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Biomedical subjects

J L Reid

Publications and source records attributed to J L Reid.

At least 55 records · Page 3Linked to original sources
PubMed1997

Moxonidine: a review.

Moxonidine is an imidazoline compound which acts on I1 imidazoline 'receptors' in the central nervous system to reduce blood pressure. This novel mechanism of action is claimed to lead to fewer adverse effects than the older centrally-acting agents such as clonidine. In this review we examine the drug's pharmacology, clinical pharmacokinetics, efficacy as an antihypertensive agent including comparative studies with pre-existing drugs, and adverse effect profile. With a growing number of effective antihypertensive agents already available to the clinician, it is not yet clear whether moxonidine represents a significant advance in hypertension management.

Animals↗
PubMed1997

Sodium-lithium countertransport, sodium-hydrogen exchange and membrane microviscosity in patients with hyperlipidaemia.

1. We measured sodium-lithium countertransport, sodium-hydrogen exchange and membrane micro-viscosity in 48 individuals with familial hypercholesterolaemia, 33 subjects with hypertriglyceridaemia and 54 normolipaemic controls. Full lipid profile, blood pressure, body mass index, fasting glucose and insulin levels were also measured. 2. Subjects with hypertriglyceridaemia had higher blood pressure, body mass index, fasting glucose and insulin levels than normal controls. 3. Vmax of the sodium-lithium countertransport was elevated in the hypertriglyceridaemic group compared with controls. Across the whole group log(e) triacylglycerols correlated with Vmax of the sodium-lithium countertransport. There was no difference in sodium-lithium countertransport K(m) between the groups. 4. Sodium-hydrogen maximal proton efflux rate (Vmax) and K(m) were not different between the three groups. There were no correlations between sodium-hydrogen exchange and sodium-lithium countertransport parameters. 5. Microviscosity as measured by diphenylhexatriene was reduced at the core of the membrane in subjects with hypertriglyceridaemia compared with those with familial hypercholesterolaemia or normolipaemic controls, suggesting an alteration in membrane structure. 6. Changes in sodium transport in hyperlipidaemia may be mediated by changes in membrane structure resulting in altered protein conformation or turnover.

Antiporters↗
PubMed1997

Clinical pharmacology and therapeutics--past, present and future.

AIMS: To obtain information about the speciality of clinical pharmacology and therapeutics in the United Kingdom. METHODS: A survey of the views of 26 individuals in academic posts in clinical pharmacology and therapeutics was carried out by postal questionnaire. Response rate was 100%. RESULTS: Of 25 assessable responses of 25 centres, there were 35 academic staff of professorial status (median 2, range 0-5) and 61 staff of reader/senior lecturer status (median 2, range 0-5) but only 20 clinical staff in training grades in 19 institutions. All had extensive clinical commitments. Two-thirds of respondents considered that the speciality was stable locally and nationally. However, recruitment of trainees was poor with only 8% of responders having several good applicants for each post and 90% reported that recruitment had deteriorated in the last 5-10 years. Likely good future careers for clinical pharmacologists in training were considered by 75-80% of respondents to likely lie in the pharmaceutical industry or regulatory authorities. Greater flexibility is required to facilitate training in clinical pharmacology and therapeutics. CONCLUSIONS: Clinical pharmacology and therapeutics in the United Kingdom has a strong academic base but a sub-optimal age structure. Recent experience in recruitment into training posts was disappointing. This may reflect wider problems of recruitment into academic medicine in this country.

Forecasting↗
PubMed1997

Sex differences in the abundance of endothelial nitric oxide in a model of genetic hypertension.

