In general, drug treatment of hypertension is started with a diuretic. If such therapy is not successful another hypotensive drug is added, either a specific sympatholytic agent or methyldopa.In order to be as objective as possible regarding which of these methods of treatment is the best a double-blind trial was carried out; this included two of the known hypotensive drugs, guanethidine (Ismelin) and methyldopa (Aldomet), and two new drugs, guanoxan (Envacar) and guanoclor (Vatensol). Chemistry and PharmacologyGuanethidine is a sympatholytic agent (Maxwell et al., 1959), and its effect is predominantly a lowering of the blood pressure in the erect position, whereas only a slight reduction is obtained In the supine position (Page and Dustan, 1959). Guanethidine reduces the concentration of catecholamine both centrally and peripherally, but not in the superior parts of the central nervous system. Intestinal absorption is constant, its elimination is mainly renal and slow, and therefore the dose should be determined cautiously in cases of impairment of renal function. When the drug is administered intravenously the cardiac output and renal blood flow are distinctly reduced, and bradycardia is a characteristic finding.Methyldopa (alpha-methyl-3-4-dihydroxyphenyl-alanine) is a decarboxylase inhibitor. Absorption takes place rapidly, but varies from patient to patient-a fact without positive correlation to the antihypertensive effect. The mechanism of the drug has not yet been explained in detail. Its decarboxylase inhibitory action is not alone responsible for the antihypertensive result; other decarboxylase inhibitors have no effect at all on the raised blood pressure. Metabolites of methyldopa such as methylnoradrenaline could be the effective agents; a replacement of noradrenaline with this metabolite in tissue stores might act as a false transmitter on stimulation. Methylnoradrenaline has in itself some, though poor, pressor effect. This hypothesis could explain the poor orthostatic effect of methyldopa and the missing clinical sympatholytic action (Sannerstedt et al., 1962Onesti et al., 1964Prescott et al., 1966).Guanoxan is 2-guanidinomethylbenzo-1, 4-dioxan. Consequently it is a guanethidine-ring with benzodioxane in the side chain. Guanoxan causes a reduction in the concentration of catecholamines in both the hypothalamus and the adrenal medulla, and peripherally. It has been shown that cats treated with guanoxan present reduced avoiding reactions and inhibited vasoconstrictive response in the skin on hypothalamic stimulation. In dogs treated with guanoxan a reduced effect of injected adrenaline due to adrenergic blockade has been found (Brit med. 7., 1964a;Davey and Reinert, 1965); similar findings were made with benzodioxane alone.In animal experiments guanoxan differs from guanethidine in that it blocks the alpha-receptors and reduces the concentration of catecholamine in the hypothalamus. On Only a few clinical trials of guanoxan and guanoclor have been published. With respect to the former drug, two i...