Acute and Sustained Changes in Sodium Balance During Nifedipine Treatment in Essential Hypertension FRANCESCOP.CAPPUCCIO,M.D., NIRMALAD. MARKANDU,R.s.N., GIUSEPPEA.SAGNELLA,Ph.D., DONALDR. J. SINGER,M.R.c.P., MICHELLEA. MILLER, B.SC., MARTIN G. BUCKLEY,B.SC., GRAHAMA. MACGREGOR,F.R.C.P., London, UnitedKingdom

PURPOSE To assess the changes in sodium excretion and sodium balance after initiation of nifedipine treatment and after withdrawal of nifedipine. PATIENTS: Eight patients with uncomplicated mild to moderate essential hypertension were entered in a single-blind, placebo-controlled study of 39 days’ duration. METHODS: Two ‘I-day periods while on a fixed sodium intake of 160 mmol/day approximately 3 weeks apart After 4 days of a placebo and fmed sodium intake, patients were given nifedipine GlTS (gastrointestinal therapeutic system) once a day and carefully studied for the following 4 daya Thereafter, patients continued to receive nifedipine GlTS, and approximately 3 weeks later they were studied again for a week while on a fixed sodium intake. Nifedipine administration was stopped and changes occurring after withdrawal were studid RESULTS: Nifedipine caused a significant increase in sodium excretion with a cumulative loss of sodium of 38 mm01 per subject within the first 4 days of treatment. The withdrawal of nifedipine treatment caused a significant decrease in sodium excretion and a cumulative retention of sodium of 42 mm01 per subject witbin the first 4 days of withdrawal. CONCLUSION: Nifedipine causes an acute and a sustained reduction in sodium balance in patients with essential hypertensior~ This proloqed effect may contribute to the mechanism whereby nifedipine lowers blood pressure.

From the Blood Pressure Unit, Department of Medicine, St. George’s Hospital Medical School, London, United Kingdom. Requests for reprints should be addressed to Graham A. MacGregor, Blood Pressure Unit, Department of Medicine, St. George’s Hospital Medical School, Cranmer Terrace, London SW17 ORE, United Kingdom. Manuscript submitted January 14, 1991, and accepted in revised form May 3,199l.

ifedipine is widely used in the treatment of both angina pectoris and essential hypertension [ 11. The decline in blood pressure that occurs in patients with hypertension taking nifedipine is thought to be due to peripheral vasodilatation secondary to inhibition of calcium-induced contraction of arteriolar smooth muscle [2]. When nifedipine was first introduced, it was in the form of a capsule that had a rapid absorption with a peak effect at 30 minutes and a half-life of 2 to 4 hours [3]. In Europe, a tablet formulation of nifedipine was developed that delayed the absorption so that the peak occurred at about 2 hours, but two to three times a day administration was still required to achieve adequate control of the blood pressure [4]. More recently, a slow-release formulation of nifedipine has been developed in the United States using a gastrointestinal therapeutic system (GITS) based on osmotic push-pull technology [5]. Previous pharmacokinetic and clinical studies of this formulation have shown that it is effective over a 24-hour period with fairly constant plasma levels of nifedipine [6]. Previous studies of both capsules and tablets of nifedipine have shown an acute increase in sodium and water excretion that is independent of hemodynamic changes [7]. Furthermore, one study found a greater increase in sodium excretion in patients with high blood pressure than in normotensive subjects [8]. However, in these studies, it was not clear whether the loss of sodium that occurred acutely did result in a long-term reduction in sodium balance, which, in itself, may be an important additional mechanism whereby nifedipine lowers blood pressure. Small, long-term changes in sodium balance are difficult to demonstrate. However, one way is to determine whether there is an initial loss of sodium with the start of treatment, then after a period of time to discontinue the treatment and ascertain if a similar amount of sodium is retained. Therefore, the aim of the current study was to determine whether any initial loss of sodium and hormonal changes occurred at the start of nifedipine GITS treatment, and whether any sodium reten-

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tion and hormonal changes developed when nifedipine GITS treatment was withdrawn after a month.

