Biomedical subjects

J L Reid

Publications and source records attributed to J L Reid.

At least 217 records · Page 12Linked to original sources

PubMed1989

Present aspects and future developments with ACE inhibitors.

With several angiotensin-converting enzyme (ACE) inhibitors currently in clinical use for the treatment of hypertension, and many others under development, potential applications of these drugs have expanded. When ACE inhibitors lower blood pressure they do not induce tachycardia. Contrary to expectations, ACE inhibitors have been found extremely useful in treating hypertension in the elderly and also patients with heart failure. Plasma renin assay is not always helpful in determining the optimum dosage range. While no evidence has yet been found for differential effects of these drugs in man, tissue-sensitive ACE inhibitors could be of considerable clinical interest.

Adult↗

PubMed1989

Rise in plasma noradrenaline with age results from an increase in spillover rate.

Venous plasma noradrenaline (NA) kinetics, determined using steady-state intravenous infusions of subpressor doses of [3H] NA, were measured in 8 young, 13 middle-aged and 8 elderly subjects. Plasma NA concentrations were 0.71 nmol/l (0.25-0.98) in the young, 1.90 nmol/l (0.98-3.65) in the middle-aged and 3.03 nmol/l (1.15-3.85) in the elderly (young vs. elderly, p less than 0.001). NA spillover rates were 2.07 nmol/l/m2 (1.05-4.91) in the young, 3.91 nmol/l/m2 (1.62-9.44) in the middle-aged and 7.57 nmol/l/m2 (4.38-24.0) in the elderly (young vs. elderly, p less than 0.001). Plasma NA clearance was similar in young and elderly subjects. NA spillover was positively correlated with age (r = 0.58; p less than 0.01) and was not independently related to blood pressure. The rise in plasma NA with age results from an increase in spillover rate rather than any alteration in clearance.

Adult↗

PubMed1989

Platelet cytosolic free calcium before and after antihypertensive treatment in perinephritis hypertension of the rabbit.

Cytosolic free calcium concentration ([Ca2+]i) in platelets has been reported to be elevated in human essential hypertension, to be positively correlated with blood pressure and to decrease with blood pressure reduction. However, some groups have been unable to confirm these findings in either humans or hypertensive rats. We have examined the relationship between platelet [Ca2+]i and blood pressure in the perinephritis model of hypertension in the rabbit. In addition, the effects of both acute and chronic treatment with verapamil or prazosin were studied. Mean arterial pressure, heart rate and platelet [Ca2+]i were measured before and after treatment. Platelet [Ca2+]i was measured by the Quin 2 fluorescence technique. Platelet [Ca2+]i was similar for the normotensive and hypertensive rabbits, and no correlation between platelet [Ca2+]i and blood pressure was observed. None of the antihypertensive treatments produced a lowering of platelet [Ca2+]i. Therefore we conclude that platelet [Ca2+]i is unlikely to be a universally useful index of ([Ca2+]i in vascular smooth muscle of resistance vessels.

Adrenergic alpha-Agonists↗

PubMed1989

Pressor responsiveness in essential hypertension and the effects of treatment with an alpha blocker, calcium antagonist or ACE inhibitor.

We have studied the contribution of neurohumoral and structural factors to pressor responsiveness and peripheral resistance in mild/moderate hypertension. Pressor responses to intravenous infusions of phenylephrine (an alpha1 agonist) and angiotensin II were studied in groups of patients with essential hypertension before and after treatment, for 6 weeks with either nifedipine (20 mg bid), enalapril (20 mg daily) or doxazosin (2 mg daily). All drugs lowered blood pressure to a similar extent. Pressor responsiveness to both phenylephrine and angiotensin II showed wide intersubject variation when expressed as the dose of agonist required to raise mean arterial pressure by 20 mmHg (PD20). A group of age-matched normotensive controls showed a similar PD20 for phenylephrine to hypertensives. Angiotensin 11 sensitivity was greater in hypertensives. Drug treatment had different effects in hypertensive patients. Doxazosin, an alpha blocker, reduced the responsiveness to phenylephrine but had no effect on responses to angiotensin II. Nifedipine attenuated responses to both agonists while treatment with enalapril increased responsiveness to both phenylephrine and angiotensin II. We have not found evidence of systematic differences in alpha 1 receptor responses in hypertensives and different "vasodilator" drugs can lower blood pressure with widely different effects on adrenergic and non-adrenergic vascular responses.

