Biomedical subjects

J L Reid

Publications and source records attributed to J L Reid.

At least 181 records · Page 10Linked to original sources

PubMed1990

Clinical studies with the potassium channel activator cromakalim in normotensive and hypertensive subjects.

Eight normotensive subjects received single and multiple doses of cromakalim (1 mg) and placebo in a randomised double-blind cross-over study to examine general tolerance to cromakalim and its effects on blood pressure (BP), heart rate (HR), and pressor responses to norepinephrine (NE) and angiotensin II (AII). In a second study, 10 hypertensive patients whose BP control was unsatisfactory with atenolol 50-100 mg received additional treatment with placebo followed by cromakalim 1 mg daily for 4 weeks. Assessments were made of BP, HR, apparent hepatic blood flow and renal blood flow (RBF), pulmonary function, and the pharmacokinetics of atenolol. Cromakalim was generally well tolerated in both normotensive and hypertensive subjects. In the normotensive group, cromakalim produced a reflex increase in HR without any detectable decrease in BP: average (placebo-subtracted) increases in HR at 4 h were 16 beats/min with subjects in an erect position after the single dose and 14 beats/min after 7 days. Cromakalim had no effect on pressor responses to NE and AII. Addition of cromakalim to atenolol was associated with modest further reductions in BP between 0.5 and 3 h after drug administration, with maximal reductions of 21/14 mm Hg (subjects in supine position) 2 h after the first dose. Cromakalim had no effect on apparent liver blood flow and RBF, pulmonary function, and the steady-state pharmacokinetics of atenolol. Single and multiple 1-mg doses of cromakalim are well tolerated but are associated with only modest vasodilator activity.

Adult↗

PubMed1990

Dose-plasma concentration--effect relationship of felodipine in essential hypertension: a review.

Calcium antagonists demonstrate a close relationship between plasma drug level and effect on blood pressure (BP). Thus, the intensity and duration of action can be influenced by dose and disposition. Felodipine has a dose-related effect on diastolic BP whether given alone or with a beta-blocker. The latter combination reduces adverse effects and improves tolerability, particularly at higher (20 mg/day) doses of felodipine. Felodipine 5 or 10 mg/day in an extended release formulation could be predicted to lower BP throughout a 24-h period. The results of formal prospective clinical trials confirm the predictions and indicate that felodipine can be used as a once-daily agent in essential hypertension.

Animals↗

PubMed1990

Pharmacodynamic, pharmacokinetic and humoral effects of oral zabicipril, an angiotensin converting enzyme inhibitor in normotensive man.

1. Zabicipril, S9650, a new angiotensin converting enzyme inhibitor, was administered to salt-replete, normotensive males in single doses of up to 10 mg. 2. The safety, tolerance and dose-response relationship with regard to inhibition of plasma ACE activity were characterised initially in an open, pilot, dose-finding study in 12 subjects and further explored in a double-blind, parallel group, placebo controlled study in another 30 subjects. 3. The drug was generally well tolerated and produced no change in routine haematology or serum biochemistry tests. 4. Dose related (0.03 to 10 mg) inhibition of plasma converting-enzyme was observed, with 2.5 mg of zabicipril producing over 90% inhibition at 4 h and 60% at 24 h. 5. There were no significant changes in blood pressure or heart rate in normotensive subjects over the dose range studied. 6. A dose related rise in plasma renin activity and angiotensin I was observed. No dose related reduction in plasma aldosterone was observed. 7. These initial studies suggest that zabicipril is a well tolerated inhibitor of converting enzyme with near maximal inhibitory effect occurring at a dose of 2.5 mg. Further exploration of the dose range after single and multiple doses is indicated.

Adult↗

PubMed1990

Binding studies of platelet alpha 2- and lymphocyte beta 2-adrenoceptors in patients with cirrhosis.

