and heart rate response to submaximal exercise on a bicycle ergometer to assess the degree of beta-adrenoceptor blockade and also the changes in blood pressure, heart rate and potassium during the intravenous infusion of (-)-adrenaline to determine the degree of beta 2-adrenoceptor blockade. 3. Subjects underwent submaximal exercise testing on the second and fifth day of each treatment period and on the seventh day received a 2 h infusion of (-)-adrenaline (0.06 microgram kg-1 min-1). Heart rate, blood pressure, plasma potassium and catecholamines were measured throughout the study period. 4. All three active treatments significantly reduced exercise induced tachycardia. The (-)-adrenaline infusion significantly reduced plasma noradrenaline levels following propranolol and metoprolol and to a lesser extent with placebo but were unaltered on CGP. Baseline heart rate was unaltered by CGP but was significantly reduced by metoprolol and propranolol. Adrenaline significantly reduced plasma potassium levels following placebo and CGP pretreatment but plasma potassium was unaltered by adrenaline with metoprolol and propranolol pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMed1989

The pharmacokinetics and angiotensin converting enzyme inhibition dynamics of cilazapril in essential hypertension.

1. In a double-blind, placebo controlled, crossover study 12 patients with essential hypertension received single doses of 5, 10 and 20 mg of cilazapril. 2. Peak plasma levels of cilazaprilat and the 24 h areas under curve were directly proportional to dose. 3. The elimination half-life during the first 8 h was about 1.7 h. 4. From 24 h onwards there was a prolonged terminal elimination phase with a half-life of about 40 h, and strict dose proportionality of plasma concentrations was not maintained. 5. The pharmacokinetics of cilazaprilat and the pharmacodynamics of plasma ACE inhibition were well described by a one compartment model with saturable binding to ACE. 6. The coefficients of the model which related to plasma ACE and its interaction with cilazaprilat were in good agreement with model independent observations. 7. The values for kinetic and dynamic parameters in hypertensive patients were comparable with those reported for healthy volunteers.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1989

The influence of cilazapril on indices of autonomic function in normotensives and hypertensives.

1. In two single dose studies, acute blood pressure reduction with cilazapril was not associated with any significant change in supine or erect heart rate in either normotensives or hypertensives. 2. To investigate the lack of reflex cardioacceleration, a series of autonomic function tests was undertaken when there was maximum ACE inhibition, maximum evidence of angiotensin II withdrawal and the lowest blood pressure. 3. There was no evidence that cilazapril had any significant impact on indices of sympathetic nervous activity or the integrity of baroreflex mechanisms. 4. The results for the bradycardic response to apnoeic facial immersion, suggested enhanced parasympathetic activity, consistent with the withdrawal of the vagolytic actions of angiotensin II. 5. These results suggest that the absence of a heart rate response to ACE inhibition is not related to a profound sympatho-inhibitory effect or an impairment of baroreflex function. While there is some evidence of enhanced cardiac parasympathetic tone it seems unlikely that this is the sole explanation for the lack of cardioacceleration.

Adult↗

PubMed1989

The pharmacokinetics and pharmacodynamics of perindopril in patients with hepatic cirrhosis.

1. Perindopril, a new ACE inhibitor, is a prodrug requiring conversion into its active form perindoprilat by hydrolysis in the liver. 2. The pharmacodynamics and pharmacokinetics of perindopril (8 mg oral) and perindoprilat (2 mg intravenously) were studied in a double-blind randomised crossover study in a group of patients with compensated biopsy-proven hepatic cirrhosis. 3. Blood pressure and heart rate responses were similar after the two routes of administration as were plasma renin activity and aldosterone levels following dosing. 4. The AUC of perindoprilat after oral administration of perindopril represented 46 +/- 4% of the total AUC of perindopril and its metabolite when expressed in molar terms. Comparison with the AUC of perindoprilat after its intravenous administration suggested that 30 +/- 6% of the oral dose of perindopril was converted to its active metabolite. 5. The findings are comparable with those in healthy subjects. It appears that the presence of relatively mild hepatic cirrhosis does not significantly alter the pharmacokinetics of perindopril.

Administration, Oral↗

PubMed1989

Concentration-effect relationships and individual responses to doxazosin in essential hypertension.