Adrenergic alpha-Antagonists↗

PubMed1989

Pharmacokinetics of perindopril: therapeutic consequences.

Perindopril has been studied in groups of normal young and elderly subjects, in patients with hepatic cirrhosis and in hypertensive patients. Plasma concentrations of perindoprilat are increased and renal clearance reduced in elderly subjects, resulting in an increase in the acute pharmacodynamic effect of perindopril. Compensated hepatic cirrhosis does not have any independent effect on the pharmacokinetics of perindopril. After intravenous administration, perindoprilat concentrations show multiexponential decay with a terminal half life of over 30 hours associated with sustained inhibition of ACE. During repeated dosing there is little accumulation of drug, and no evidence of increased haemodynamic effect after chronic treatment in hypertensives. The therapeutic consequences of these findings are: binding of perindoprilat to ACE prolongs the haemodynamic effect, giving the option of once daily administration; despite the long terminal elimination half life of the drug, significant accumulation is not a problem during chronic treatment; increased plasma concentrations of active metabolite in the elderly and reduced renal elimination may require reduced doses to be used; further dose adjustment in compensated hepatic cirrhosis is not routinely necessary.

Adolescent↗

PubMed1989

Pharmacokinetics of perindopril: therapeutic consequences.

Perindopril has been studied in groups of normal young and elderly subjects, in patients with hepatic cirrhosis and in hypertensive patients. Plasma concentrations of perindoprilat are increased and renal clearance reduced in elderly subjects, resulting in an increase in the acute pharmacodynamic effect of perindopril. Compensated hepatic cirrhosis does not have any independent effect on the pharmacokinetics of perindopril. After intravenous administration, perindoprilat concentrations show multiexponential decay with a terminal half-life of over 30 hours, associated with sustained inhibition of ACE. During repeated dosing, there is little accumulation of the drug and no evidence of increased hemodynamic effect after chronic treatment in hypertensives. The therapeutic consequences of these findings are: (1) Binding of perindoprilat to ACE prolongs the hemodynamic effect, giving the option of once daily administration. (2) Despite the long terminal elimination half-life of the drug, significant accumulation is not a problem during chronic treatment. (3) Increased plasma concentrations of active metabolite in the elderly and reduced renal elimination may require reduced doses to be used. (4) Further dose adjustment in compensated hepatic cirrhosis is not routinely necessary.

Adult↗

PubMed1989

Captopril versus perindopril: a double blind study in essential hypertension.

This was a double blind, parallel group, multicentre comparison of the therapeutic efficacy and acceptability of perindopril and captopril in essential hypertension. After one month of placebo, 165 patients with supine diastolic blood pressure (DBP) between 95 and 125 mmHg were randomised to perindopril 4 mg once daily or captopril 25 mg twice daily orally. The perindopril group (n = 82) had significantly higher pretreatment DBP (105.4 +/- 0.8 mmHg vs 102.3 +/- 0.6 mmHg) but other demographic variables were similar. Assessment was monthly for three months: 'uncontrolled' patients (DBP greater than 90 mmHg) had the dose doubled and then hydrochlorothiazide added. Two of the six withdrawals were attributed to drug side effects and were in the captopril group. There was no significant difference in the number of withdrawals or incidence of side effects between the drugs. The final titrated treatments were similar and monotherapy normalised DBP in 49% of each group. The final 'control' rate was higher with perindopril than captopril: 75% vs 57%, P = 0.016. The overall fall in DBP was greater in the perindopril group: 26.5 +/- 1.9 mmHg vs 18.9 +/- 1.9 mmHg, P = 0.005. The doses of diuretic were similar in the two groups. The DBP of patients who received only monotherapy for three months also fell more in the perindopril group (-17.5 +/- 1.4 mmHg vs -13.9 +/- 1.0 mmHg, P less than 0.01). At the doses studied, perindopril was more effective than captopril in lowering DBP, either as monotherapy or in combination with a diuretic.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1989

Endothelin stimulates phosphatidylinositol hydrolysis in rat vascular smooth muscles.