Radioligand binding studies were performed on 10 patients with cirrhosis and 10 healthy subjects. Bmax and KD of platelet alpha 2-adrenoceptors, studied using [3H]-yohimbine, were similar in both groups (Bmax 24.9 vs 22.1 fmol/10(9) platelets, P = 0.47; KD 4.6 vs 5.5 nmol 1-1, P = 0.56). Bmax and KD of lymphocyte beta 2-adrenoceptors, studied using [125I]-iodocyanopindolol, were also similar in both groups (Bmax 24.0 vs 27.2 fmol mg-1 protein, P = 0.55; KD 49.6 vs 55.3 pmol 1-1, P = 0.65). In this model there is no evidence of adrenoceptor down-regulation in cirrhosis despite the increased sympathetic activity in this condition.

Adult↗

PubMed1990

An evaluation of the alpha-adrenoceptor antagonism produced by SK&F 86466 in healthy normotensive males.

SK&F 86466 is a novel, potent alpha-adrenoceptor antagonist which, in animal experiments, is reported to show a high selectivity for alpha 2-adrenoceptors at both pre- and post-junctional sites. The effects of two intravenous doses of 80 and 200 micrograms kg-1 of SK&F 86466 were assessed in a placebo-controlled, double-blind, randomised study in eight young, healthy, normotensive males. Two indices of alpha-adrenoceptor activity were investigated: i) Pressor responsiveness to the relatively selective alpha 1-adrenoceptor agonist phenylephrine and to the preferential alpha 2-adrenoceptor agonist alpha-methylnoradrenaline. ii) Circulating levels of noradrenaline. SK&F 86466 at a dose of 200 micrograms kg-1 produced rightward shifts of the pressor dose-response curves to both agonists: a 1.4 fold shift for phenylephrine (P = 0.023) and a 1.6 fold shift for alpha-methylnoradrenaline (P = 0.051). Erect plasma noradrenaline sampled at 105 min into the infusion was significantly increased from 2.9 to 5.0 nmol l-1 by SK&F 86466 200 micrograms kg-1 (P = 0.002). The change in the phenylephrine responses indicates post-junctional alpha 1-adrenoceptor blockade and the rise in noradrenaline is consistent with pre-junctional alpha 2-adrenoceptor antagonist activity. Overall the results of this study suggest that SK&F 86466, at a dose of 200 micrograms kg-1, causes both alpha 1- and alpha 2-adrenoceptor antagonism in human subjects.

Adrenergic alpha-Antagonists↗

PubMed1990

Desensitization and down-regulation of brain alpha 2-adrenoceptors by centrally acting antihypertensive drugs.

Rabbits were treated with intravenous clonidine (8 mumol kg-1 day-1), guanabenz (20 mumol kg-1 day-1), rilmenidine (80 mumol kg-1 day-1) or vehicle via osmotic minipumps. After 6 days treatment mean arterial pressure (MAP), pressor responses to intravenous alpha-methyl noradrenaline and depressor responses to intracisternal clonidine were studied, and [3H]-yohimbine binding to forebrain and hindbrain examined in vitro. Clonidine, guanabenz and rilmenidine had similar effects on MAP and caused a similar attenuation of the depressor response to intracisternal clonidine, but only guanabenz attenuated pressor responses to intravenous alpha-methyl noradrenaline. Rilmenidine had no effect on [3H]-yohimbine binding to brain membranes. Clonidine treatment decreased binding in hindbrain while guanabenz treatment decreased binding in both fore- and hindbrain. Thus, the depressor effects of chronic treatment did not correlate with the effects on [3H]-yohimbine binding sites in rabbit brain suggesting that the blood pressure lowering effects of many centrally acting antihypertensive drugs are not necessarily dependent on binding to the alpha 2-adrenoceptor site labelled by [3H]-yohimbine.

Animals↗

PubMed1990

Noradrenaline sensitivity and calcium fluxes in arteries from rabbits with perinephritis hypertension.

