Slow-release Nifedipine Research Articles

Prevention and Treatment of High Altitude Pulmonary Edema by a Calcium Channel Blocker

High altitude pulmonary edema (HAPE) is characterized by marked pulmonary hypertension. Treatment of 6 subjects suffering from radiographically documented HAPE with the calcium channel blocker nifedipine, lowered pulmonary artery pressure and resulted in clinical improvement, better oxygenation, reduction of alveolar-arterial oxygen gradient and a progressive clearing of alveolar edema on chest x-ray. This amelioration occurred despite continued exercise at an altitude above 4000 m and without supplementary oxygen. Prophylactic application of nifedipine slow release preparation, 20 mg every 8 hours, prevented HAPE in 9 out of 10 subjects with a history of radiographically documented HAPE upon rapid ascent and subsequent stay to an altitude of 4559 m. Seven of 11 comparable subjects who received placebo developed pulmonary edema at 4559 m. As compared with the subjects who received placebo, those who received nifedipine had a significantly lower mean systolic pulmonary artery pressure, alveolar-arterial pressure gradient of oxygen and symptom score of acute mountain sickness at 4559 m. Thus nifedipine offers a potential emergency treatment of HAPE when descent or evacuation is impossible and oxygen is not available. Prophylactic administration of nifedipine prevents HAPE in susceptible subjects. High pulmonary artery pressure has an important role in the pathogenesis of HAPE.

Unmasking of the hypotensive effect of nifedipine in normotensives by addition of the angiotensin converting enzyme inhibitor benazepril

To study the pharmacological interaction between a dihydropyridine derivative (nifedipine slow release 20 mg) and inhibition of the renin-angiotensin system (benazepril 10 mg). Single application at intervals of 2 weeks in an open-label three-way cross-over design. Institutional pharmacological unit. Nine healthy male volunteers. Blood pressure and heart rate were recorded in the supine position for 24 h as well as plasma drug levels, plasma angiotensin converting enzyme activity and active plasma renin concentration. Nifedipine increased active plasma renin two-fold and benazepril increased it five-fold. The combination of the two drugs accelerated the increase of active renin during the first 2 h after drug intake. Whereas no hypertensive effect could be detected after nifedipine or benazepril alone, a significant fall in systolic and diastolic blood pressure was observed for up to 9 to 12 h after the combination. The increase in heart rate induced by nifedipine was minimized by the addition of benazepril. There was no interaction between the pharmacokinetics of benazeprilate and nifedipine which would explain these pharmacodynamic effects. These results demonstrate that, in normotensive volunteers, the renin-angiotensin system contributes to mask the hypotensive effect of a single oral dose of dihydropiridine. The concomitant administration of a converting enzyme inhibitor discloses the hypotensive effect and limits the baroreflex-mediated increase in heart rate secondary to vasodilation.

Long-term comparison between captopril and nifedipine in the progression of renal insufficiency

To verify the hypothesis that angiotensin-converting enzyme (ACE) inhibitors possess a unique renoprotective effect in progressive chronic renal disease, we decided to compare the effects of an ACE inhibitor and a calcium antagonist on both hypertension and the progression of non-diabetic renal insufficiency in a long-term study. A four-year, multicenter, prospective, randomized trial was conducted on 142 hypertensive patients (pts) with established chronic renal failure from six Italian nephrology departments. They were on standard antihypertensive therapy with a low-protein diet and underwent twice-monthly surveillance for a one year pre-randomization period. After that year, 121 pts were randomly allocated to captopril or slow-release nifedipine therapies for a three-year study period. The progression of renal insufficiency was monitored every two months. Blood pressure control was significantly better after randomization than during the year of standard antihypertensive therapy. The progression rate before randomization (BR) was definitely higher before than after randomization (AR): Creatinine clearance (CCr) change BR = -0.46 +/- 0.45 ml/min/month, creatinine clearance change AR = -0.23 +/- 0.43 ml/min/month (P less than 0.01). After randomization, the mean blood pressure values were virtually the same throughout the three year period of the study in the two groups treated by captopril (group I), or nifedipine (group II).(ABSTRACT TRUNCATED AT 250 WORDS)

Beta blockade and intermittent claudication: placebo controlled trial of atenolol and nifedipine and their combination.

