The Gardner report: potential implications for radiology and nuclear medicine?
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Adult↗
Biomedical subjects
D J Sumner
Publications and source records attributed to D J Sumner.
Vascular pressor responses in treated and untreated essential hypertension.
Thirty-seven essential hypertensives received placebo for 3 weeks followed by nifedipine retard (n = 14) or enalapril (n = 13) or doxazosin (n = 10) as monotherapy for 6 weeks and attended study days to evaluate the effects of placebo, first dose, and chronic (1-6 weeks) treatment. On each study day, pressor responses to i.v. infusions of phenylephrine (PE) and angiotensin II (AII) were measured 1.5-3 h after drug administration and the derived PD20 values (dose required to increase mean blood pressure by 20 mm Hg) compared. Each treatment produced comparable reductions in BP. Nifedipine significantly attenuated the pressor responses to AII and PE: for AII, the mean PD20 (ng/kg/min) increased from 8.2 (placebo) to 9.9 (first dose), 13.9 (1 week), and 17.4 (6 weeks). Pressor responsiveness to both AII and PE was unchanged following enalapril: for PE, the mean PD20 (micrograms/kg/min) was 2.1 (placebo), 1.5 (first dose), and 1.5 (6 weeks). Doxazosin produced rightward shifts of the PE pressor dose-response curves but had no effect on responses to AII. The relationship between the simultaneous BP and HR changes during the infusion of PE was used as an index of cardiac baroreflex activity. In contrast to enalapril and doxazosin, which had no effect, nifedipine reduced the slope of the HR/BP relationship from -0.62 (placebo) to -0.38 (first dose) and -0.31 beats/min/mm Hg (6 weeks). For comparable reductions in BP, doxazosin only affects adrenergic mechanisms whereas nifedipine affects both adrenergic and non-adrenergically mediated vasoconstriction. The ACE inhibitor enalapril had no effect on pressor responses to AII and PE.
Adult↗
Pressor responsiveness, age and hypertension.
It has long been accepted that enhanced vascular reactivity is an integral part of the hypertensive state. This study investigates pressor responsiveness to the selective alpha 1-adrenoceptor agonist, phenylephrine, in 62 normotensive and hypertensive subjects aged 20-70 years. Since blood pressure increases with age, it is possible that effects attributed specifically to blood pressure will be confounded by age. The present study showed no correlation between responsiveness and starting blood pressure. However, responsiveness was positively correlated with age. These results suggest that it may be an oversimplification to attribute increased vascular responsiveness to the hypertensive state.
Adult↗
Ebastine: the effect of a new antihistamine on psychomotor performance and autonomic responses in healthy subjects.
1. Ebastine, through its carboxylic acid metabolite has antihistamine (H1-receptor) activity in man. 2. We have examined in a single blind placebo controlled study the effects of 10 mg and 50 mg of ebastine on cardiovascular, autonomic and psychomotor function in healthy subjects. 3. Ebastine had no effect on blood pressure or heart rate and there was no evidence of any anticholinergic activity on circulatory reflexes or salivation. 4. Ebastine did not impair psychomotor performance as assessed by critical flicker fusion at either dose. 5. Ebastine 10 mg had no effect on sedation measured by visual analogue scale or direct questioning, however ebastine 50 mg did cause a modest increase in indices of sedation. 6. Ebastine did not have detectable sedative properties at the 10 mg dose where long-lasting antihistamine effects can be demonstrated.
Adult↗
Initial blood pressure as a predictor of the response to antihypertensive therapy.
1. The relationship between fall in systolic blood pressure and initial systolic blood pressure has been investigated in 255 mixed normotensive and hypertensive subjects given placebo or one of five types of antihypertensive drug (ACE inhibitors, calcium antagonists, direct vasodilators, alpha-adrenoceptor blocker, beta-adrenoceptor blocker). 2. In all cases there was a significant correlation between the change in blood pressure and initial blood pressure. When Oldham's transformation was used (replacing the initial blood pressure by the mean of the initial and minimum pressures) the correlation coefficients were all reduced, although five out of six were still statistically significant. 3. In a subset of 43 hypertensive subjects given four antihypertensive agents, concentration-effect analysis was carried out. For three of the agents a linear model was used to relate effect to concentration; for the remaining agent a Langmuir type model was used. 4. For all four sets of data for which concentration-effect analysis was carried out, there was a significant correlation between the sensitivity of response and the initial blood pressure. 5. The observed relationships between initial blood pressure, change in blood pressure and sensitivity of response can be qualitatively explained by postulating a general form of dose-response relationship for all antihypertensive agents.
