A number of investigators have evaluated the antihypertensive potency of spironolactone in both benign and accelerated hypertension and have found a generally small magnitude of response, somewhat comparable to the thiazide diuretics.1-5 This study was undertaken, originally, to demonstrate a possibly enhanced antihypertensive effect of spironolactone when administered to a. group of hypertensive patients showing evidence of secondary aldosteronism. Our attempt to cull such a group of patients with hyperaldosteronism from a pre-selected group of hypertensives with hypokalemia produced a disappointingly low yield. In addition to blood pressure response, the effect of spironolactone on renal function, serum potassium and carbon dioxide content have been studied.
METHODThorough screening of our hypertension clinic (consisting of 102 patients) for non-thiazide induced hypokalemia (serum potassium of less than 4.0 Meq./L mean of 3 determinations) provided only six subjects. These six patients comprised the study group and it was not known until following the completion of the study which members, if any, had increased urinary aldosterone excretion levels. Six patients with an equivalent degree of hypertension were selected as a control group and differed from the study group by the presence of normokalemia. One member of the control group was subsequently discarded upon learning that he had failed to take the medication as prescribed. Both groups received spironolactone in doses of 300 mg daily (75 mg four times a day) over a four week period.Patients were seen every two weeks by one of the authors. Interval history and brief physical examination were done and laboratory tests carried out. Patients were instructed at each visit to take their medication, usual exercise and adhere to a minimum of six grams of salt (NaCI) intake. Medication fidelity was checked only by counting remaining tablets. Salt intake was confirmed by 24 hour urine sodium content.
Extensive pharmacological studies have shown that Hydralazine* (1-hydrazinophthalazine) is a promising drug in the treatment of hypertension (1-4). Clinical studies to date have confirmed its hypotensive effect and have indicated that in many patients the drug may be difficult to use because of its side effects (5-8). We began our study two years ago in an attempt to evaluate the hypotensive action of Hydralazine in a group of ambulatory patients. We were particularly interested in the side effects that were encountered early in the use of the drug and rather than discontinue it, an effort was made to circumvent or minimize these side effects by various measures. One of these measures was the use of Veriloid in combination with Hydralazine. We were gratified to find that not only were troublesome side effects ameliorated in some instances, but a more pronounced depressor effect was obtained with the combination of the two drugs.
1 We are indebted to Elva Hiscock, B.S., for the careful dietary management and handling of patients.The root of the plant, Rauwotfia serpentina, has been mentioned in the literature of India for centuries as a useful agent in the treatment of anxiety and hyperactive mental states. Although its use in the treatment of hypertension was first described in 1933 (1), it received little attention in the American literature until very recently. Attempts to isolate the active principle from crude Rauwol~a serpentina began at the end of the last century, but the first crystalline alkaloid was not isolated until 1931 (2). Today, some 14 substances have been extracted from the crude plant. Most of these have proved to be pharmacologically inert. In 1952, however, Muller, Schlittler, and Bein (3) isolated an active alkaloid from the plant which they named reserpine. Reserpine possesses both the sedative and hypotensive properties of the whole root and is believed to be the principal active component (4).
PHARMACOLOGYThe pharmacology of reserpine has been rather extensively studied. It has been found to have a unique sedative effect, inasmuch as a dosage many times greater than the effective sedative dosage does not produce narcosis (5). Reserpine does not produce the electroencephalographic changes characteristic of barbiturate administration, thus indicating that the sites of action are different for these two drugs (6). Again, in contrast to the barbiturates, reserpine lowers the convulsive threshold in animals subjected to electroshock (7). With acute intravenous administration of reserpine, sedation occurs before any hypotensive effect is observed (8). Furthermore, no correlation has been noted between the degrees of sedative and hypotensive response. It would, therefore, seem that these two effects of reserpine are distinct from each other.With regard to its hypotensive effect, a mass of evidence has been accumulated which indicates that reserpine's site of action is central rather than peripheral. Experimentally, it suppresses hypertension resulting from stimulation of afferent fibers of the vagus and sciatic nerves and from pressure changes in the carotid sinus (5). The absence of any marked postural hypotension following reserpine administration suggests that it produces no ganglionic blockade (4,9). The possibility of a peripheral site of action is precluded by the absence of sig-
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