1. Contractions of isolated vascular and cardiac preparations taken from rabbits with perinephritis (one kidney, one wrapped) hypertension were compared with those of preparations from control operated animals. 2. Significantly increased sensitivity to noradrenaline, which acts on alpha 1-adrenoceptors, was found in mesenteric arterial rings but not in aortic rings. The degree of hypersensitivity was the same in the presence and absence of cocaine, suggesting that there is no increase in uptake of noradrenaline into adrenergic nerves in this model of hypertension. In contrast to these agonist-induced contractions, no increased sensitivity was found to potassium chloride, suggesting that hypersensitivity is specific for receptor mediated rather than membrane potential mediated effects. 3. No hypersensitivity to noradrenaline was found in the isolated left or right atria, which suggests that the hypertension is associated with changes in excitation-contraction coupling in blood vessels but not in cardiac muscle. 4. Hypertension increased basal 45Ca uptake in the mesenteric artery but not in the aorta. However, there was no significant difference between preparations from normotensive and hypertensive rabbits in 45Ca uptake or efflux stimulated by noradrenaline or KCl. 5. Increased basal 45Ca uptake could contribute to the increased sensitivity to noradrenaline found in the mesenteric artery in rabbit perinephritis hypertension.

Angiotensin II↗

PubMed1990

Effect of chronic pretreatment of guinea-pigs with beta-adrenoceptor agonists on the Na+,K(+)-pump in skeletal muscle.

1. The Bmax values for the radioligand [3H]-ouabain in gastrocnemius muscle membranes from guinea-pigs pretreated with vehicle (0.9% saline, 0.1% ascorbic acid), isoprenaline (50 micrograms kg-1) or terbutaline (125 micrograms kg-1) subcutaneously three times daily for 7 days were 5.3 +/- 0.6; 3.1 +/- 0.4 (P less than 0.05) and 2.0 +/- 0.2 pmol mg-1 protein (P less than 0.01) (means +/- S.E.M.) respectively. Thus chronic pretreatment of the guinea-pigs with isoprenaline or terbutaline reduced the density of [3H]-ouabain binding sites by 40 and 60% respectively. 2. The ouabain-sensitive uptake of 86Rb in intact soleus muscles from control and terbutaline pretreated animals were 10.8 +/- 1.2 and 9.0 +/- mmol g-1 wet tissue 20 min-1 respectively. Pretreatment of guinea-pigs with terbutaline did not therefore significantly alter ouabain-sensitive uptake of 86Rb (P greater than 0.1). 3. The results support a close relationship between regulation of beta-adrenoceptors and [3H]-ouabain binding sites. 4. Additional investigations are required to confirm further the dissociation between the function of the pump and the ouabain binding sites measured under the present experimental conditions.

Adrenergic beta-Agonists↗

PubMed1990

The role of alpha- and beta-adrenoceptor subtypes in mediating the effects of catecholamines on fasting glucose and insulin concentrations in the rat.

1. The role of alpha- and beta-adrenoceptor subtypes in the regulation of plasma glucose and immunoreactive insulin (IRI) levels has been investigated in normal conscious fasted rats by employing selective agonists and antagonists. 2. Adrenaline (0.2 mg kg-1)-induced hyperglycaemia was abolished by the selective alpha 2-adrenoceptor antagonist idazoxan (1.0 mg kg-1), unaltered by non-selective beta-adrenoceptor blockade (propranolol, 1.0 mg kg-1) and potentiated by the selective alpha 1-adrenoceptor antagonist prazosin (0.3 mg kg-1). Adrenaline increased plasma IRI levels in the presence of idazoxan but not in the presence of either prazosin or propranolol. 3. The selective alpha 2-adrenoceptor agonists UK 14304 (0.1 and 0.3 mg kg-1) and BHT-920 (0.2 and 0.5 mg kg-1) elicited dose-dependent hyperglycaemic responses, but did not alter plasma IRI levels. UK 14304 (0.1 mg kg-1)-evoked hyperglycaemia was blocked by idazoxan but not by prazosin. 4. The selective alpha 1-adrenoceptor agonists methoxamine (0.3 mg kg-1) and phenylephrine (0.3 mg kg-1) failed to modify either plasma glucose or IRI levels. 5. Isoprenaline (0.2 mg kg-1) elicited hyperglycaemic and insulinotropic responses which were attenuated by propranolol (1.0 mg kg-1) and the selective beta 2-adrenoceptor antagonist ICI 118551 (1.0 mg kg-1), but not by the beta 1-selective antagonists atenolol (1.0 mg kg-1) and betaxolol (1.0 mg kg-1). 6. None of the antagonists per se affected basal plasma glucose or IRI concentrations, except prazosin (1.0 mg kg-1). 7. The results indicate that adrenoceptors do not appear to be involved in regulating basal plasma glucose and IRI concentrations in the fasted rat. However, the effects of catecholamines on these parameters are mediated by alpha 2- and beta 2-adrenoceptors, whereas alpha,- or beta l-adrenoceptors do not appear to be involved.