A deficiency of nitric oxide may be responsible for the increased vascular resistance associated with human essential hypertension and that seen in animal models of hypertension. Premenopausal females are relatively protected from hypertension and cardiovascular complications. Levels of superoxide can influence the availability of nitric oxide. We hypothesize that there are differences in nitric oxide availability between stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) and that superoxide may be responsible for at least some of these differences. We studied vascular reactivity in endothelium-intact aortic rings from WKY and SHRSP. We measured nitric oxide synthase activity in endothelial cells removed from aortas and also measured circulating nitrite/nitrate levels. We found the response to N(G)-nitro-L-arginine methyl ester to be significantly greater in WKY compared with SHRSP (95% CI: 20 to 174; P=.015) and in females compared with males in WKY (95% CI: 143 to 333; P=.00004) and SHRSP (95% CI: 70 to 224; P=.0006). Endothelial nitric oxide synthase activity was significantly greater in SHRSP compared with WKY (95% CI: 2.3 to 17.6; P=.016). The EC50 for relaxation to carbachol was significantly greater in male rats compared with female rats (95% CI: -1.1 to -0.2; P=.003) within the SHRSP strain. The maximum relaxation to carbachol was significantly attenuated in stroke prone spontaneously hypertensive compared with Wistar-Kyoto rats (95% CI: 1.7 to 14.4; P=.015). Diethyldithiocarbamate had a significantly greater effect on the stroke prone spontaneously hypertensive rats' carbachol response than that of Wistar-Kyoto rats (95% CI: 14.3 to 47.0; P=.0008). We conclude that superoxide may be responsible for strain differences in vascular reactivity, whereas nitric oxide availability may be responsible for sex differences independently of endothelial nitric oxide synthase activity and superoxide.

Animals↗
PubMed1997

Attitudes toward euthanasia.

A 72-item questionnaire regarding attitudes toward euthanasia was administered to 240 residents of Humboldt County, California, who ranged from 18 to 86 years of age. The relationships between their attitudes and their demographic characteristics including age, religion, and education were examined.

Adolescent↗
PubMed1996

White-coat hypertension as a cause of cardiovascular dysfunction.

BACKGROUND: The increasing use of 24 h ambulatory blood pressure monitoring has allowed diagnosis of white-coat hypertension, in which blood pressures are higher on clinic measurements than on ambulatory monitoring. Treatment is not generally thought to be necessary for this disorder. However, there is evidence that patients with white-coat hypertension develop renal impairment and left ventricular hypertrophy. We undertook this study to assess whether white-coat hypertension, in the absence of cardiovascular structural abnormalities, is associated with cardiovascular functional abnormalities. METHODS: Cardiovascular function was assessed by ultrasonography in three groups of patients classified as normotensive, persistently hypertensive, or white-coat hypertensive (23, 20, and 22 patients, respectively) on the basis of ambulatory blood pressure monitoring, carried out for 28 h with recordings taken every 15 min during the day and every 20 min during the night, and clinic measurements, made with a semi-automatic oscillometric device. RESULTS: Similar abnormalities of diastolic left ventricular function were identified in the patients with persistent hypertension and those with white-coat hypertension; both groups differed in these indices from the normotensive group (E/A ratios 0.94 [SD 0.23], 1.06 [0.21], and 1.24 [0.31] respectively; ANOVA p < 0.005). In addition, the white-coat and persistently hypertensive groups, when compared with the normotensive group, showed similar abnormalities of elasticity, compliance, and stiffness (stiffness index 4.32 [1.90], 4.53 [1.38], and 3.27 [0.95] respectively; ANOVA p < 0.05) of the large arteries. INTERPRETATION: Functional cardiovascular abnormalities were identified in white-coat hypertensive patients who had no identifiable structural abnormalities. Such functional abnormalities can be reversed by antihypertensive treatment. We propose that patients with white-coat hypertension might benefit from antihypertensive treatment as well as those with persistent hypertension. This hypothesis should be addressed in prospective clinical trials.

Aged↗
PubMed1996

New therapeutic agents for hypertension.

1. Over the last 40 years a range of therapeutic strategies has been introduced for the long term treatment of hypertension. 2. Although safe effective agents are available a significant number of patients are unable or unwilling to take these drugs as long term treatment. 3. Both insufficient efficacy and adverse effects justify the search for new antihypertensive strategies. 4. Recent developments include orally active angiotensin (AT1) receptor antagonists (ARA) which appear to offer the benefits of prevention of angiotensin II effects without the adverse effects of bradykinin potentiation, such as cough, which limit the usefulness of angiotensin converting enzyme (ACE) inhibitors. 5. Imidazoline receptor agonists offer the potential of centrally active antihypertensives without the adverse effects of sedation and dry mouth. Further clinical experience is necessary to confirm whether the clinical efficacy and good tolerability are confirmed with long term use. 6. Both ARA and imidazoline preferring substances offer the bonus of a desirable haemodynamic profile in patients with heart failure and may open new therapeutic avenues in the management of cardiac failure.