The ability of endothelin to stimulate phosphatidylinositol hydrolysis in rings of rat aorta was studied. Endothelin 10(-8)-10(-5) mol/l caused increases of 200-1000% in inositol phosphate levels. However, physiological responses to endothelin have been reported in the concentration range 10(-10)-10(-8) mol/l. Thus phosphatidylinositol hydrolysis as measured in the present study does not correlate directly with functional responses. Phosphatidylinositol hydrolysis in response to endothelin was attenuated but not abolished by removal of endothelium. Attenuation of inositol phosphate production was also observed with time, consistent with the hypothesis that continuous exposure to the agonist can cause desensitization of the endothelin receptor.

Animals↗

PubMed1989

Clinical pharmacological evaluation of calcium antagonists and other drugs modifying myogenic tone in essential hypertension.

The factors determining the acute and long-term response to calcium antagonists have been studied in controlled trials in essential hypertension. The importance of dose and plasma level in determining the response has been confirmed. The blood pressure response has been modelled and mathematically described, with drug concentrations related to blood pressure falls by linear or Emax (maximum fall in blood pressure) models. The acute response predicted the response after 6 weeks of treatment. Neither age nor plasma renin activity independently influenced the response to calcium antagonists. The level of pretreatment blood pressure (starting blood pressure) was positively related to indices of response. In similar studies with other drugs modifying myogenic tone, while vascular reactivity to selective agonists was reduced, enhanced or unchanged, blood pressure falls were related to plasma levels in all cases.

Blood Pressure↗

PubMed1989

Treatment of high blood pressure--the effect on coronary morbidity and mortality.

Established drugs used in the treatment of hypertension have reduced stroke but have had disappointingly little impact on coronary artery disease and its complications. This could be due to inadequate falls in blood pressure (or excessive falls). It is possible that the role of blood pressure in ischaemic heart disease has been over-estimated compared to other risk factors. Alternatively, the drugs used previously may have adversely affected other factors. Mortality in treated hypertensives remains higher than normotensives but so does their blood pressure. The blood pressure on treatment is a much better predictor of outcome than initial blood pressure. This suggests that improved blood pressure control may be desirable. In our hospital-based hypertension clinic many patients have more than one risk factor. In spite of intensive efforts between 1980 and 1988, smoking habits changed little and serum cholesterol and random blood glucose actually rose. Cholesterol is high in our population of hypertensive patients and the mean (+/- SD) rose from 6.4 +/- 1.3 to 6.6 +/- 1.3 (n = 127; P less than 0.01). These observations highlight the importance of a multiple risk factor approach. The benefits of alternative drugs which can lower total cholesterol and/or low-density lipoprotein (LDL) and/or raise high-density lipoprotein (HDL) deserve study in this population. A final possibility is that the widely observed association between hypertension and ischaemic heart disease is not causal (or is weak compared to other risk factors). If a common underlying mechanism caused both atheroma and hypertension then reduction of blood pressure would not be expected to reverse atheroma and its complications. At present this possibility cannot be excluded.

Antihypertensive Agents↗

PubMed1989

Basal platelet intracellular free calcium concentrations in untreated hypertensive patients and normotensive controls.

Basal platelet intracellular free calcium concentrations were measured in 18 untreated essential hypertensive patients and 18 age and sex matched normotensive controls. No significant difference was observed between the mean platelet intracellular free calcium concentrations for these two groups. There was a weak, but significant positive correlation between both systolic and diastolic BP and basal platelet intracellular free calcium concentration. These results suggest there is a real, but quantitatively small relationship between platelet intracellular free calcium levels and BP in essential hypertension which may be of pathophysiological significance in the genesis and maintenance of hypertension.

Adult↗

PubMed1988

Regulation of beta-adrenoceptors by catecholamines in the rabbit skeletal muscle.