To determine the effects of the beta 1 selective adrenoceptor blocker atenolol, the dihydropyridine calcium antagonist nifedipine, and the combination of atenolol plus nifedipine on objective and subjective measures of walking performance and foot temperature in patients with intermittent claudication. Randomised controlled double blind four way crossover trial. Royal Hallamshire Hospital, Sheffield. 49 patients (40 men) aged 39-70 with chronic stable intermittent claudication. Atenolol 50 mg twice daily; slow release nifedipine 20 mg twice daily; atenolol 50 mg plus slow release nifedipine 20 mg twice daily; placebo. Each treatment was given for four weeks with no washout interval between treatments. Claudication and walking distances on treadmill; skin temperature of feet as measured by thermistor and probe; blood pressure before and after exercise; subjective assessments of walking difficulty and foot coldness with visual analogue scales. Atenolol did not significantly alter claudication distance (mean change -6%; 95% confidence interval 1% to -13%), walking distance (-2%; 4% to -8%), or foot temperature. Nifedipine did not alter claudication distance (-4%; 3% to -11%), walking distance (-4%; 3% to -10%), or foot temperature. Atenolol plus nifedipine did not alter claudication distance but significantly reduced walking distance (-9%; -3% to -15% (p less than 0.003)) and skin temperature of the more affected foot (-1.1 degrees C; 0 to -2.2 degrees C (p = 0.05)). These effects on walking distance and foot temperature seemed unrelated to blood pressure changes. There was no evidence of adverse or beneficial effects of atenolol or nifedipine, when given singly, on peripheral vascular disease. The combined treatment, however, affected walking ability and foot temperature adversely. This may have been due to beta blockade plus reduced vascular resistance, which might also explain the reported adverse effects of pindolol and labetalol on claudication.

Effects of atenolol, slow-release nifedipine, and their combination on respiratory gas exchange and exercise tolerance in stable effort angina

The effects of atenolol, nifedipine, and their combination on gas exchange and exercise tolerance were studied in 27 patients with effort angina and normal global ventricular function in an open-label and randomized cross-over trial. Symptom-limited semi-supine exercise tests using a ramp protocol (20 W/min) with simultaneous breath-by-breath analysis of gas exchange were carried out after a 4-day wash-out period and after consecutive 2-week treatment periods with atenolol (50 mg b.i.d.), slow-release nifedipine (20 mg b.i.d.), and their combination (b.i.d.). Exercise tolerance was not significantly higher with atenolol than with nifedipine [118(24) vs 113(23) W]. Combination therapy [120(23) W] was more effective than monotherapy with nifedipine (p less than 0.05) but produced no further increase in exercise tolerance over atenolol monotherapy. Maximum oxygen uptake was not significantly different among the treatments. In the range of light to moderate exercise, the slope of the VO2-workload regression line expressed as ml.min-1.W-1 was lower with atenolol than with nifedipine [8.64(1.59) vs 10.28(1.74), p less than 0.005] and intermediate with combination therapy [9.99(1.83)]. The intercept on the VO2 axis was higher with atenolol than with nifedipine [366(111) vs 299(113) ml.min-1, p less than 0.05]. A similar pattern of results was seen when the drug effects on the slope of the VCO2-workload relation were analyzed. VE was higher with nifedipine than with atenolol at all points of the regression analysis [greater than 30 W].(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of slow-release nifedipine on myocardial ischemic episodes in variant angina pectoris