Antihypertensive Agents↗
PubMed1996

Effects of manipulation of dietary cholesterol on the function of the thoracic aorta from New Zealand white rabbits.

Animal studies, while generally showing loss of endothelium-dependent responses after an elevation in plasma cholesterol, have provided conflicting reports with regard to recovery of function after normalisation of cholesterol level. Therefore, we assessed changes in vascular function after a period of hypercholesterolaemia and the subsequent effect of normalisation of cholesterol levels. Contractile responses to phenylephrine (PE) and endothelium-dependent relaxation in response to carbachol were examined in thoracic aorta from New Zealand White rabbits (NZW) fed a 0.3% cholesterol diet for 20 weeks, from NZW fed a 0.3% cholesterol diet for 20 weeks, followed by standard diet for 20 more weeks, and from their respective age-matched controls. Cholesterol levels were increased in rabbits receiving the 0.3% cholesterol diet (12.7 +/- 3.2 mM; 0.5 +/- 0.1 mM control) and returned to normal when standard diet was reintroduced (0.8 +/- 2.0 mM). Contractile responses were not affected by the period of hypercholesterolaemia. Carbachol-induced relaxation of a submaximal PE contraction was impaired after the period of hypercholesterolaemia (Emax 69 +/- 9%; 95 +/- 3% age-matched (control); the effect was reversed after reintroduction of standard diet (Emax 79 +/- 6%; 82 +/- 2% age-matched control). Our results demonstrate that endothelium-dependent relaxation is impaired after a long-term 0.3% cholesterol diet. Furthermore, after reintroduction of a normal diet, there is no further impairment of endothelium-dependent relaxation and endothelium function improves.

Adrenergic alpha-Agonists↗
PubMed1996

Differing early blood pressure and renin-angiotensin system responses to the first dose of angiotensin-converting enzyme inhibitors in congestive heart failure.

We previously demonstrated differing blood pressure (BP) responses to the first dose of angiotensin-converting enzyme (ACE) inhibitors in congestive heart failure (CHF). We wished to confirm the disparate responses to the first dose of these agents, study the response to repeated dosing, and explore possible explanations (slow, tight binding, and steric hindrance) for the phenomenon. Forty-eight elderly patients (aged 51-85 years) with stable CHF were studied for 48 hours. Groups (n = 12) received one of the following: (a) perindopril 2 mg orally (p.o.) + placebo intravenously (i.v.) (day 1) and perindopril 2 mg p.o. (day 2); (b) enalapril 2.5 mg p.o. + placebo i.v. (day 1) and enalapril 2.5 mg p.o. (day 2); (c) placebo p.o. + perindopril at 0.167 mg i.v. (day 1) and perindopril 2 mg p.o. (day 2); or (d) placebo p.o. + placebo i.v. (day 1) and placebo p.o. (day 2). Supine BP was measured on day 1. On day 2, BP was recorded by ambulatory BP monitor. Blood samples were taken at baseline and at intervals during the 48-h study period for estimation of neurohumoral parameters. Inhibition of the renin-angiotensin system (RAS) was estimated by plasma ACE inhibition and also by the ratio of angiotensin II (Ang II)/Ang I + Ang II. On day I, enalapril 2.5 mg caused a greater decrease in BP than did placebo response between 6 and 9 h postdose. Perindopril 2 mg produced a profile of BP response similar to that of placebo. Ambulatory BP on day 2 was consistently lower with enalapril as compared with perindopril. Profiles of plasma ACE inhibition were similar with each active therapy. Enalapril therapy produced a greater increase in plasma renin activity (PRA) than did other treatments. There was no temporal dissociation between plasma ACE inhibition and profile of Ang peptides for any treatment. We have confirmed the disparate BP responses to perindopril and enalapril in CHF. We noted no evidence of slow, tight binding or steric hindrance to explain these differences.

