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Biomedical subjects

J L Reid

Publications and source records attributed to J L Reid.

At least 253 records · Page 14Linked to original sources
PubMed1988

Risk-benefit of specific antihypertensive regimens: relevance of metabolic and haemodynamic effects of alpha 1-blockers.

1. Existing strategies for the control of high blood pressure have had a disappointing impact on coronary heart disease--the major cause of death in hypertension. 2. There is a need for more work to identify the relationship between blood pressure, atheroma and other risk factors. 3. A more aggressive approach to treatment may be indicated, especially in high risk groups. 4. In addition to treatment of blood pressure, other major risk factors (lipids and smoking) must be tackled. 5. Alternative treatment regimens with different mechanisms of action and/or effects on lipids should be evaluated in practice. 6. Selective alpha 1-blockers have potential haemodynamic advantages, improve the lipid profile and are well tolerated as first or second line therapy.

Adrenergic beta-Antagonists↗
PubMed1988

Nifedipine: individual responses and concentration-effect relationships.

Dynamic and kinetic variability account for the large intersubject differences in the antihypertensive response to nifedipine, and a clear concentration-effect relationship has not been established. The effects of placebo, first dose, and chronic (1 and 6 weeks) treatment with nifedipine were studied in 14 subjects with essential hypertension using an integrated kinetic-dynamic model to calculate individual subject responsiveness in terms of fall in blood pressure per unit change in drug concentration. Nifedipine concentrations were well correlated with the fall in systolic blood pressure in individual subjects, and the mean responsiveness was -0.48 mm Hg/ng/ml after the first dose, -0.45 mm Hg/ng/ml after 1 week, and -0.49 mm Hg/ng/ml after 6 weeks. The responsiveness to the first dose of nifedipine was significantly correlated with the responsiveness after 1 (r = 0.83) and 6 weeks (r = 0.78) of therapy and with the height of the pretreatment blood pressure (r = 0.6). This study incorporated kinetic as well as dynamic information to characterize the antihypertensive response to nifedipine and identify nifedipine concentration-effect relationships in individual hypertensive subjects.

Adult↗
PubMed1988

Pharmacokinetic and pharmacodynamic modelling of the alpha adrenoceptor antagonist doxazosin.

1. The pharmacokinetic and pharmacodynamic profiles of intravenous and oral doxazosin were investigated in 6 normotensive volunteers. 2. The pharmacokinetics of i.v. and oral doxazosin were fitted simultaneously and independently. The parameters derived were in good agreement with a mean elimination half-life of 539 +/- 75 min, bioavailability of 0.65 +/- 0.11 and clearance of 140 +/- 26 ml/min. 3. Pharmacokinetic-pharmacodynamic modelling indicated that the sensitivities to oral and i.v. doxazosin in individual subjects were in good agreement. 4. Based on these findings it is unlikely that doxazosin metabolites contribute significantly to the pharmacodynamic profile of doxazosin.

Administration, Oral↗
PubMed1988

Effects of ketanserin on peripheral vascular pressor mechanisms in essential hypertension.

The principal aim of this study was to investigate the effects of ketanserin on peripheral vascular pressor mechanisms in nine patients with essential hypertension, including an assessment of the responsiveness to intravenous infusions of the alpha 1-adrenergic agonist, phenylephrine, and the nonadrenergic vasoconstrictor, angiotensin II. There were small but significant rightward shifts in the phenylephrine pressor dose-response curves (by 1.5- to twofold) following ketanserin but no shifts for angiotensin II. This modest shift in phenylephrine responsiveness contrasted with the fivefold shift obtained with a single oral dose (1 mg) of prazosin. The relationship between the phenylephrine-induced increase in blood pressure and the reduction in heart rate was used as an index of baroreflex responsiveness: there were no significant effects attributable to ketanserin. There were no significant differences in plasma aldosterone or renin activity, nor in 24-h urinary volume or electrolytes, following ketanserin. The principal mechanism underlying the antihypertensive effect of ketanserin is unlikely to involve peripheral vascular alpha 1-adrenoceptor antagonism, altered baroreflex responsiveness, or perturbation of the renin-angiotensin-aldosterone system.