PATIENTS AND METHODS Patients with essential hypertension referred to the Blood Pressure Unit by local general practitioners were included in the study if no underlying cause for their high blood pressure had been found. Patients with renal failure (plasma creatinine level greater than 140 pmol/L), ischemic heart disease, or cerebrovascular disease or who were taking the oral contraceptive pill were excluded from the study. The protocol was approved by the local ethical committee. Eight patients who gave their informed consent entered and completed the study. They had been seen regularly every 2 to 4 weeks at least 2 months before entry to the study and had either received no previous treatment or, if they had, it was stopped at least 2 weeks before the study. Diuretics were discontinued 4 weeks before the study. The patients were then included in the study if their supine diastolic blood pressure was greater than 95 mm Hg after a further month of observation without treatment. There were three men and five women; three were white, two were black, and three were Asian. The mean age was 56 years (range: 48 to 67 years). The average supine blood pressure after a month of observation without treatment was 174/105 f 613 mm Hg. At the end of the run-in observation period, patients were entered into a single-blind study of 39 days’ duration. They were given, in a single-blind fashion, one placebo tablet to be taken in the morning for 7 days. On the fourth day of the placebo period, each patient was placed on a constant diet (provided by the Metabolic Ward kitchen) that contained 150 mmol of sodium per day and 80 mmol of potassium per day up to Day 11. After 4 days of placebo treatment (Day 4 to Day 7), patients were given nifedipine GITS (Pfizer) one tablet a day in the morning to be titrated upwards daily from 30 mg/day to 60 mg/day to 90 mg of nifedipine once a day from Day 8 to Day 11. From Day 10 onwards, patients continued to receive 90 mg of nifedipine throughout the study. After Day 11 up to Day 31, patients followed their usual diet and continued to take nifedipine GITS 90 mg once a day in the morning. On Day 32, patients were restarted on a fixed diet as above up to Day 39. On Day 35, patients were switched to single-blind placebo once a day and continued on their metabolic diet up to Day 39 when the study was completed. Throughout the study, patients were allowed to pursue their normal activities. They were not admitted to the hospital but they were discouraged from vigorous exercise. Patients were seen in the

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Blood Pressure Unit at the same time of day, by the same nurse, in the same room. Blood pressure was measured between 10 AM and 12 PM in the same arm, with a semiautomatic ultrasound sphygmomanometer (Arteriosonde, Roche, Nutley, New Jersey) [9] with attached recorder and appropriate cuff size. The measurements were therefore free from observer bias. Supine and standing blood pressures were taken as the mean of five readings obtained at l- to 2-minute intervals with the patient in the corresponding position. Supine blood pressure was measured before standing blood pressure. Pulse rate was measured with a Cambridge 3048 pulse monitor (Kent Cambridge Instrument Co., Ossining, New York). Body weight was recorded in the morning after voiding, with the patients wearing indoor clothing and no shoes. Daily 24-hour urine collections were obtained throughout the metabolic part of the study (Days 4 to 11 and Days 32 to 39) for measurements of urinary volume, sodium, potassium, calcium, and creatinine. Urinary electrolytes were measured by flame photometry. Venous blood was taken without stasis and in fasting conditions after the patient had been sitting upright for 10 minutes between 10 AM and 12 PM on Day 7, Day 11, Day 35, and Day 39 for measurements of plasma renin activity (PRA) [lo], plasma aldosterone [ll], and plasma atrial natriuretic peptide (ANP) [12]. All results are given as means f SEM or as median (interquartile range) as appropriate. Sodium balance was calculated as the cumulative sum of the differences between the average urinary sodium excretion during the last 3 days of each control period (Days 5 to 7 and Days 33 to 35, respectively) and the daily urinary sodium excretion during either active (Days 8 to 11) or placebo treatment (Days 36 to 39). Repeated-measurements analysis of variance and Student t-tests for paired observations or Wilcoxon rank sum test when appropriate were used for the statistical analysis using the Statistical Package for the Social Sciences [13].

RESULTS Day 4 to Day 11 During the administration of nifedipine GITS, both supine (Figure 1) and standing (Table I) blood pressures decreased significantly. Supine systolic and diastolic blood pressures dropped from 169/100 f 3/l mm Hg on the last day of placebo to 145/87 f 4/3 mm Hg (p

Acute and sustained changes in sodium balance during nifedipine treatment in essential hypertension.

To assess the changes in sodium excretion and sodium balance after initiation of nifedipine treatment and after withdrawal of nifedipine...
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