John F. Marwood

Influence of alpha 1-adrenoceptor antagonism of ketanserin on the nature of its 5-HT2 receptor antagonism.

1. In order to investigate α1‐adrenoceptor interactions with 5‐HT2 receptors, the effect of ketanserin (which antagonizes both types of the above receptors) on responses to 5‐hydroxytryptamine (5‐HT) and phenylephrine (PE) was measured in isolated perfused rat tail arteries.

STUDIES ON THE VASODILATOR ACTIONS OF BUCINDOLOL IN THE RAT

1. Experiments were performed in anaesthetized rats to investigate the vasodilator actions of the β‐adrenoceptor antagonist bucindolol. Bucindolol (3 mg/kg) lowered blood pressure significantly in rats pretreated with (i) prazosin (0.4 mg/kg) (ii) prazosin (0.4 mg/kg) plus propranolol (0.5 mg/kg) or (iii) labetalol (0.5 mg/kg). Thus, a portion of the hypotensive effect of bucindolol was independent of effects on α‐ or β‐adrenoceptors. This was attributed to direct vasodilatation.

Erythrocyte Cation Transport is Sex-Related and is Modified by Oral Contraceptives

Cation transport across the erythrocyte membrane was studied in normotensive male and female subjects, 20 to 45 years of age. Inward sodium-potassium cotransport was found to be significantly greater in men than in women who were not taking oral contraceptives. Intracellular potassium concentration was lower in men than in women, and was inversely correlated with cotransport. Women who were using oestrogen-progestogen oral contraceptives had higher cotransport than those who were not. It is concluded that a difference in cotransport exists between Caucasian men and women, which is not evident if women are taking oral contraceptives, and which could invalidate comparisons of cation transport between subject groups that are not sex-matched.

INVESTIGATIONS INTO THE NATURE OF α2-ADRENOCEPTORS IN RAT TAIL ARTERIES

1. In rat isolated perfused tail arteries, dose‐response curves were established for the vasopressor effects of phenylephrine (α1‐adrenoceptor agonist), clonidine (α1‐ and α2‐adrenoceptor agonist), clonidine in the presence of 10‐7 mol/l prazosin (α2‐agonist), and BHT‐920 (α2‐agonist).

Comparative and combined efficacy of doxazosin and enalapril in hypertensive patients

Twenty patients with essential hypertension were randomised to a 7-week period of dose titration with doxazosin, 1-8mg/day or enalapril, 5-20mg/day. In a further 7-week period the dosage level reached with the initial drug was halved, and titration with the second agent was carried out. Blood pressure responses at the end of each treatment period were assessed by clinic measurements made 24 hours post-dose. In the first treatment period, enalapril (mean dose 19mg/day) reduced serum free ACE activity by 40% and had a greater effect than doxazosin (mean dose 5.2mg/day) on clinic supine blood pressure (systolic and diastolic). In the second period, the addition of enalapril to doxazosin was associated with a significant fall in clinic standing blood pressure (systolic and diastolic), despite the doxazosin dose reduction and consequent decrease in median plasma doxazosin concentration (from 10.6 to 5.2ng/ml). Alternatively, when doxazosin was added to enalapril, free ACE activity remained 40% decreased despite enalapril dose reduction, and blood pressure was not further affected. Plasma renin activity was increased by enalapril. No changes were observed in plasma aldosterone or lipid concentrations with either drug. The combination of doxazosin and enalapril was well tolerated and lowered blood pressure overall. Judged by clinic measurements 24 hours post-dose, most of the antihypertensive effect was attributable to the enalapril component. However, ambulatory blood pressure monitoring 0-12 hours post-dose in a subset of patients suggested a contribution of doxazosin earlier in the dose interval.

EFFECT OF ANGIOTENSIN II RECEPTOR BLOCKADE ON THE INTERACTION BETWEEN ENALAPRILAT AND DOXAZOSIN IN RAT TAIL ARTERIES

1. Previous work has shown that enalaprilat, an inhibitor of angiotensin‐converting enzyme (ACE), potentiated the actions of ai‐adrenoceptor antagonists; it was hypothesized that angiotensin II (Angll) modulated the activity of α1‐adrenoceptors. This hypothesis was tested in Sprague‐Dawley rat isolated perfused tail arteries using the AT1 receptor antagonist losartan and the AT2 receptor antagonist PD123319.

EFFECTS OF 5HT2 RECEPTOR ANTAGONISTS ON RESPONSES TO POTASSIUM DEPOLARIZATION IN RAT ISOLATED AORTA

1. In order to determine whether 5HT2 receptor antagonists can modify Ca2+ uptake via voltage‐operated Ca2+ channel (VOC) in arterial smooth muscle, a comparative study of the effects of selected Ca2+ uptake blockers and 5HT2 receptor antagonists on K+‐induced contractions of rat aortic strip was undertaken.

Investigations into interactions between doxazosin and enalaprilat at α1-adrenoceptors in anaesthetized rats

1. In anaesthetized intact Sprague‐Dawley rats, the angiotensin‐converting enzyme inhibitor enalaprilat, 1 mg/kg, had no significant effect on the pressor responses to the α1‐adrenoceptor agonist phenylephrine (PE). Doxazosin 1 mg/kg was found to be a potent α1‐adrenoceptor antagonist.

AN IN VITRO STUDY OF INTERACTIONS BETWEEN DOXAZOSIN AND ENALAPRILAT AT VASCULAR α1-ADRENOCEPTORS

1. Isolated perfused male Sprague‐Dawley rat tail artery segments were used to investigate interactions between the α‐1‐adrenoceptor antagonist, doxazosin, and the angiotensin converting enzyme (ACE) inhibitor, enalaprilat, using phenylephrine (PE) as the α1‐adrenoceptor agonist.

THE INTERACTION BETWEEN ENALAPRILAT AND SELECTED α-ADRENOCEPTOR ANTAGONISTS IN ISOLATED RAT TAIL ARTERIES

1. Isolated perfused rat tail artery preparations were used to investigate the effects of the angiotensin converting enzyme inhibitor enalaprilat on the actions of a series of α‐adrenoceptor antagonists. The agonist used was phenylephrine.