Aldosterone↗
PubMed1988

Vascular reactivity, adrenergic mechanisms, and arteriolar resistance in hypertension.

Hypertension, both essential and experimental is characterised by increased vascular resistance. This is in part structural, due to increases in the wall-to-lumen ratio secondary to vascular hypertrophy; however, functional increases in responses to neurohumoral stimuli also occur. The latter may be a consequence of hypertrophy or if a selective increase is observed, an indication of a primary underlying hypertensive mechanism. In essential hypertension, enhanced responsiveness to both angiotensin II and alpha-adrenoceptor agonists are seen. However, in some experimental models, more selective increased responses have been reported. The mechanism of alpha-adrenoceptor-mediated vascular smooth muscle contraction is reviewed and the role of inositol phosphates and diacylglycerol as second messengers is discussed. The precise mechanism of increased vascular responses in hypertension is still uncertain.

Arteries↗
PubMed1988

Renin-angiotensin modulation of sympathetic reflex function in essential hypertension and in the elderly.

The renin-angiotensin system and the sympathetic nervous system are important control mechanisms in blood pressure regulation. A large body of in vitro and in vivo animal data indicate that angiotensin II regulates noradrenaline release and modifies sympathetic reflexes, although the physiological relevance of these to normal man remains unclear. It is established, however, that increasing age and hypertension independently modify autonomic responses in man. The hypothesis was therefore examined that angiotensin II exerts a pre-junctional effect on noradrenaline release and sympathetic cardiovascular function, in the elderly and in patients with essential hypertension. Inhibition of angiotensin-converting enzyme with enalapril and cilazapril, after short-term administration at doses sufficient to reduce circulating angiotensin II concentrations, did not alter sympathetically mediated orthostatic test, Valsalva's manoeuvre and cold pressor test, in young or elderly normotensives. Similarly, but in a separate study, the pressor, chronotropic and sympathoadrenal response to submaximal dynamic exercise were unchanged, following short-term converting enzyme inhibition in normal persons and essential hypertensive patients. These findings do not support a role for angiotensin II in presynaptic facilitation or post-junctional potentiation of noradrenergic transmission. It is proposed that the renin-angiotensin system exerts an independent, rather than a regulatory influence on sympathetic function in blood pressure control, in normal and hypertensive man.

Adult↗
PubMed1988

Desensitization of vascular and platelet alpha 2-adrenoceptors in rabbits with perinephritis hypertension.

The effects of infusion of alpha-adrenoceptor agonists on blood pressure, pressor responses to bolus doses of agonists and to platelet aggregation were examined in rabbits with perinephritis hypertension and in sham-operated controls. Pressor responses to bolus doses and infusions of phenylephrine, an alpha 1-selective agonist, were greater in hypertensive rabbits. In contrast, responses to boluses but not infusions of alpha-methylnoradrenaline, a selective alpha 2-agonist, were increased in hypertensives. During alpha-methylnoradrenaline infusions pressor responses to bolus doses of alpha-methylnoradrenaline and the aggregatory response of platelets to adrenaline were attenuated in all rabbits, consistent with alpha 2-adrenoceptor desensitization. Attenuation and recovery were observed within minutes of commencing and ceasing infusion. The extent of attenuation and rate of change were generally increased in hypertensive animals. This could explain the apparent increase in pressor responses to bolus doses but not infusions of alpha-methylnoradrenaline in the hypertensive rabbits. It might also contribute to the lability in blood pressure observed in these animals.

Adrenergic alpha-Agonists↗
PubMed1988

Indirect assessment of tissue angiotensin II converting enzyme inhibition in vivo in man.

