David J. Sumner

Effect of Age on the Responsiveness of Vascular α-adrenoceptors in Man

Aging has been reported to alter the responsiveness of β-receptors, but there have been few comparable studies of α-receptors. This study compares in six young and six healthy elderly subjects the haemodynamic effects of the α1-antagonist prazosin and the pressor responses to the α1-agonist phenylephrine. Prazosin orally lowered erect (but not supine) blood pressure in both groups by a similar amount between 2 and 6 h after dosing. Maximal falls in systolic pressure were 19.5 ± 15.7 and 29.3 ± 11.4 mm Hg (mean ± SD) in young and old, respectively. There was a significant difference in the associated heart rate response: in the young group mean heart rate increased to 103 beats/min, but there was no corresponding increase in the elderly group, which had a mean heart rate of 80 beats/min. Following the intravenous infusion of increasing doses of phenylephrine, log dose—response curves were derived, and the dose required to raise mean arterial pressure by 20 mm Hg (PD20) was compared. The mean PD20, was significantly different in the two groups: 2.5 ± 1.6 in the young, compared to 4.6 ± 2.3 μg/kg/min in the elderly, indicating reduced pressor responsiveness in the elderly. However, no significant difference was apparent when pressor responsiveness was determined following the administration of prazosin. Thus, while there is no evidence of an age-related increase in the sensitivity of α-adrenoceptor-mediated vaso-constriction, the data are not inconsistent with an age-related reduction in responsiveness to α-adrenoceptor activation.

Prospective survey of use of therapeutic drugs, alcohol, and cigarettes during pregnancy.

Use of drugs during pregnancy was recorded prospectively in 2765 women attending the antenatal clinics of a general hospital from October 1982 to March 1984. Of these women, 2588 (93.6%) avoided exposure to drugs during the first trimester, 1802 (65.2%) took no drugs at any stage, 963 (34.8%) took a total of 154 different drugs from 35 groups of drugs, and 243 (8.8%) took a self administered drug. The most commonly used drugs were non-narcotic analgesics, usually self administered, and antibacterials. The last survey of use of drugs in pregnancy in the United Kingdom 20 years ago showed fewer women avoiding drugs throughout pregnancy (195 of 911 (21.4%), p less than 0.001) and in taking a self administered drug (586 (64.4%), p less than 0.001) than at present. Most women nowadays abstain totally from alcohol (1786 (64.6%) v 109 (12.0%) previously, p less than 0.001), but while more women are non-smokers compared with previously (1811 (65.5%) v 392 (43%), p less than 0.001) the trend has been far less dramatic than that for use of alcohol.

The effect of the calcium antagonist nifedipine on pressor and aldosterone responses to angiotensin II in normal man

SummaryThe effects of the calcium entry blocker nifedipine on blood pressure (BP) and the pressor and aldosterone responses to graded infusions of angiotensin II were studied in normal subjects using 3 protocols. Study 1 was a randomised double-blind placebo-controlled trial of nifedipine (20 mg p.o.) on supine and erect BP in 9 subjects. There was a highly significant fall in BP: (8±4 mmHg; mean±SDM;p<0.001) with maximum changes occurring 30 min after drug administration. Significant reciprocal changes in pulse rate were observed. These changes were not altered by prior administration of the prostaglandin synthetase inhibitor flurbiprofen (100 mg). In Study 2, 6 subjects were given nifedipine (20 mg) or no treatment mid-way between 2 identical graded infusions of angiotensin II (5, 10 and 20 ng/kg/min) separated by an interval of 1 h on each of 2 study days, and blood pressure and aldosterone responses were measured. There was a significant attenuation of both pressor (p<0.05) and aldosterone (p<0.05) responses. The changes in aldosterone responses were not due to changes in plasma renin, potassium or adrenocorticotrophin. In study 3 the pressor and aldosterone responses to angiotensin II (2, 5, 10 and 20 ng/kg/min) were studied after 3 days treatment with nifedipine (20 mg thrice daily) or placebo. Pressor dose response curves to both angiotensin II and noradrenaline were shifted in parallel to the right, but not significantly, and aldosterone responses to angiotensin II were unchanged by nifedipine. These results show that nifedipine may decrease BP in normal subjects by decreasing pressor and aldosterone responses to angiotensin II and that the aldosterone response to angiotensin II in man is possibly calcium-dependent.