Adrenergic alpha-Agonists↗

PubMed1990

Kinetic-dynamic relations and individual responses to enalapril.

Pharmacokinetic and pharmacodynamic variability largely account for interindividual differences in the response to antihypertensive drugs including angiotensin converting enzyme inhibitors. The factors determining the response to enalapril have been investigated in a placebo-controlled study in essential hypertension. The effects of placebo, the initial dose of enalapril, and long-term (1 and 6 weeks) treatment with enalapril were studied in 13 subjects. By using an integrated kinetic-dynamic model that incorporates a parameter for saturable protein binding, individual responses for blood pressure reduction and angiotensin converting enzyme inhibition were characterized in terms of the maximum effect (Emax) and the drug concentration required to produce 50% of Emax (Ce50). In individual subjects, plasma enalaprilat concentrations could be correlated with falls in blood pressure and changes in plasma angiotensin converting enzyme activity. For the group, Emax was -46.1 +/- 16.5 and -19.7 +/- 3.8 mm Hg for systolic and diastolic blood pressure, respectively, and the corresponding Ce50 values were 66.1 +/- 20.2 and 61.6 +/- 22.5 ng/ml. For angiotensin converting enzyme inhibition, Emax (%) and Ce50 (ng/ml) were, respectively, 102.4 +/- 5 and 19.8 +/- 13 after the first dose, 103 +/- 5 and 33.4 +/- 20.3 after 1 week, and 101.3 +/- 2.2 and 31.3 +/- 18.9 after 6 weeks. There was no relation between the responsiveness to enalapril (Emax or Ce50) and patient age or plasma renin activity, but there was a significant positive correlation between Emax and the pretreatment blood pressure. In individual subjects, Emax (first dose) was directly correlated with Emax after 1 and 6 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1990

Concentration-effect analysis of antihypertensive drug responses.

It is now widely recognized that a rigid stepped-care approach to antihypertensive therapy is not universally appropriate. Individualized treatment may result in good or better blood pressure control and a simpler regimen without troublesome side effects. Successful development of such a strategy depends on accurate characterization of a dose-response relation and quantitative assessment of the response in each individual. In the past such relations have proved to be hard to identify for antihypertensive drugs, often because of inappropriate study design during drug development. Despite failure of earlier studies to identify drug concentration-antihypertensive response relations, use of concentration-effect modeling, which recognizes and characterizes the temporal discrepancy between drug concentration and effect, has proved more successful. By using such approach, it has been possible to characterize the concentration-effect relations after acute and steady-state antihypertensive therapy with prazosin, doxazosin, nifedipine, verapamil, and enalapril. With enalapril and nifedipine, it has been demonstrated that the mathematical parameters of effect derived from the first dose can predict the response to these drugs after 4-6 weeks of treatment. These findings suggest that the definition of individual concentration-effect relations may be of value in the rational choice of antihypertensive drug therapy and optimization of dose and dose frequency. In particular, the approach can provide valuable information on dose-effect relations and should optimize choice of dose intervals in drug development and practice.

Antihypertensive Agents↗

PubMed1990

Perindopril. A review of its pharmacokinetics and clinical pharmacology.

