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
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.