To evaluate the efficacy of slow-release nifedipine (a single dose of 20 mg given at 10 p.m. or 2 doses of 20 mg at 10 p.m. and 6 a.m.) on ischemic episodes in patients with variant angina, a single-blind crossover study with ambulatory electrocardiographic monitoring was performed in 15 patients (13 men and 2 women, mean age 63 years). In all, there were 646 ischemic episodes detected with ambulatory electrocardiographic monitoring during the study period, and 618 episodes of them occurred during placebo periods with a circadian variation. Sixty-nine percent of the episodes in placebo periods were asymptomatic. The number of anginal attacks, nitroglycerin tablets taken, ST-segment elevation and the total ischemic duration significantly decreased during nifedipine therapy compared with results after the placebo therapy period, respectively (p < 0.01 or 0.05). Twenty-eight ischemic episodes occurred during nifedipine therapy when the plasma level of nifedipine was low. Thus, asymptomatic ischemic episodes more frequently occur than symptomatic episodes and the administration of slow-release nifedipine is highly effective in suppressing not only symptomatic but also asymptomatic myocardial ischemia in patients with variant angina. The timing of the administration of slow-release nifedipine is an important factor in suppressing ischemic episodes.

Double-Blind, randomized comparative study of the antihypertensive effect of nicardipine slow-release and nifedipine slow-release in hypertensive patients with coronary heart disease

The main aim of this study was to investigate whether a new slow-release formation of nicardipine can control hypertension and whether its antihypertensive effect is manifest throughout the dose intervals. In a randomized, double-blind placebo-controlled study, the antihypertensive effect of two calcium antagonists (Type II) was investigated in two independent groups of hypertensive patients with coronary artery disease. One group of patients received 40 mg nicardipine slow-release b.i.d. and the other 20 mg nifedipine slow-release b.i.d. The effect of the active drugs on blood pressure (BP), heart rate, and hemodynamics was compared with placebo within each group. In addition, a group comparison was made to establish whether nicardipine had any advantage over nifedipine. Twenty-eight patients [27 female, 1 male; 55 (41-72) years old], 18 with previous myocardial infarction (MI) entered the study (nicardipine, 15 patients; nifedipine, 13 patients). A placebo period of 3 days was followed by a 13-day drug treatment period. From the first to last trial day, BP and heart rate were measured three times daily. At the end of the placebo and the active drug periods, the following measurements were carried out: ambulatory BP monitoring by half-hourly recording for 12.5 hours with the Remler system, ergometric tests with ECG, and right heart catheterization. Both drugs lowered the BP at rest, during exercise, and during usual daily activities. The antihypertensive effect of nicardipine was significant for the daytime mean arterial BP (MAP) and for systolic BP and diastolic BP at various stages of the exercise tests. The difference between the effect of nicardipine and nifedipine was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of effect by nifedipine on hepatic mixed function oxidase in man

Nifedipine (NF), a calcium channel blocker, is often prescribed in association with other drugs. Therefore, it was interesting to know whether or not, nifedipine, which is metabolized by the cytochrome P-450NF, was able to induce or to inhibit in vivo the activity of the hepatic mixed function oxidase system. The study was conducted in ten young healthy male volunteers receiving 20 mg NF slow release bid for 15 days. Due to the small number of subjects, comparison of the NF pharmacokinetics at dose 1 and 26 failed to show a bimodality in the frequency distribution of its area under the plasma concentration-time curve (AUC 274.5 to 317.1 ng ml-1 h, NS). Hepatic microsomal autoinduction (t1/2 2.87 to 3.06 h, NS) was not found. No statistically significant effect was seen on the aminopyrine breath test and on the debrisoquine metabolic molar ratio performed before and at the end of the treatment. Unlike what has been suggested by in vitro studies, NF treatment did not modify significantly the urinary excretion of 6 beta-hydroxycortisol (318 to 265 micrograms/d, NS). After the last dose, the total oral clearance of NF was highly correlated with the metabolic clearance to 4-hydroxyantipyrine (r = 0.88; P = 0.005) but the other parameters of antipyrine biotransformation remained unchanged. We conclude that repeated nifedipine oral intake does not modify enzymatic activities of hepatic P-450 cytochromes involved in the biotransformation of antipyrine, aminopyrine, debrisoquine and cortisol.

