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Medroxalol, a new antihypertensive agent with alpha- and beta-adrenoreceptor blocking properties in both animals and humans, was administered in a single-blind study for 12 weeks to 29 patients with mild and moderate hypertension (standing blood pressure: 188-130/130-100 mm Hg). After 4 weeks of placebo administration, treatment with oral medroxalol was begun. Six weeks later, half the subjects added hydrochlorothiazide, 12.5 mg twice daily, to medroxalol for an additional 6 weeks, and the other half added placebo. During the final 4-week period medroxalol, but not hydrochlorothiazide, was discontinued and placebo substituted. Oral medroxalol doses of 100-400 mg twice daily reduced standing diastolic pressure to less than 100 mm Hg in 21 of the 26 subjects who completed the study. Compared to the last values on placebo, mean standing blood pressure was decreased by 15.6/12.0 mm Hg during the first 6 weeks of medroxalol at mean daily doses of 388-407 mg. Addition of hydrochlorothiazide permitted some decrease in medroxalol dosage. Upon medroxalol withdrawal, blood pressure and heart rate returned toward pretreatment values, with subjects continuing on diuretic showing lower blood pressures than the untreated individuals. Tolerance to medroxalol, with or without hydrochlorothiazide, was good. Mild orthostatic dizziness was the most frequent complaint associated with therapy, but postural hypotension was not found on physical examination. Medroxalol appears to be effective and well tolerated for reducing the blood pressure of most patients with mild to moderate hypertension and may be useful for chronic oral therapy of this disease.

We investigated the effects on peripheral sympathetic nervous function of monofluoromethyldopa (MFMD, RMI 71963), a selective, enzyme-activated, irreversible inhibitor of L-aromatic amino acid decarboxylase. Three daily injections of 2.5, 25, or 100 mg/kg MFMD to rats reduced the dopamine and norepinephrine concentrations in the heart and increased those of L-dopa. Sedation was seen with the two highest doses of MFMD. Cardiovascular responses in the pithed rat to stimulation of the whole spinal sympathetic outflow and to injections of tyramine were reduced by treatment with MFMD. Both the reduced sympathetic function and the depleted transmitter store were restored by infusions of dopamine. Norepinephrine depletion and functional inhibition were obtained with smaller doses of MFMD (3, 6, and 10 mg/kg daily) given for longer periods (10 days). Blood pressure in spontaneously hypertensive rats was reduced by treatment with MFMD, 25 mg/kg, daily for 3 days. In vitro responses to nerve stimulation of portal veins declined during incubation with MFMD or alpha-methyl-p-tyrosine; responses of atria were unaffected. Changes in norepinephrine concentrations of portal veins and atria closely paralleled the changes in function. MFMD is the first compound which depletes peripheral norepinephrine concentrations by inhibiting transmitter biosynthesis at the decarboxylase step. Such depletion results in inhibition of sympathetic function in vivo and introduces a novel approach to pharmacological manipulation of the activity of the peripheral sympathetic nervous system.

We investigated the mechanism of the antihypertensive action of DL-alpha-monofluoromethyldopa (MFMD), an irreversible inhibitor of L-aromatic amino acid decarboxylase, in spontaneously hypertensive rats (SHR). MFMD, 25 mg/kg i.p. daily for 3 days, reduced mean arterial blood pressure by 47 +/- 11 mm Hg (n = 6; p less than 0.001). The effect was associated with marked attenuation of the responses to stimulation of the whole sympathetic outflow in pithed preparations and with substantial reductions in the norepinephrine concentrations of hearts and portal veins. Similar functional and biochemical deficits were produced in age-matched, Wistar--Kyoto, normotensive rats, but blood pressure in these animals fell only by an average of 8 +/- 4 mm Hg (n = 5; NS). Blood pressure of SHR, lowered by MFMD, was restored to pretreatment levels by infusion with dopamine (0.1 mg/kg/min for 5 min), and there was a concomitant return towards normal of both the peripheral sympathetic transmitter stores and the response to stimulation of the nerves supplying the cardiovascular system. Neither the dopamine nor the norepinephrine concentrations of the brain, depleted by treatment with MFMD, were altered following infusion of dopamine. These results provide direct evidence that attenuation of sympathetic function arising from depletion of the peripheral transmitter store is the mechanism by which MFMD lowers blood pressure in SHR. They further lend strong support to the view that hyperactivity of the sympathetic nervous system plays a primary role in the maintenance of the elevated blood pressure in the genetically hypertensive rat.