1. This study investigates aspects of the pharmacokinetics, pharmacodynamics and concentration-effect relationships in 10 patients with essential hypertension during acute and chronic treatment with doxazosin, an alpha 1-adrenoceptor antagonist. 2. Following the first dose of doxazosin (2 mg) there were significant reductions in blood pressure, increases in heart rate and in plasma noradrenaline, and parallel rightward shifts of the phenylephrine pressor response curves, consistent with alpha-adrenoceptor antagonism. There was no significant change in the pressor response to angiotensin II. 3. Using an integrated kinetic-dynamic model, individual blood pressure responsiveness was characterised as the fall in blood pressure (mm Hg) per unit drug concentration. Responsiveness to the first dose of doxazosin was directly correlated with the responsiveness after 1 and 6 weeks treatment although there was a systemic reduction (of approximately 30%) which occurred during the first week of treatment. 4. Neither the acute nor long-term responsiveness to doxazosin was related to age, plasma renin activity, plasma noradrenaline or the pretreatment sensitivity to phenylephrine. There was a significant relationship between responsiveness and the height of the initial (pretreatment) blood pressure. 5. Integration of pharmacokinetic and pharmacodynamic data provides a reproducible index of responsiveness which can be used to investigate the consistency of the long-term anti-hypertensive response, to identify factors which influence the magnitude of the response, and to optimise the choice of dose and dose interval.

Aged↗

PubMed1989

Beta-adrenoceptors and human skeletal muscle characterisation of receptor subtype and effect of age.

1. Rectus abdominis muscle biopsies were obtained from 28 patients undergoing abdominal surgery. In membranes prepared from these biopsies beta-adrenoceptor binding was examined. The apparent affinity (KD) and the density (Bmax) of the receptors for the radioligand (-)-[125I]cyanopindolol were 28.5 +/- 2.7 (pM) and 25.9 +/- 2.1 (fmol mg-1 protein) (mean +/- s.e. mean) respectively. In forceps biopsies from vastus lateralis muscle from four healthy volunteers the values for KD and Bmax were 22.5 +/- 4.4 (pM) and 16.4 +/- 2.2 (fmol mg-1 protein). The binding characteristics for the radioligand were similar in the biopsies from the two muscle sites. 2. Inhibition of the radioligand binding by the selective beta 2-adrenoceptor antagonist ICI 118551 (KI = 117 +/- 45 nM) and selective beta 1-adrenoceptor antagonist metoprolol (KI = 15229 +/- 5046 nM) suggests the dominance of beta 2-adrenoceptor subtype in human skeletal muscle. 3. There were no significant differences in the skeletal muscle beta-adrenoceptor densities or affinities between the young and older patients.

Adolescent↗

PubMed1989

Skeletal muscle beta 2-adrenoreceptors and the effect of adrenergic drugs on plasma potassium in perinephritis hypertension in rabbits.

1. It has been suggested that beta 2-adrenoreceptors in skeletal muscle regulate plasma potassium. The possibility that alterations in the function and/or density of these receptors occurs in perinephritis hypertension in rabbits was studied. 2. Intravenous infusion of adrenaline (0.2 micrograms kg-1 min-1) caused a fall in potassium while intravenous bolus injection of propranolol (0.75 mg kg-1) resulted in an increase in serum potassium which was of similar magnitude in both perinephritis hypertensive and sham-operated normotensive rabbits. 3. Binding studies with the radioligand [125I] cyanopindolol (ICYP) showed that there were no significant differences between the hypertensive and normotensive rabbits in the density (Bmax) or affinity (KD) of the skeletal muscle beta 2-adrenoreceptor. 4. The results suggest that function and density of skeletal muscle beta 2-adrenoreceptors are not altered in rabbits with perinephritis hypertension.

Animals↗

PubMed1989

The cardiovascular actions of clonidine and neuropeptide-Y in the ventrolateral medulla of the rat.

1. The cardiovascular responses to neuropeptide-Y (NPY) (25 and 50 pmol) and clonidine (10 and 20 nmol) were examined following microinjection into the rostral ventrolateral medulla (RVLM) and the caudal ventrolateral medulla (CVLM). Mean arterial pressure (MAP) and heart rate (HR) were measured in anaesthetized rats, pre- and post-injection. 2. The alpha 2-adrenoceptor agonist clonidine (10 and 20 nmol) reduced MAP and HR significantly when microinjected into the CVLM and RVLM. 3. NPY (25 and 50 pmol) microinjected into the CVLM decreased MAP and HR. However, in the RVLM neither dose had a significant cardiovascular effect. 4. The possibility of a functional interaction between the adrenergic system and NPY was examined by co-administration of clonidine and NPY in doses that gave submaximal blood pressure responses. In the CVLM this produced hypotension and bradycardia which was similar in magnitude to the sum of their individual responses, indicating that in this area their actions appear to be independent. 5. In the RVLM, where NPY has no significant cardiovascular effects, co-administration with clonidine, did not alter the response to clonidine. 6. It appears that in the areas investigated, there is no functional interaction between NPY and clonidine.

Animals↗