Effects of slow-release nifedipine on nighttime blood pressure.

With the advent of long-acting or slow-release antihypertensive drugs, we should be aware of a fall in nighttime blood pressure (BP) as well as daytime blood pressure. In the present study, casual BPs at the physician's office as well as ambulatory BP was recorded every hour throughout 24 hours with a noninvasive automated BP monitoring device in 24 essential hypertensives treated with slow-release nifedipine. Administration of slow-release nifedipine (20-40 mg, b.i.d.) decreased not only casual BPs but also ambulatory mean BP during the whole day or daytime (6 am to 10 pm). Slow-release nifedipine at 10 mg in the morning did not affect casual BPs at the office. However, mean BP obtained by ambulatory BP monitoring during the daytime was significantly attenuated. In addition, a profound fall in mean BP amounting to more than 20 mmHg during the night in some of the patients was observed during treatment with slow-release nifedipine not only at 20-40 mg (b.i.d.) but also at 10 mg once a day. These results suggest that we have to take into consideration the possibility that long-acting hypotensive agents may cause a great fall in nighttime BP during sleep, especially in the elderly.

Bopindolol

Bopindolol is a nonselective beta-adrenoceptor antagonist [corrected] with partial agonist activity which is used in the treatment of hypertension. The drug is rapidly metabolised to an active hydrolysed form. The antihypertensive effects of bopindolol 0.5 to 4 mg are sustained for more than 24 hours after once daily dosing, and the drug appears similar in efficacy to propranolol, metoprolol, atenolol, pindolol and slow release nifedipine in the treatment of mild to moderate forms of this disease. In limited trials bopindolol has also successfully reduced symptoms in patients with angina pectoris, anxiety and essential tremor. Thus, bopindolol is an effective and well-tolerated beta-adrenoceptor antagonist.

Comparative Study of Lacidipine and Nifedipine SR in the Treatment of Hypertension

The aim of this study was to compare the antihypertensive efficacy and tolerability of lacidipine, a new dihydropyridine calcium antagonist, and slow-release nifedipine (SR) in patients with mild-to-moderate essential hypertension. After a 1-month placebo run-in period, 435 patients were randomized into a double-blind, parallel-group study to receive either 4 mg of lacidipine once daily (n = 220) or 20 mg of nifedipine twice daily (n = 215). After 4 weeks, the doses for "nonresponders" were increased to 6 mg of lacidipine once daily (n = 82) and to 40 mg of nifedipine SR twice daily (n = 62). After 4 weeks, 50 mg of atenolol once daily was added to the regimens of patients still uncontrolled by lacidipine (n = 32) and nifedipine SR (n = 23) as monotherapy. Sitting blood pressure and heart rate were measured at 22-24 h after lacidipine and 10-12 h after nifedipine SR. Both calcium antagonists similarly and significantly reduced the blood pressure at rest (sitting) and on exercise, while the heart rate did not change significantly. The nature and incidence of side effects and withdrawals also did not differ between the two. In conclusion, lacidipine once daily is as effective and well tolerated as nifedipine SR twice daily in patients with mild-to-moderate essential hypertension.

A Comparative Study of Carvedilol, Slow-Release Nifedipine, and Atenolol in the Management of Essential Hypertension

Carvedilol is a novel treatment for hypertension, having a balanced pharmacology of vasodilation and beta-receptor blockade. We present here the results of a three-way, multicenter, comparative study on the use of carvedilol, slow-release nifedipine, and atenolol in the management of essential hypertension. A total of 311 patients was entered into the study, of which 293 were randomized to one of the three treatment regimens. Full data are available on 255 patients. Systolic and diastolic blood pressure measurements, in both sitting and standing positions, were taken, together with the heart rate. There was no consistently significant difference between treatments with respect to blood pressure control. Differences in heart rate were more pronounced, with the reduction due to carvedilol being generally intermediate between nifedipine and atenolol. Further studies of carvedilol in hypertension, as well as other indications, are warranted.