(-)-[125I]Cyanopindolol (ICYP) was used to characterise beta-adrenoceptors in the gastrocnemius muscle of the rabbit. The binding of ICYP was saturable. The KI value for the selective beta 2-adrenoceptor antagonist, ICI 118551, was 0.16 +/- 0.01 nM (mean +/- S.E.M) and for the selective beta 1-adrenoceptor antagonist, metoprolol, was 300.1 +/- 33.3 nM. Hofstee plots for both antagonists were linear indicating the presence of homogeneous beta 2-adrenoceptors in the skeletal muscle of the rabbit. In gastrocnemius muscles obtained from rabbits chronically pretreated in vivo with vehicle (0.1% ascorbic acid), adrenaline (40-50 nmol.kg-1.h-1) or noradrenaline (80-100 nmol.kg-1.h-1) via osmotic mini-pumps implanted for 10 days, the Bmax values were 44 +/- 3, 25 +/- 4 (P less than 0.05) and 41 +/- 7 (fmol.mg-1 protein) and KD values were 7.3 +/- 0.9, 6.3 +/- 0.8 and 9.3 +/- 2.5 (pM), respectively. Thus pretreatment with the circulating hormone adrenaline but not noradrenaline down-regulated the number of skeletal muscle beta 2-adrenoceptors but did not influence the affinity.

Adrenergic beta-Antagonists↗

PubMed1988

Idazoxan and brain alpha 2-adrenoceptors in the rabbit.

The effect of intravenous infusion of idazoxan on the depressor response to intracisternal clonidine 1 microgram/kg and on [3H]yohimbine binding in the fore- and hindbrain of the rabbit was examined. Idazoxan was infused either acutely (30 min) or chronically (5 days) at doses of 0.56 or 1.1 mg/h. Idazoxan 1.1 mg/h reduced the fall in blood pressure after clonidine. This attenuation of the depressor response was observed in the groups that were given the higher dose of idazoxan both acutely and chronically. The extent of attenuation was not modified by the duration of treatment. The low dose of idazoxan given acutely had no significant effect on the response to clonidine but the chronically infused group showed an enhanced response. A significant increase in the number of [3H]yohimbine binding sites (83%) was observed in the forebrain after 5 days infusion of 1.1 mg/h idazoxan with no change in the hindbrain. The lower dose of infusion did not cause any significant change in [3H]yohimbine binding in either brain region. Thus it appears that the susceptibility of the alpha 2-adrenoceptor binding sites to up-regulation by idazoxan may depend on the brain region observed.

Animals↗

PubMed1988

Alpha 1-adrenoceptor desensitisation.

The effects of intravenous infusion with phenylephrine on pressor responses to bolus doses of phenylephrine were examined in conscious rabbits. Four hours infusions failed to attenuate responses except in animals pretreated with phenoxybenzamine to eliminate the alpha 1-adrenoceptor reserve. However, the doses of phenylephrine required to attenuate responses were very large and were not well tolerated. Thus alpha 1-adrenoceptors in rabbit vascular smooth muscles are relatively resistant to in vivo agonist desensitisation compared to alpha 2- and beta-adrenoceptors.

Animals↗

PubMed1988

Cardiovascular significance of neuropeptide Y in the caudal ventrolateral medulla of the rat.

The cardiovascular effects of intracisternal and intraparenchymal injection of neuropeptide Y (NPY) into the caudal ventrolateral medulla (CVLM) were investigated in anaesthetized normotensive rats. Intracisternal administration of 1.25 nmol NPY gave rise to a significant fall in blood pressure and heart rate, maximal 1 h postinjection. More localized microinjections of NPY into the CVLM similarly produced dose-dependent falls in blood pressure and heart rate. The bradycardia was significantly reduced or abolished by cardiac vagal blockade induced by: (1) pretreatment with the peripheral muscarinic antagonist methylatropine; or (2) ipsilateral vagotomy. These procedures also gave rise to a small reduction in the hypotensive response to NPY but the remaining component of the response was still significantly different from control, saline responses which were without significant haemodynamic effects. The results of this study provide further evidence for a central role for NPY in cardiovascular control. In the CVLM NPY responses appear to involve at least two different mechanisms: the fall in heart rate results from activation of cardiac vagal neurons in the nucleus ambiguus. The hypotensive response is more complex. The fall in blood pressure may be due in part to an activation of A1 noradrenergic neurons resulting in reduced sympathetic outflow but a small component of the response is a result of the profound slowing of the heart.