Aged↗
PubMed1996

Dose-ranging study of the angiotensin II receptor antagonist irbesartan (SR 47436/BMS-186295) on blood pressure and neurohormonal effects in salt-deplete men.

We characterised the blood pressure (BP) and hormonal responses to the oral angiotensin II (Ang II) receptor antagonist irbesartan (SR47436/BMS-186295) or placebo in normal men with an activated renin-angiotensin system (RAS) during salt depletion. We also evaluated safety and tolerability. Twelve healthy, normotensive male volunteers followed a standardised salt-depletion regimen for 3 days before each study day. Six different single oral doses of irbesartan (1, 5, 10, 25, 50, and 100 mg) were administered double-blind in a three-panel, dose escalation with placebo randomised in each panel. Supine and erect BP and heart rate (HR), serum and urinary electrolytes: plasma renin activity (PRA), and Ang II were measured at intervals. Urinary electrolytes were measured for the 24-h period before dosing (to confirm salt depletion) and for 24 h afterward. No drug-related side effects were noted. There was a dose-related decrease in supine and erect systolic and diastolic BP (SBP, DBP) with irbesartan from 10 mg and beyond, with no change in HR. Supine mean arterial pressure (MAP) decreased by 18.8 mm Hg. There was a dose-related reactive increase in PRA (to 35 ng/ml/h) and Ang II (to 450 pg/ml) with irbesartan. Irbesartan is an orally active AT1 receptor antagonist. In salt-deplete normal men, it has a dose-related haemodynamic, hormonal, and electrolyte profile characteristic of AT1 antagonists. The dose range studied did not show a plateau or maximum effect.

Adult↗
PubMed1996

Vascular smooth muscle polyploidy and cardiac hypertrophy in genetic hypertension.

We studied the mechanisms responsible for vascular and cardiac hypertrophy in hypertension (pressure load and humoral and genetic factors) in two experimental approaches: (1) We carried out a cosegregation analysis to correlate cardiac and vascular hypertrophy with subphenotypes of blood pressure in an F2 generation of a cross between stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats; (2) we treated 8-week-old SHRSP with perindopril, an angiotensin-converting enzyme inhibitor; losartan, an angiotensin type 1 receptor antagonist; or perindopril combined with a nitric oxide synthase inhibitor to investigate the relative contributions of blood pressure and angiotensin II to the pathogenesis of cardiac hypertrophy and vascular smooth muscle polyploidy. Vascular smooth muscle polyploidy was measured with flow cytometry DNA analysis. Cardiac hypertrophy was assessed by measuring the ratios of heart weight to body weight and left ventricle + septum weight to body weight. Blood pressure was measured with radiotelemetry in the F2 cosegregation experiment and with tail-cuff plethysmography in the pharmacological study. In the F2 rats, the best predictor of smooth muscle polyploidy by ANCOVA was systolic pressure (F=29.28, P < .0001). The ratio of left ventricle + septum weight to body weight had four major predictors: the male progenitor of the cross, sex, pulse pressure, and change in systolic pressure during salt (F=43.67, P < .0001; F=16.37, P < .0001; F=8.41, P=.0022; and F=12.39, P= .0003, respectively). The ratio of heart weight to body weight had similar predictors. In the pharmacological study, treatment with losartan alone, perindopril alone, or perindopril in combination with N(G)-nitro-L-arginine methyl ester prevented the development of smooth muscle polyploidy and cardiac hypertrophy. The prevention of cardiac hypertrophy was most marked in the SHRSP treated with perindopril plus N(G)-nitro-L-arginine methyl ester, despite blood pressure being higher in this group than in the two other treatment groups. We conclude that vascular and cardiac hypertrophy in this form of hypertension are regulated by different variables. However, suppression of the action of angiotensin II lessens hypertrophy of both types of muscle.