Perindopril is an orally active, non-thiol angiotensin-converting enzyme (ACE) inhibitor, which in doses of 4 to 8mg is effective in the control of essential hypertension. As monotherapy it is as effective as once-daily atenolol and possibly more effective than twice-daily captopril. A synergistic response has been noted when perindopril is combined with a thiazide diuretic. Maximal pharmacodynamic effects (ACE inhibition, increase in plasma renin activity and angiotensin I, reduction in aldosterone and angiotensin II and blood pressure) are seen 4 to 6 hours after dosing, with substantial effects still present at 24 hours. Perindopril is a prodrug which requires de-esterification to perindoprilat for useful ACE inhibition. Maximal plasma perindoprilat concentrations are reached 2 to 6 hours after oral administration of perindopril, and 70% of the active metabolite is cleared by the kidneys. The other major metabolite of perindopril is an inactive glucuronide. Ageing is associated with increased serum perindoprilat concentrations, which are probably caused by a combination of enhanced conversion to the active metabolite and diminished renal clearance. Compensated cirrhosis does not appear to have an independent effect. There is little published experience of the use of perindopril in patients with cardiac failure or other cardiac disease, but preliminary evidence would support the general value of this class of agent as adjunctive therapy.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1990

First-choice antihypertensive drug use in the Glasgow Blood Pressure Clinic.

The evolution of antihypertensive drug use in the Glasgow Blood Pressure Clinic between 1969 and 1986 was determined, from computerized data, by extracting percentages of new patients prescribed different drugs at their first clinic visit. Prescribing of adrenergic neuron blockers and centrally acting drugs (methyldopa and clonidine) was common in the early years but declined rapidly until, after 1975 and 1980, respectively, it remained at 10% or less. Diuretics, mainly thiazides, were prescribed for 20% of patients in 1969 to a peak of 55% in 1980. beta-Blockers were first used during the early 1970s and their use peaked in 1980, when they were prescribed for over 60% of new patients. They remained a first-choice treatment in more than 40% of patients. Calcium channel blockers were first used in 1980 and by 1986 were prescribed for 15% of new patients. Angiotensin-converting enzyme inhibitors were used from 1982 and in 1986 were prescribed for 7% of new patients. These two classes of drugs are more expensive than older drugs. However, because of their low usage, this did not greatly influence treatment costs up to 1986, as beta-blockers and thiazides remained widely used.

Adrenergic beta-Antagonists↗

PubMed1990

Policies for managing hypertensive patients: a survey of the opinions of British specialists.

In September 1988 medically-qualified members of the British Hypertension Society were asked to complete anonymously a questionnaire relating to their views on the management of hypertensive patients. Of 149 questionnaires posted, 90 were returned (60%). There was general agreement that non-pharmacological measures, particularly weight loss and alcohol restriction, are effective treatments. However, there was wide variation in the minimum level of blood pressure considered to warrant drug treatment and little consensus regarding measurement policies or target blood pressures. The drugs of first choice were beta-blockers (54% in men, 35% in women) and thiazide diuretics (28% in men and 47% in women), and they were also the most frequent second choices with 54% of respondents advocating 'stepped-care' based on these drugs. The maximum age at which respondents would be prepared to introduce antihypertensive drugs varied widely although 63% considered that thiazide diuretics are first choice in the elderly. These findings demonstrate a broad range of opinion on the management of hypertension among British specialists, and suggest a continuing need for large clinical trials.

Adrenergic beta-Antagonists↗

PubMed1990

A comparison of the management of hypertensive patients by nurse practitioners compared with conventional hospital care.