Antihypertensive Agents↗
Haemodynamic, metabolic, and lymphocyte beta 2-adrenoceptor changes following chronic beta-adrenoceptor antagonism.
We have examined the effects of 7 days treatment with beta adrenoceptor antagonists in 8 healthy volunteers in a placebo controlled, crossover study. We investigated three beta-adrenoceptor antagonists (atenolol, oxprenolol, and propranolol), which have differing profiles of selectivity and partial agonist properties (intrinsic sympathomimetic activity, ISA). We studied adrenaline-induced hypokalaemia, the vasodilator response to an infusion of adrenaline (0.06 micrograms X kg-1 X min-1 for 90 min), and lymphocyte beta 2-adrenoceptor number, determined by (-) [125I]-iodocyanopindolol binding, and measured these variables both before and after 7 days of treatment. The beta 2-mediated depressor response to adrenaline infusion was abolished by propranolol and oxprenolol but persisted after atenolol. In contrast, the hypokalaemia induced by adrenaline was abolished by all three beta-blockers. Lymphocyte beta 2-adrenoceptor number increased significantly following propranolol treatment, but not after oxprenolol for atenolol. We conclude that up-regulation of lymphocyte beta 2-adrenoceptors is dependent on beta 2-receptor blockade and is modified by ISA. The reversal of the hypokalaemic response by atenolol suggests that beta 1 receptors may contribute to the former effect. Alternatively, since different populations of beta 2-adrenoceptors differ in their susceptibility to antagonists there may also be differences in agonist coupling to beta 2-responses between tissues.
Adrenergic beta-Antagonists↗
The pressor dose-response in clinical cardiovascular pharmacology.
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Animals↗
A pragmatic approach to the pressor dose-response as an index of vascular reactivity and adrenoceptor function in man.
In clinical pharmacological studies, where it is not possible to describe the full dose-response curve, the construction of dose-response relationships ideally depends upon achieving a reproducible and readily measurable response for each dose administered. This study investigates in normotensive males the technique of dose-response analysis for the blood pressure and heart rate increases with constant infusions of incremental doses of vasoactive drugs, particularly catecholamines. Steady state responses could be adequately obtained using 5 min infusion periods (at each dose level) for noradrenaline and alpha-methyl noradrenaline. At least 7 min was required for phenylephrine and 8 min for isoprenaline. There was an approximate correlation between the time to achieve the steady state response and the half-life of the offset of the agonist effect. For interindividual comparisons it is desirable to compare steady state responses and so the time at each dose level will vary according to which agonist is being used. For intraindividual comparisons it may not be essential that steady state responses are achieved. For example, assessment of the effect of prazosin on the responses to phenylephrine, by calculation of dose ratios, indicated that 5 min dose intervals were adequate.
Adult↗
The effects of calcium antagonists on blood pressure and responses to alpha-adrenoceptor agonists in hypertensive rabbits.
The effects of the calcium antagonists verapamil and nifedipine on mean arterial blood pressure, heart rate and pressor responses to a range of alpha-adrenoceptor agonists were examined in male normotensive New Zealand white rabbits and in rabbits with perinephritis hypertension. Verapamil and nifedipine caused a greater fall in mean arterial pressure in hypertensive compared to normotensive rabbits both when the fall was expressed as an absolute and as a percentage change. Effects on heart rate were similar in normotensive and hypertensive animals. Pressor responses to phenylephrine were attenuated by nifedipine and verapamil in normotensive and hypertensive rabbits. Pressor responses to alphamethyl noradrenaline were also attenuated by nifedipine, but pressor responses to BHT 920 were not significantly altered by either calcium antagonist in normotensive or hypertensive rabbits at the dose used. Thus the calcium antagonists had a greater effect on alpha 1 - than alpha 2-adrenoceptor mediated responses in both normotensive and hypertensive rabbits. Hypertensive animals showed an increased responsiveness to phenylephrine and alphamethyl noradrenaline but not BHT 920 compared to normotensives. This difference remained after treatment with both the calcium antagonists.
Adrenergic alpha-Agonists↗
The prevention of vitamin D deficiency in the elderly.