Angiotensin II↗
PubMed1995

Clinical pharmacology of drugs acting on imidazoline and adrenergic receptors. Studies with clonidine, moxonidine, rilmenidine, and atenolol.

Centrally acting antihypertensive drugs are recognized to be safe and effective treatment for high blood pressure. Centrally mediated side effects, such as sedation, are commonly dose- and treatment-limiting events. Imidazoline-preferring receptors, while functionally similar to alpha 2 adrenoceptors, are distinguishable not only on the basis of in vitro radioligand binding but also in vivo in terms of side effects. Drugs with an imidazoline structure lower blood pressure but are less likely to impair psychomotor function. A placebo-controlled study compared moxonidine 0.1 mg with clonidine 0.1 mg orally in nine normal subjects. Both active drugs lowered blood pressure compared to placebo (clonidine more than moxonidine). However, psychomotor function and self-scored sedation and dry mouth were significantly affected only by clonidine. In a long-term (4 weeks) double-blind cross-over study in essential hypertension, rilmenidine was well tolerated and had similar effects to those of atenolol on erect and supine blood pressure. Rilmenidine had no effect on a wide range of autonomic and psychomotor tests or on responses to mental or physical stress. Atenolol, by contrast, had the predicted effects of a beta adrenoceptor antagonist on heart rate during exercise and the Valsalva maneuver. Imidazoline-preferring drugs offer a new and realistic approach to antihypertensive therapy with blood pressure reduction not limited by marked sedation within the therapeutic dose range.

Antihypertensive Agents↗
PubMed1995

Oxidized-LDL induced changes in membrane physico-chemical properties and [Ca2+]i of bovine aortic endothelial cells. Influence of vitamin E.

The effects of 3 days' exposure to native and oxidatively modified human low density lipoprotein (LDL and Ox-LDL) on cultured bovine aortic endothelial cell cholesterol content, membrane microviscosity and intracellular free calcium concentration ([Ca2+]i) were studied. Free cholesterol content increased by 35% and 100% in LDL and Ox-LDL treated cells, respectively, these effects being reversed by vitamin E; esterified cholesterol, which rose by 110% in the Ox-LDL group only, was not affected by vitamin E. Membrane microviscosity, measured as the fluorescence polarization of the trimethylammonium derivative of diphenyl-hexatriene, increased by 9% in Ox-LDL treated cells only. This effect was also reversed by vitamin E. Using the calcium sensitive fluorescent dye fura 2-AM, increases in basal [Ca2+]i of 36% in LDL and 81% in Ox-LDL treated cells were observed. The bradykinin mediated increase in [Ca2+]i was enhanced in both the LDL and, to a greater extent, the Ox-LDL group. Vitamin E reversed the effects of LDL on [Ca2+]i but had no influence in the Ox-LDL group. The lipoproteins affected all parameters measured in this study. Oxidized LDL produced reversible and irreversible alterations to the membrane and the [Ca2+]i. All changes associated with LDL were abolished by vitamin E. Such modifications in the physicochemical properties of the membrane and [Ca2+]i could be involved in the initiation of the atherosclerotic process.

Animals↗
PubMed1995

Responses to an orally active renin inhibitor, remikiren (Ro 42-5892), after controlled salt depletion in humans.

The biological effects of dose-dependent inhibition of renin have rarely been extensively studied after oral (p.o.) dosing in humans. We studied remikiren (Ro42-4892), a selective renin inhibitor, in normal volunteers after activation of the renin-angiotensin system (RAS) based on salt depletion. Twelve normal men (28 +/- 9 years, 77 +/- 10 kg), comprising three consecutive dose panels of 4 subjects, received four treatments, double-blind and randomised 2 weeks apart: panel I, placebo (P), or 30, 100, and 300 mg, remikiren; panel II, placebo or 300, 600 mg, 1,000; panel III, placebo or 30, 600, and 1,000 mg. The RAS was activated by 40 mmol/day sodium diet plus frusemide (40 mg BDS), for 3 days before each study day. Data (mean +/- SD) were examined by repeated-measures analysis of variance (ANOVA). RAS activation was confirmed by 24-h urinary sodium excretion (screen, 142 +/- 74 mmol/24 h; prestudy, 66 +/- 33, 59 +/- 41, 78 +/- 4, 73 +/- 30 mmol/24 h) and increase in plasma renin activity (PRA) (screen, 0.8 +/- 0.3 ng AI/ml/h; before dosing, P, 6.5 +/- 3.1; 30 mg, 8.2 +/- 3; 100 mg, 9.4 +/- 5.7; 300 mg, 6.5 +/- 2.4; 600 mg, 5.2 +/- 2; 1,000 mg, 6.2 +/- 4.4 ng AI/ml/h).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Haemodynamic and renal responses to oral losartan potassium during salt depletion or salt repletion in normal human volunteers.

