HAeMODYNAMIC STUDIES WITH METHYLDOPA: EFFECT ON CARDIAC OUTPUT AND RESPONSE TO PRESSOR AMINES

Abstract

Methyldopa has been shown to be an effective hypotensive agent both in animals and in man (Oates et al., 1960), and valuable in the treatment of hypertension, particularly in the management of mild or moderately severe cases (Dollery and Harington, 1962;Bayliss and Harvey-Smith, 1962). Pharmacological activity resides entirely in the L-isomer (Gillespie et al., 1962). The mechanism of the anti-hypertensive action of methyldopa is not fully understood. Although known to be an inhibitor of decarboxylase (Sourkes, 1954), and thus potentially capable of reducing the biosynthesis of noradrenaline and other pressor amines, there is evidence that the cardiovascular effects of the drug are independent of this mechanism, and more closely related to depletion of noradrenaline from sympathetic nerve endings (Hess et al., 1961). The present paper reports certain further observations on the clinical pharmacology of methyldopa, in particular measurements of the cardiac output before and after treatment, and the effect of the drug on the response to pressor amines. SUBJECTS AND METHODSBecause the action of methyldopa is slow in onset, even after intravenous injection, it has been found impracticable to record the acute effects of the drug in a single study. Paired studies have therefore been carried out on 10 hypertensive patients, first before commencement of oral treatment and again after a period of 4 to 10 days' treatment in doses of 0 75-2 0 g. daily. The patients ranged in age from 33 to 62 years, had not previously been receiving hypotensive treatment, and were considered to be suitable subjects for long-term treatment with methyldopa. All had high levels of resting blood pressure (Table I), but none showed exudative retinopathy or papilloedema. None of the patients had severe renal failure, the highest urea level being 46 mg./100 ml.Blood pressure was recorded from an indwelling catheter in the femoral artery, and intravenous injections were given through a polythene catheter, the tip of which lay in the superior vena cava. Cardiac output was measured by indicator dilution using the dye Coomassie blue and recording with an arterial cuvette and Cambridge dye recorder. Arterial blood was drawn through the cuvette by a constant speed syringe pump at a rate of 35 ml./min. The curves were recorded from the cuvette in the normal way and the whole curve to the point of recirculation was sampled by the motor-driven syringe. The concentration in this mixed blood sample was used to calibrate the integrated curve area over the time of sampling. 1311-labelled human serum albumin was added to the Coomassie blue dye before injection so that each injection contained about 2 ,uc. Instead of estimating the dye concentrations, the radioactivity in the blood samples was

GUANETHIDINE AND METHYLDOPA: A HAeMODYNAMIC STUDY

“…3. As far as we know, only Dollery et al (1961) in a study of patients treated with guanethidine have previously stressed this as a likely principal mechanism of action. On the evidence of the small number of patients studied, we cannot exclude increased venous pooling as one factor that may play a part in the postural hypotension induced by the drugs, but it is clear that it is unimportant in most patients.…”

“…Lowe and Rosenheim (1960) suggested this might be caused by a failure of the cardiac output to rise normally on exercise. Later, Dollery et al (1961) and Taylor et al (1962) showed that cardiac output did rise in a normal fashion on exercise, but these observations were made with the subjects in the supine position. Sannerstedt et al (1962) also found little effect on the cardiac output during exercise on a bicycle ergometer after treatment with oral methyldopa.…”

“…Secondly, most hiemodynamic studies were of the acute effects of the drugs given intravenously: their pharmacology is complicated, and the results may not be comparable to those obtained in investigations of the long-term action of orally administered drugs. Thirdly, the response of patients in heart failure to hypotensive agents is peculiar in that a fall in atrial filling pressure resulting from venous pooling may increase cardiac output (Freis et al, 1953): data obtained from a study of patients with raised venous pressure are therefore not applicable to those in whom it is normal. Finally, there is almost certainly more than one mechanism by which guanethidine and methyldopa reduce blood pressure, and the pattern of response may vary from patient to patient.…”

The Hemodynamics of Hypertension and Anti Hypertensive Therapy

“…Pargyline and a-methyldopa also produce a further blood pressure reduction in an upright position, but the effect does not appear to be related to venous pooling. With both drugs the cardiac output is maintained at normal levels in the erect position, while the increase in peripheral resistance is abolished (91,(93)(94)(95)(98)(99)(100).…”

Professional discipline.

“…Drugs that blockade adrenergic neurones increase sensitivity to circulating catecholamines several-fold, as do the tricyclic antidepressants such as imipramine, which block the uptake of adrenaline and noradrenaline into nerves. 3 4 In each case potentiation of the effect of the catecholamines is likely to be important only if a dose is injected intravenously. Chloroform, halothane, trichlorethylene, cyclopropane, and hypothermia sensitize the myocardium to circulating catecholamines and increase the risk of arrhythmia.…”