Vitamin D deficiency is common in the house-bound and institutionalised elderly population of Britain. A study of patients over 65 years discharged with a diagnosis of osteomalacia from Greater Glasgow Health Board hospitals between 1970 and 1981 inclusive showed a low incidence in the 65 to 74 years age group but a steeply rising incidence in older age groups. The majority (83%) of patients were female. The fortification of margarine, butter and milk with concentrations of vitamin D acceptable to the general population does not produce significant elevations in serum 25-hydroxyvitamin D (25-OHD) levels in vitamin D-deficient elderly patients. Low intensity background ultraviolet radiation (UVR) and intermittent high intensity UVR produce significant elevations in serum 25-OHD levels in elderly patients but both methods have disadvantages which limit their widespread use. Vitamin D supplements equivalent to 10 micrograms daily produce significant elevations in serum 25-OHD levels in vitamin D-deficient elderly patients. A vitamin D supplement policy for the housebound and institutionalised elderly population of Britain is required.
Aged↗
Blood pressure and correlations.
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Humans↗
Verapamil pharmacokinetics and apparent hepatic and renal blood flow.
The effect of acute and continued administration of verapamil on pharmacokinetics and regional blood flow has been studied in eight normotensive subjects. Continued administration resulted in a significant decrease in verapamil clearance, compared to that following acute dosing, as assessed by increases in both terminal elimination half-life (from a mean +/- s.d. of 5.2 +/- 2.3 h to 6.7 +/- 2.0 h) and AUC (from a mean +/- s.d. of 800 +/- 353 ng ml-1 h to 1455 +/- 244 ng ml-1 h). The relative clearance of norverapamil was not changed. Acute administration of verapamil resulted in a significant increase (P less than 0.005) in apparent liver blood flow which with continued administration fell significantly (P less than 0.01) towards placebo values. Effective renal plasma flow similarly increased with acute verapamil administration (P less than 0.05) and with chronic administration reduced again to be not significantly different from placebo. Acute and chronic verapamil administration did not significantly alter glomerular filtration rates. These results suggest that there may be a relationship between the acute increase in liver blood flow and the relatively increased clearance of verapamil following acute dosing.
Adult↗
Recovery of alpha-adrenoreceptor mediated responses and binding site number after intravenous benextramine in the rabbit.
The densities of [3H]-prazosin and [3H]-clonidine binding sites were determined in spleen and brain membrane preparations from rabbits treated 1 to 48 h previously with benextramine (5 mg/kg). In other rabbits pressor responses to phenylephrine and BHT 920 were examined 1 to 72 h after benextramine administration. After benextramine there was a reduction in the density of both [3H] prazosin and [3H] clonidine binding sites in spleen and a non-parallel shift in pressor dose response curves to selective alpha 1- and alpha 2-adrenoreceptor agonists. Recovery of in vivo responses and binding site densities were relatively slow. No reduction in the maximum density of either [3H] prazosin or [3H] clonidine binding sites in brain was found after intravenous administration of benextramine. It is concluded that after intravenous administration benextramine binds irreversibly to peripheral alpha 1- and alpha 2-adrenoreceptors in the rabbit but fails to cross the blood brain barrier in appreciable quantities and bind to central alpha-adrenoreceptors. Recovery of in vivo responses was more rapid than that previously observed after alpha-adrenoreceptor blockade with phenoxybenzamine. The longer time course of recovery after phenoxybenzamine may be a result of redistribution of this lipophilic drug from fat.
Adrenergic alpha-Agonists↗
The effect of calcium channel blockers on alpha 1- and alpha 2-adrenoceptor-mediated vascular responsiveness in man.
This study investigated the effects in normotensive males of the calcium channel blockers, verapamil and nisoldipine, on the pressor responses mediated via alpha-adrenergic and non-adrenergic mechanisms. After the first doses of each drug and after 4 days continued treatment both verapamil and nisoldipine significantly attenuated the responses to angiotensin II with three- to fivefold rightward shifts of the pressor dose-response curves. Rightward shifts of comparable magnitude were obtained for phenylephrine (selective alpha 1-agonist), but with alpha-methylnoradrenaline (preferential alpha 2-agonist) only nisoldipine caused a significant twofold rightward shift and only during continued treatment. This study demonstrated that peripheral vascular adrenergic responses mediated via both alpha 1- and alpha 2-adrenoceptors in man are affected by calcium channel blocking drugs. There was no evidence that this effect was specifically linked to the alpha 2-adrenoceptor. The functional antagonism of peripheral vasopressor mechanisms was not significantly different for verapamil and nisoldipine.
Adult↗
The recovery of alpha-adrenoceptor function and binding sites after phenoxybenzamine. An index of receptor turnover?