Patients with hypertension (n = 198) managed by a nurse practitioner hypertension clinic (NPC) were compared over a four-year period with an age-sex matched group of patients attending conventional hospital hypertension outpatient clinics (CHC) for follow-up in two other hospitals in the same city. Mortality is reported for an additional two years from initial presentation. There was no difference between the groups for initial supine systolic or diastolic blood pressure, weight, obesity index, alcohol use, cholesterol or glucose. The reported causes of hypertension were similar. There were more smokers initially in the CHC (46% vs. 37%). Initial drug treatment was less varied in the NPC. At the end of one year there was no significant weight loss in either group, and drug treatment was broadly similar between the two groups. Those attending the NPC, however, had a greater decrease in both supine systolic blood pressure (P less than 0.05) and diastolic blood pressure (P less than 0.01). At the end of four years there were 136 patients (69%) attending the NPC and 70 (35%) remaining in the CHC. For those remaining systolic blood pressure control was similar. Diastolic blood pressures were lower in the NPC (P less than 0.001). Mortality was not significantly different between the groups over a six-year period. This study shows that a nurse practitioner clinic can control blood pressure in a greater proportion of patients, maintain contact with more efficient follow-up of a greater percentage of patients and collect the information needed to assess the effectiveness of care over the long term.

Adult↗

PubMed1990

The cardiovascular and endocrine effects of cilazapril, a new angiotensin-converting enzyme inhibitor, in man.

The cardiovascular and renin-angiotensin-aldosterone effects of cilazapril, a new angiotensin-converting enzyme (ACE) inhibitor was evaluated in healthy Caucasians in a double-blind, placebo-controlled, cross-over study. Cilazapril significantly inhibited plasma ACE activity, with a peak inhibition of 82% at 2 h and a residual inhibition of 41% persisting at 24 h. There was a biphasic and significant hypotensive effect, corresponding temporally to plasma ACE inhibition (P less than 0.02, ANOVA). The hypotensive action was not accompanied by reflex tachycardia. Plasma renin activity rose significantly as a consequence of ACE inhibition (P less than 0.05, ANOVA) but plasma aldosterone was unaltered. Cilazapril is a potent ACE inhibitor with a rapid onset and prolonged duration of antihypertensive and endocrine effects. Studies of the effects on ACE inhibition on the renin-angiotensin system in Africans are required.

Administration, Oral↗

PubMed1990

Factors determining the response to angiotensin-converting enzyme inhibitors in hypertension.

Converting enzyme inhibitors, alone or in combination, are a safe and effective treatment for many hypertensives. However, the range of responses varies between individual patients and it has been claimed that there are two or three phases to the response. Pretreatment plasma renin (as an indication of activation of the renin angiotensin system) and the patient's age have been claimed to predict blood pressure fall. We have investigated whether these factors are useful indications of clinical response in mild-moderate essential hypertension. We have also investigated how well the response to the first dose correlates with the response to long-term (6 weeks) treatment. In a placebo-controlled trial of enalapril (20 mg daily), the blood pressure fall was analysed using an integrated pharmacokinetic/dynamic model of the concentration-effect relationship. The relation between the active drug concentration and blood pressure fall was best described by a non-linear Langmuir (Emax) model: E = (Emax C/C50 + C), where E is the effect, C the drug concentration, Emax is the maximum blood pressure fall and C50 is the drug concentration which causes a fall in blood pressure of 50% of the maximum. For a group of 13 essential hypertensives Emax was 46/20 mm Hg and C50 77 +/- 17 ng/ml. Emax was not related to age or pretreatment renin, but was positively correlated with pretreatment blood pressure (r = 0.69; p less than 0.01). Emax after 6 weeks of treatment (48 +/- 22 and 50 +/- 20 mm Hg, respectively, r = 0.89; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1990

Impairment of autonomic reflexes in cirrhosis.

Autonomic dysfunction may contribute to the hemodynamic disturbances in cirrhosis. Tests of autonomic function were performed in 20 patients with cirrhosis and 20 healthy subjects. The patients with severe cirrhosis (Child's grade B or C) had significant reductions in the Valsalva ratio, the heart rate variation during both facial immersion in water and deep breathing, the pressor response to forearm isometric exercise, and the heart rate response to dynamic exercise. The cold pressor test and the heart rate response to lying down were unaffected. These results indicate impairment of both sympathetic and parasympathetic reflexes in severe cirrhosis which may contribute to the hemodynamic disturbances of cirrhosis. Further studies are required to define the site of these defects.

Adult↗