Kathleen McLean

Noradrenaline release and clearance in relation to age and blood pressure in man

Abstract. Plasma noradrenaline concentration increases with age. This study was designed to investigate whether an increased rate of noradrenaline release into the circulation or a decrease in clearance is primarily responsible for this age related change in concentration. Sixteen healthy male subjects were studied, eight young (21–36 years) and eight old (65–78 years). Clearance was calculated from steady state noradrenaline concentrations during constant rate infusions of unlabelled noradrenaline. Clearance did not differ between the two groups: young 4.8 1/min (range 2.7–6.1), old 4.1 (range 2.6–8.2). The old subjects had significantly greater rates of release. Supine: young 10.3 nmol/min (range 5.3–17.6), old 19.7 (range 10.1–30), P<0.05. Standing: young 17.2 (range 11–36.4), old 29.2 (range 21.8–47.9), P<0.01. No significant relationship was found in either supine or standing position between rate of noradrenaline release and either systolic or diastolic blood pressure. These results indicate that plasma noradrenaline concentration rises with age because of an increased rate of release, but that this increased release is not responsible for the higher blood pressure seen in the elderly.

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.

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.

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.

Absence of an effect of mianserin on the actions of clonidine or methyldopa in hypertensive patients

SummaryThe concurrent administration of tricyclic antidepressants has been shown in man to result in a clinically significant impairment of the antihypertensive effect of clonidine. This interaction is thought to be related to competition for central α2 receptors where clonidine acts as an agonist and the tricyclics act as antagonists. Although it seems to cause less cardiovascular effects than tricyclic antidepressants, the tetracyclic antidepressant, mianserin also has been reported to be an α receptor antagonist and may, therefore, also interfere with the antihypertensive activity of centrally-acting drugs. This study investigates the effects of acute and chronic mianserin administration in patients with essential hypertension established on long term treatment with either clonidine or methyldopa. The first dose of mianserin was not associated with an increase in blood pressure and during a further two weeks of mianserin therapy there were no significant alterations in blood pressure, supine or erect. Similarly, mianserin did not alter heart rate either after acute or after chronic administration. Mianserin itself had a sedative effect but there was no interference with the sedation attributable to clonidine or methyldopa. Mianserin caused no reduction in salivary flow and did not influence the reduced saliva production caused by clonidine. Both clonidine and methyldopa are associated with a reduction in sympathetic outflow but there was no evidence in this study of any further change in plasma noradrenaline or 24 h urinary catecholamine excretion. This study demonstrates that if mianserin is given acutely or chronically, it does not interfere with the effects of the centrally acting antihypertensive drugs, clonidine and methyldopa. Mianserin may therefore be a suitable antidepressant for patients receiving these antihypertensive agents if drug treatment for depression is indicated.

Pharmacodynamic studies on mianserin and its interaction with clonidine.

SummaryThere is evidence that clonidines hypotensive effect is reduced by the concurrent administration of tricyclic antidepressants. It has been proposed that this results from an interaction at α2-receptors in the brain stem where clonidine acts as a relatively selective agonist and the tricyclic antidepressants as antagonists. Mianserin is an antidepressant with a tetracyclic structure and, although it has been reported to cause less cardiovascular disturbance, there is evidence that it also has α-adrenoceptor blocking effects. This study in 6 normotensive healthy male volunteers was designed to investigate a possible interaction between clonidine and the antidepressant mianserin. Administration of the first dose of 20 mg mianserin was associated with acute cardiovascular effects, notably transient postural hypotension, but no significant disturbance of heart rate or blood pressure was detected after 3 days continuous treatment with mianserin 20 mg tid. Following pre-treatment with mianserin or placebo the responses to a single oral dose of 300 µg clonidine were then assessed. The combination of mianserin and clonidine was not associated with any attenuation of clonidines hypotensive effect, erect or supine, but there was significant attenuation of clonidines supine bradycardic effect. There was no evidence that mianserin interfered with the ability of clonidine to diminish salivary flow, cause sedation, and reduce catecholamine output, but it was noted that mianserin itself had a very pronounced sedative effect. Mianserin alone had no significant effect on salivary flow. This short term study demonstrates that mianserin does not significantly interfere with the responses to a single oral dose of clonidine.

Pharmacodynamic studies with a specific alpha 2-adrenoceptor agonist (BHT-933) in man.

We conducted pharmacodynamic studies in man with a specific alpha 2-adrenoceptor agonist BHT-933. The study involved nine male normotensive volunteers each of whom received BHT-933 5 mg or placebo in random order. BHT-933 significantly lowered systolic and diastolic blood pressure (BP) in supine and standing positions, the greatest effect occurring 3-4 h following drug administration. Supine values: placebo 116/73; BHT-933 99/64. Standing values: placebo 114/79; BHT-933 92/67. Heart rate was uninfluenced by BHT-933 even at the time of maximum fall in BP. Plasma noradrenaline concentration in the supine position was significantly reduced: placebo 2.5 +/- 0.8 nmol/L; BHT-933 1.7 +/- 0.6. The haemodynamic changes accompanying Valsalvas manoeuvre and cold pressor test were uninfluenced by BHT-933. All subjects experienced sedation and dry mouth following BHT-933 with a time course similar to that of the fall in BP. These results are consistent with an effect of BHT-933 on BP control through an action on alpha 2-receptors at the level of the brainstem.

The effect of food on the pharmacokinetics and pharmacodynamics of tolmesoxide in essential hypertensives.

SummaryTolmesoxide is a new, direct-acting vasodilator drug for use in the management of both hypertension and cardiac failure. In 6 essential hypertensives inadequately controlled by combined β-blocker and diuretic therapy (average supine blood pressure 178/103 mm Hg) the addition of tolmesoxide (300–900 mg daily) was associated with a significant improvement in blood pressure control (average supine blood pressure 161/89 mmHg). The effect of food on the pharmacokinetics and pharmacodynamics of tolmesoxide have also been studied because, particularly at higher doses, the drug has been associated with upper gastrointestinal upset and it has been empirically recommended that it be taken with food. The blood pressure and heart rate responses were not significantly different when tolmesoxide was taken fasting or with food. Food resulted in a significant reduction in the peak plasma tolmesoxide concentration (2.14 µg/ml compared to 2.97 µg/ml) and a significant increase in the time to reach peak plasma concentration (1.67 h compared to 0.63 h). Although there was no impairment of its hypotensive effect, food significantly altered the pharmacokinetics of tolmesoxide and may therefore be useful in reducing the gastrointestinal disturbance associated with its use. In the treatment of inadequately controlled hypertension, tolmesoxide has a limited role as an alternative vasodilator.