The recovery of peripheral alpha-adrenoceptor function and binding sites was studied in male New Zealand white rabbits after treatment with the irreversible adrenoceptor antagonist phenoxybenzamine. Phenoxybenzamine (5 mg/kg) was administered intravenously and the animals studied 30 min to 12 days later. Pressor dose response curves to intravenous phenylephrine, noradrenaline and guanabenz were constructed in vivo in conscious animals. The contractile response of abdominal aorta and renal artery to phenylephrine and noradrenaline was examined in vitro and the recovery of specific prazosin and clonidine binding to spleen membranes investigated in radioligand binding studies. The half life (t 1/2) for recovery of maximum pressor response in vivo ranged from 0.9 +/- 0.2 days for phenylephrine to 1.4 +/- 0.1 days for guanabenz. The t 1/2 for recovery of ED50 was not significantly different to t 1/2 for recovery of maximum pressor response and ranged from 0.8 +/- 0.2 days for noradrenaline to 1.3 +/- 0.3 days for phenylephrine. Half life for recovery of maximum response and EC50 in the isolated tissues was similar to that obtained in vivo for recovery of pressor responses and ranged from 0.4 +/- 0.1 days for the EC50 of noradrenaline in the renal artery to 1.2 +/- 0.6 days for maximum response to phenylephrine in the abdominal aorta. The rate of recovery of specific clonidine binding did not differ significantly from the rate of recovery of pressor responses to the alpha 2-selective agonist guanabenz. t 1/2 for maximum number of specific clonidine binding sites, Bmax was 1.6 +/- 0.9 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Comparison between short-term renal haemodynamic effects of propranolol and nadolol in essential hypertension: a cross-over study.
The effect of 4-6 weeks' treatment with propranolol and nadolol on effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) was studied, in 14 patients with essential hypertension, in single blind, random and cross-over design. Both drugs caused comparable effective lowering of pulse and blood pressure. When taken as the first drug, propranolol caused significant reduction in ERPF and GFR and a rise in filtration fraction (FF) and renal vascular resistance (RVR), whereas nadolol caused distinct rise in ERPF and a fall in FF and RVR but GFR remained unchanged. These haemodynamic effects were reduced when propranolol was given immediately after the withdrawal of nadolol and were obviated when nadolol followed propranolol therapy. This suggested a carry-over effect of the first drug into the second phase of treatment. We conclude that with short term therapy in essential hypertension, propranolol has a renal vasoconstrictor and nadolol a vasodilator effect.
Adrenergic beta-Antagonists↗
Comparison of medroxalol and labetalol, drugs with combined alpha- and beta-adrenoceptor antagonist properties.
Medroxalol, a new drug which has been reported to possess both alpha- and beta-adrenoceptor antagonist properties, was compared with labetalol in single dose studies in normotensive males. Oral doses of 400 mg of each drug significantly reduced blood pressure, both supine and erect, without significant changes in heart rate. The chronotropic and diastolic depressor responses to isoprenaline were significantly antagonised by both drugs, for at least 6-8 h after drug administration. Medroxalol was associated with significantly greater beta-adrenoceptor antagonism than labetalol. There was no significant antagonism by either drug of the pressor response to noradrenaline. However, in a sub-group of subjects the responses to the selective alpha 1-adrenoceptor agonist, phenylephrine, were consistent with modest alpha 1-adrenoceptor antagonism. This was significant only for labetalol. The ratios of beta 1- to alpha 1-adrenoceptor antagonism as calculated from the relative shifts of the isoprenaline and phenylephrine dose-response curves, were 3 to 1 for labetalol and about 7 to 1 for medroxalol.
Adrenergic alpha-Antagonists↗
Comparison of the clinical pharmacokinetics and concentration-effect relationships for medroxalol and labetalol.
The pharmacokinetics of medroxalol are described in normal subjects and compared with those of labetalol. Both drugs were administered in doses of 400 mg orally and 1 mg/kg intravenously. The data for both drugs was most appropriately described by a two compartment model. For oral medroxalol the clinical pharmacokinetic parameters were a terminal elimination half-life (t 1/2,Z) of 15.6 h, a peak level of 450 ng/ml and a time to peak of 2-3 h. Following intravenous medroxalol the bioavailability was calculated as 64%, the plasma clearance was 948 ml/min and the t 1/2,Z was 7.3 h. The t 1/2,Z following intravenous administration was significantly shorter than that following oral administration. The significant differences between medroxalol and labetalol were in time to peak, respectively 2.3 and 1.1 h; oral t 1/2,Z, 15.6 and 5.5 h; clearance 948 and 1560 ml/min; and bioavailability, 64 and 20%. Despite the pharmacokinetic differences a similar plasma concentration-hypotensive effect relationship was described for each drug.
Adrenergic alpha-Antagonists↗