Animals↗

PubMed1988

[3H]yohimbine and [3H]idazoxan bind to different sites on rabbit forebrain and kidney membranes.

The binding of the alpha 2-adrenoceptor ligands [3H]yohimbine and [3H]idazoxan to rabbit kidney and forebrain membranes was compared. The maximum number of [3H]yohimbine binding sites was higher than the number of [3H]idazoxan binding sites in forebrain and lower in kidney. Large differences were observed in the ability of noradrenaline, adrenaline, idazoxan, rauwolscine, yohimbine and WY 26392 to displace [3H]yohimbine and [3H]idazoxan from their binding sites. These data suggest that [3H]idazoxan and [3H]yohimbine bind to different sites on rabbit tissue membranes.

Animals↗

PubMed1988

Regulation of adrenergic receptor number following chronic noradrenaline infusion in the rabbit.

In order to study noradrenaline-induced regulation of alpha- and beta-adrenoceptors, groups of male New Zealand White rabbits (n = 8) were treated with intravenous noradrenaline (0.09 mumol/kg x h) or ascorbate (0.1%) for 10 days via osmotic minipumps implanted in the femoral vein, and the number of cardiac, lung and lymphocyte beta-adrenoceptors as well as renal and platelet alpha 2-adrenoceptors were determined. 1. The mean arterial blood pressure, heart rate and catecholamine levels were measured before commencing, and after 24 h and 10 days infusion. Circulating noradrenaline concentrations were elevated approximately 6-fold at 24 h and were sustained at these levels after 10 days administration of noradrenaline. There were no significant alterations in the blood pressure while a significant decrease in the heart rate was observed at 24 h. 2. Alpha 2-adrenoceptor density was assessed using [3H]-yohimbine. A significant decrease in the number of alpha 2-adrenoceptors in the kidney was observed following the 10 days infusion with noradrenaline. This down-regulation was in marked contrast to the lack of alteration in platelet alpha 2-adrenoceptor number and the platelet alpha 2-adrenoceptor mediated aggregatory response. 3. The density of beta-adrenoceptors in lymphocytes, heart and lung were quantified using (-)[125I]iodocyanopindolol (ICYP). The noradrenaline infusions caused significant reductions in beta-adrenoceptor number in the heart and lung (containing predominantly beta 1-adrenoceptors) but not in lymphocytes (possessing mainly beta 2-adrenoceptors). The KD-values (pM) for ICYP binding to heart and lung were also significantly decreased in the present studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

The effect of diuretic therapy on adrenaline-induced hypokalaemia and hypomagnesaemia.

We have examined the interaction between the administration of bendrofluazide, frusemide, spironolactone, and placebo and increased plasma adrenaline concentrations in a double-blind, placebo-controlled, cross over study. We studied healthy subjects on the fourteenth day of each treatment period and after a two hour infusion of adrenaline (0.06 micrograms.kg-1.min-1 [0.33 nmol.kg-1.min-1]) we measured their heart rates, blood pressures, and plasma potassium and magnesium concentrations. There were no differences in heart rates or blood pressures for all four treatments. Baseline potassium concentrations were not significantly different compared to placebo, and plasma potassium fell during the period of the infusion on all study days. this fall was significantly greater on frusemide (0.5 mmol.l-1) and bendrofluazide (0.4 mmol.l-1) compared with both placebo and spironolactone. Baseline plasma magnesium concentration were not different and similar falls in plasma magnesium were seen on all four treatments during and after the adrenaline infusion. We conclude that chronic diuretic therapy with a thiazide diuretic or frusemide may increase the severity of hypokalaemia during short-term rises in plasma adrenaline. Pretreatment with spironolactone had no effect on adrenaline-induced hypokalaemia. None of the diuretics studied altered adrenaline-induced hypomagnesaemia.

Adult↗