The pharmacokinetics of long-acting angiotensin converting enzyme (ACE) inhibitors show features which are consistent with saturable binding of the drugs to ACE. Their pharmacokinetics may thus be used to assess the extent and affinity of plasma and tissue binding of the drug. For 16 subjects, a hierarchy of pharmacokinetic models was fitted by weighted, least squares, non-linear regression analysis to the concentration-time profile during and after an intravenous infusion of S-9780. A one-compartment model which included saturable tissue and plasma binding gave the best description of the data. The median parameter estimates from this model suggested that total binding capacity for drug was 333 micrograms, of which 62% was in tissue sites, and that the total plasma concentration of drug at half maximum saturation was 6.3 ng/ml. Thus the extent and affinity of ACE inhibitor binding to tissue ACE may be estimated from appropriate analysis of pharmacokinetic data in man.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Identification and characterisation of beta-adrenoceptors in guinea-pig skeletal muscle.

(-)-[125I]Iodocyanopindolol (ICYP) was used to characterise beta-adrenoceptors in skeletal muscle of the guinea-pig. The binding if ICYP to soleus and gastrocnemius muscles was saturable and reversible with KD values of 10.7 +/- 1.1 and 11.6 +/- 1.4 pM and Bmax values of 84.0 +/- 5.7 and 59.9 +/- 8.6 fmol/mg protein for gastrocnemius and soleus muscles respectively. Hofstee plots for the selective beta 1-adrenoceptor antagonists atenolol and metoprolol and for the selective beta 2-adrenoceptor antagonist ICI 118551 were linear in both skeletal muscles suggesting the presence of homogenous populations of beta-adrenoceptors. Furthermore, from the Ki values for atenolol (8381 +/- 2063 nM), metoprolol (585 +/- 80 nM) and ICI 118551 (0.39 +/- 0.05 nM) in gastrocnemius and ICI 118551 (0.47 +/- 0.09 nM) in soleus muscle, it is concluded that the beta-adrenoceptors in skeletal muscle of the guinea-pig are predominantly if not exclusively of the beta 2-subtype.

Animals↗
PubMed1987

Pharmacokinetic overview of doxazosin.

After both oral and intravenous administration, doxazosin is extensively metabolized, with only about 5% of the administered dose excreted unchanged in urine. For single doses, oral bioavailability has been calculated to be about 65%; terminal elimination half-life is approximately 10 to 12 hours. In later multiple-dose studies in which doxazosin concentrations were measured beyond 24 hours after administration, the terminal elimination half-life was 22 hours. Clearance of doxazosin, presumably in the liver, involves the production of mainly O-demethylated and C-hydroxylated metabolites, and is low in comparison with hepatic blood flow. Protein binding is reported to be 98.3% in humans. Relatively low clearance (1.0 to 2.0 ml/min/kg) in association with a moderate volume of distribution (1.0 to 1.9 liters/kg) is responsible for doxazosin's relatively long plasma half-life. There is no evidence to suggest that active metabolites contribute significantly to the pharmacologic activity of doxazosin; both hypotensive effect and alpha-adrenoceptor inhibitor activity have been directly related to the concentration of doxazosin in blood. During long-term treatment, no significant changes in the disposition of doxazosin have been reported; with dosages up to the maximum clinically used dosage of 16 mg daily, there is no evidence of dose-dependent pharmacokinetics. Studies in elderly patients have shown no major pharmacokinetic differences. Overall, these pharmacokinetic results suggest that doxazosin is suitable for once-daily administration in the long-term treatment of patients with essential hypertension.

Administration, Oral↗
PubMed1987

Clinical pharmacology of selective alpha blockers. Hemodynamics and effects on lipid levels.

Selective alpha 1 antagonists decrease blood pressure by reducing elevated peripheral resistance and preserving normal cardiac reflexes. They have also been reported to usually decrease total cholesterol and low-density lipoprotein cholesterol levels, and, in some studies, to increase high-density lipoprotein cholesterol levels. Prazosin, a quinazoline derivative, is well tolerated and is not associated with chronic toxicity. Prazosin has been successfully used in the treatment of hypertension for more than 10 years. Its short plasma half-life requires twice-daily dosing. Although the hypotensive response to an initial dose of prazosin is usually greater than to subsequent doses during long-term therapy, the initial response is an accurate predictor of the hypotensive response in patients during long-term therapy. The vasodilatory action of prazosin is largely due to its blockade of vascular postjunctional alpha 1 receptors. The mechanism involved in its effect on lipid levels is currently under investigation and is an important consideration since hypercholesterolemia, as well as hypertension, is an independent risk factor for stroke and coronary heart disease. Reduction of blood pressure with conventional agents, such as beta blockers or diuretics, has not had the expected impact on coronary heart disease. However, since alpha 1 blockers may influence both hemodynamics and lipids, they warrant evaluation as first-line treatment of hypertension to confirm that they also have an effect on coronary heart disease.