Analysis of the pressor dose response

(1) When incremental infusions of drugs that increase blood pressure are given to human subjects to assess “pressor responsiveness,” only the lower part of the sigmoid dose‐response curve can be obtained. (2) Fitting a quadratic function does not involve discarding data points, which is usually the case with a linear fit, and it provides a more satisfactory fit to the lower part of a sigmoid dose‐response curve. (3) In the presence of a competitive antagonist, a pressor dose‐response curve will be shifted to the right. In this situation the dose‐response curves obtained before and after treatment with antagonist should be fitted simultaneously to a quadratic model in which the parallel shift is one of the parameters. (4) The use of quadratic fitting is illustrated by reference to clinical experiments to obtain the following three curves for drugs that modify peripheral alpha adrenoceptors: norepinephrine pressor response curves after placebo and doxazosin, an alpha1 antagonist; norepinephrine pressor response curves after placebo, labetalol, and medroxalol (drugs with combined alpha 1 and beta blocking properties); and phenylephrine pressor response curves before and after prazosin. (5) Fitting a quadratic function is the appropriate initial step in the analysis of pressor dose‐response curves in man.

Kinetic and dynamic comparison of piretanide and furosemide

In a comparative study with the use of a randomized crossover design, piretanide, a new “loop” diuretic, was given intravenously to 8 normal volunteers. Following the injection of radioiodinated human serum albumin to allow assessment of plasma volume changes, subjects were submaximally water loaded to facilitate urine collection for a period of 210 min after the intravenous injection of 12 mg piretanide, 40 mg furosemide, and placebo. Plasma piretanide concentrations, measured by a sensitive spectrofluorimetric assay, declined biexpoentially after intravenous bolus injection. The mean total body clearance was 246 ± 52 ml min−1 and the mean renal clearance was 136 ± 61 ml min−1. Significant increase in urine flow, natriuresis, and kaliuresis were evident within 15 min of piretanide injection and persisted for 90 min. A calciuric effect was also observed over this period. While a uricosuric action was observed during the first 15 min the overall effect was urate retention which became evident between 45 and 150 min. In none of these measured effects did 12 mg piretanide differ from 40 mg furosemide. Plasma volume declined linearly from the time of drug injection, a variable plateau being reached at approximately 90 min. From 15 min after injection, individual subjects showed a good linear correlation between the piretanide or furosemide urinary excretion rate and the concomitant sodium or potassium excretion rate. Corresponding concentration‐effect regression lines showed no important differences between the two diuretics. The relative potency of the drugs (piretanide : furosemide) for sodium excretion was 2.42: 1. For both piretanide and furosemide the time course of diuretic effect closely paralleled the extrapolated amount of drug in the peripheral compartment of the proposed open 2‐compartment model.

Immediate cardiovascular responses to oral prazosin—Effects of concurrent β‐blockers

Initiation of prazosin therapy may be complicated by the first‐dose response of acute postural hypotension and tachycardia. The effects of β‐blocker on the responses to oral prazosin were studied in eight normotensive men. After 1 mg oral prazosin there was a marked postural fall in blood pressure to a lowest mean standing systolic pressure of 88 ± 7 mm Hg (x̄ ± SD), associated with a tachycardia of 117 ± 13 bpm, and an increase in mean plasma norepinephrine concentration to 9.6 ± 7.9 nmole/l. There was a linear relationship (r = 0.93) between plasma prazosin concentration and hypotensive effect. Concurrent propranolol 80 mg or primidolol 100 mg (a cardioselective β‐blocker) increased the severity and duration of the postural hypotensive response, with lowest mean systolic blood pressure (BP) of 79 ± 7 and 75 ± 9 mm Hg. There was no effect on the orthostatic release of norepinephrine but there was attenuation of the postural tachycardia. Concurrent β‐adrenergie blocking therapy, selective or nonselective, intensifies the immediate postural hypotensive response to the initial oral dose of prazosin.