We examined the haemodynamic and renal response to oral losartan potassium (100 mg) during activation of the renin system in humans. Eight healthy volunteers followed a low-salt (40 mmol sodium) diet for 4 days on four occasions 2 weeks apart. Double-blind salt depletion was achieved by 3-day administration of frusemide (40 mg twice daily, b.i.d.) with placebo salt replacement, salt repletion by placebo frusemide (b.i.d.), and active salt replacement (100 mmol/day). On day 4, subjects received randomised double-blind placebo or losartan. Prestudy salt depletion was associated with nonsignificant decreases in serum sodium (138 +/- 2 mM), potassium (3.5 +/- 0.2 mM) and increased urea (6.5 +/- 1.1 mM), and creatinine (91 +/- 6 microM) as compared with screening. Prestudy (day 3) 24-h urinary volume was similar during deplete preparation (placebo 1.707 +/- 0.81 L, losartan 1.509 +/- 0.626 L) or deplete preparation (placebo 1.726 +/- 0.5 L, losartan 1.764 +/- 0.52 L), but sodium excretion was greater during replete preparation. Salt replete supine blood pressure (BP) profiles showed little effect of losartan (mean maximal supine BP -9 +/- 6 mm Hg) as compared with placebo (-1 +/- 4 mm Hg), with a similar relative result for erect BP. After salt depletion, losartan caused a greater response in both supine (-24 +/- 9) and erect (-33 +/- 15) BP than did placebo (supine -12 +/- 5, erect -14 +/- 9). In this protocol after salt depletion, losartan caused a transient increase in urea and creatinine (143 +/- 40 microML) 8 h after dosing as compared with placebo (105 +/- 13 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Comparison of the oral angiotensin II receptor antagonist UP 269-6 or enalapril 20 mg on blood pressure and neurohormonal effects in salt-deplete man.

We compared the response of the oral angiotensin II (Ang II) receptor antagonist (ARA) UP 269-6 with an angiotensin converting enzyme inhibitor (ACEI) enalapril 20 mg or placebo, during salt depletion in normal men. We also evaluated safety and tolerability. Sixteen healthy, normotensive male volunteers followed a standardised salt-depletion regimen for 3 days before each study day. Seven different doses of UP 269-6 (5, 10, 20, 40, 80, 120 and 180 mg) were administered double blind in a four-panel dose escalation, with enalapril and placebo randomised within each panel. Supine and erect blood pressure (BP) and heart rate (HR); serum and urinary electrolytes; plasma active renin (PAR), aldosterone, and Ang II were measured at intervals. Urinary electrolytes and aldosterone were measured for the 24 h before dosing and for 24 h after dosing. Dizziness and light-headedness on standing were reported after UP 269-6 at higher doses. Enalapril caused one episode of symptomatic postural hypotension. No other drug-related adverse events (AE) were noted. There was a dose-related decrease in supine and erect systolic and diastolic BP (SBP, DBP) with UP 269-6 at > or = 40 mg, with no change in HR. Based on the maximal decrease in mean arterial pressure (MAP), UP 269-6 at 180 mg had an effect largely comparable to that of enalapril 20 mg. There was a dose-related increase in PAR with UP 269-6. Although this was greater with UP 269-6 180 mg than with enalapril, serum and 24-h urinary aldosterone suppression was greater with enalapril than with any dose of UP 269-6.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