Hemodynamics↗
PubMed1987

Rapid and reversible desensitisation of vascular and platelet alpha 2 adrenoceptors.

The effects of intravenous infusion with the alpha2 adrenoceptor selective agonist alpha methylnoradrenaline on pressor responses to alpha adrenoceptor agonists, alpha2 adrenoceptor mediated platelet aggregation and adenylate cyclase were examined in conscious rabbits. Pressor responses to alpha methylnoradrenaline but not phenylephrine were decreased in a dose dependent manner during methylnoradrenaline infusion at all times examined. Recovery of these responses after stopping infusion was dependent on both the dose infused and the duration of the infusion. Alpha methylnoradrenaline infusion resulted in a dose and time dependent decrease in the pro-aggregatory response of platelet to adrenaline without any significant change in the response to ADP or in the number of [3H]yohimbine binding sites. The ability of PGE1 to stimulate adenylate cyclase was not influenced by alpha methylnoradrenaline infusions. However, reversal of this stimulation by adrenaline was decreased by relatively long (30 min) infusions of the highest dose of alpha methylnoradrenaline examined. It is concluded that alpha methylnoradrenaline infusions resulted in desensitisation of all the alpha2 adrenoceptor mediated responses examined. However the time course for the desensitisation apparently differed according to the response examined.

Adrenergic alpha-Agonists↗
PubMed1987

The effects of omeprazole on endocrine function in man.

We have assessed the effect of omeprazole on various endocrine functions in man. Eight healthy subjects took 60 mg omeprazole or placebo daily for 1 week in a double-blind, randomized, cross-over study. On Day 7 basal concentrations of follicle-stimulating hormone (FSH), luteinising hormone (LH), prolactin, testosterone, thyroid-stimulating hormone (TSH), and serum thyroxine (T4) and tri-iodothyronine (T3) were measured, followed by the gonadotrophin response to luteinising hormone releasing hormone (LHRH) and the prolactin and TSH responses to thyrotrophin releasing hormone (TRH). There were no differences in basal or stimulated values between omeprazole and placebo. In a second study, a further 8 subjects were similarly treated, and on Day 7 serial measurements of cortisol and 11-deoxycortisol were made before and for 2.5 h after intravenous adrenocorticotrophin (ACTH). There were no differences in basal values or pattern of response to ACTH for either hormone. Omeprazole in clinical practice is unlikely to cause any significant interference in endocrine function.

Adult↗
PubMed1987

The haemodynamic and humoral effects of treatment for one month with the angiotensin converting enzyme inhibitor perindopril in salt replete hypertensive patients.

We have studied the effects of treatment for one month with perindopril, 4 or 8 mg once daily, in seven hypertensive patients. Blood pressure was lowered from 164/93 mm Hg to 145/84 mm Hg by 4 mg of perindopril and after one month remained at 142/82 mm Hg. Neither postural hypotension nor tachycardia occurred. Inhibition of plasma angiotensin converting enzyme (ACE) lasting for over 24 h was achieved and there was a significant increase in plasma renin activity (PRA). Maximum plasma concentrations of the active metabolite of perindopril, S-9780, were detected four h after oral administration. After treatment for one month there was evidence of reduced sensitivity of plasma ACE to the action of the inhibitor. The plasma concentration of S-9780 required to produce 50% inhibition of plasma ACE rose from 2.4 ng X ml-1 following the first dose to 5.5 ng X ml-1 after one month.

Adolescent↗