Haemodynamic, metabolic, and lymphocyte beta2-adrenoceptor changes following chronic beta-adrenoceptor antagonism

SummaryWe 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 µg·kg−1·min−1 for 90 min), and lymphocyte beta2-adrenoceptor number, determined by (-) [125I]-iodocyanopindolol binding, and measured these variables both before and after 7 days of treatment.The beta2-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 beta2-adrenoceptor number increased significantly following propranolol treatment, but not after oxprenolol for atenolol.We conclude that up-regulation of lymphocyte beta2-adrenoceptors is dependent on beta2-receptor blockade and is modified by ISA. The reversal of the hypokalaemic response by atenolol suggests that beta1 receptors may contribute to the former effect. Alternatively, since different populations of beta2-adrenoceptors differ in their susceptibility to antagonists there may also be differences in agonist coupling to beta2-responses between tissues.

Obstetric aspects of the use in pregnancy-associated hypertension of the β-adrenoceptor antagonist atenolol+

The obstetric implications of the use of the beta-adrenoceptor antagonist atenolol have been evaluated in a prospective, randomized, double-blind, and placebo-controlled study involving 120 women with pregnancy-associated hypertension. The clinical interpretation of antenatal and intrapartum cardiotocographs was uninfluenced by atenolol. Human placental lactogen concentration fell in the atenolol group, but this was not an indicator of subsequent fetal distress. Other obstetric indices, such as urinary estriol excretion, were the same in both groups. Spontaneous premature labor occurred in five women receiving placebo but in none who received atenolol. Together with previously reported findings on pregnancy outcome, our study leads us to conclude that beta-blockers such as atenolol can appropriately be used in the management of hypertension during pregnancy.

Digoxin kinetics in patients with thyroid dysfunction

The disposition of intravenously administered (3H)‐digoxin has been studied in 9 hyperthyroid and 4 hypothyroid patients. In 9 of these subjects the handling of simultaneously administered oral digoxin was assessed from serum digoxin levels determined by radioimmunoassay. Glomerular filtration rate was measured in each individual at the end of the period of study. There was a close correlation (p < 0.001) between digoxin renal clearance and glomerular filtration rate. Considerable overlap was observed when estimates of digoxin renal clearance in hyperthyroid persons were compared with those obtained in normal control subjects and hypothyroid patients, and there was no correlation between the severity of thyrotoxicosis and digoxin renal clearance; in fact, 3 thyrotoxic patients with established or paroxysmal atrial fibrillation showed impaired digoxin renal clearance. No consistent abnormality of digoxin extrarenal clearance was observed in this group of patients with thyroid disease and digoxin absorption was normal in 9 subjects in whom measurement of this parameter was possible (percent absorption, 71 ± 15). Analysis of the ratio of digoxin concentration in the “deep” compartment to digoxin concentration in the “central” compartment was made by means of a three‐compartment open kinetic model; this revealed a significantly greater “tissue” concentration of digoxin in thyrotoxic patients when compared with hypothyroid patients. These results suggest that the well‐recognized insensitivity of thyrotoxic patients to cardiac glycosides is inexplicable on pharmacokinetic grounds.

Effect of calcium channel blockers on adrenergic and nonadrenergic vascular responses in man.

Summary: There is evidence that responses mediated via α adrenoceptors are dependent on calcium fluxes and it has been suggested that the α2 adrenoceptor is particularly associated with the increased entry of extracellular calcium ions, which is preferentially antagonised by calcium channel blocking drugs. This study investigates in normotensive men the effects of calcium antagonism with verapamil and the dihydropyridine nisoldipine on the pressor responses to adrenergic and nonadrenergic vasoconstriction. Phenylephrine and alphamethylnoradrenaline were intravenously infused to assess respectively α1, and α2 adrenoceptor-mediated peripheral vascular responsiveness and angiotensin II was used to assess nonadrenergic responsiveness. After 4 days oral treatment, both verapamil and nisoldipine significantly attenuated the responses to angiotensin II with three- to fivefold rightward shifts of the mean pressor dose–response curves. Rightward shifts of comparable magnitude were obtained for phenylephrine but with alphamethylnoradrenaline, although the overall trend was similar, only nisoldipine caused a significant twofold rightward shift. These data demonstrate, in humans, that peripheral vascular adrenergic responses mediated via both α1 and α2 adrenoceptors are affected by calcium channel blocking drugs. There was no evidence that this effect was specifically linked to the α2 adrenoceptor.