A Comparative Study of Carvedilol, Slow-Release Nifedipine, and Atenolol in the Management of Essential Hypertension

Journal of Cardiovascular Pharmacology™ is a peer reviewed, multidisciplinary journal that publishes original articles and pertinent review articles on basic and clinical aspects of cardiovascular pharmacology. Appropriate subjects include new drug development and evaluation, physiological and pharmacological bases of drug action, metabolism, drug interactions and side effects, clinical results with new and established agents and novel methods. The focus is on pharmacology in its broadest applications, incorporating not only traditional approaches, but new approaches to the development of pharmacological agents and the prevention and treatment of cardiovascular diseases.

Clinical significance of ambulatory blood pressure monitoring. Evaluation of severity of hypertension, efficacy of treatment and effects on nighttime blood pressure.

Blood pressure (BP) obtained by the physician in his office and ambulatory BP recorded every hour throughout 24 hours with a noninvasive automated BP monitoring device were compared in 10 normotensives and 162 hypertensives. Casual BPs significantly correlated with averages in ambulatory BPs (ABPs) throughout the whole day, day (7 am - 10 pm) and night (0-5 am). However, it was noted that 6 of 10 normotensives and all of the moderate to severe hypertensives had ABPs of more than 150/90 mmHg at least once during the 24-hour period. The incidence of ABPs greater than 150/90 mmHg among all readings was higher in untreated and treated hypertensives with diastolic BPs in the office of more than 105 mmHg, and, when checked along with the clock time, higher not only in the morning but also in the evening. On the other hand, one-third or one-fifth of treated hypertensives with diastolic office BPs less than 90 mmHg or between 90 and 105 mmHg respectively had ABPs less than 150/90 mmHg throughout the whole day. When the effect of nicardipine (60 mg, t.i.d.) or slow-release nifedipine (27.3 +/- 3.0 mg, b.i.d.) on minimum BP during the night was analyzed, long-acting nifedipine decreased BP throughout the night to levels not significantly different from normotensive controls, whereas short-acting nicardipine did not affect nighttime BPs. These results suggest that simple ABP monitoring throughout the day gives us useful information to evaluate the severity of hypertension and the efficacy of antihypertensive medication as well as to avoid overtreatment with long-acting hypotensive agents resulting in a great fall in BP during sleep.

Comparative Study of Lacidipine and Nicidipine SR in the Treatment of Hypertension

The aim of this study was to compare the antihypertensive efficacy and tolerability of lacidipine, a new dihydropyridine calcium antagonist, and slow-release nifedipine (SR) in patients with mild-to-moderate essential hypertension. After a 1-month placebo run-in period, 435 patients were randomized into a double-blind, parallel-group study to receive either 4 mg of lacidipine once daily (n = 220) or 20 mg of nifedipine twice daily (n = 215). After 4 weeks, the doses for nonresponders were increased to 6 mg of lacidipine onced daily(n = 82) and to 40 mg of nifedipine

Efficacy of slow-release nifedipine on ischemic attacks in patients with variant angina

We examined the effects of slow-release nifedipine on ischemic attacks in eight patients with variant angina. The study period was divided into four parts: placebo I period; nifedipine I period, when 20-mg slow-release nifedipine was given once a day at 10:00 p.m.; placebo II period; and nifedipine II period, when 20-mg slow-release nifedipine was given twice a day at 10:00 p.m. and 6:00 a.m. Each period consisted of 4 days, and 48-hour Holter monitoring was done at the end of each period. There was a significant decrease in the number of the episodes per 48 hours during the nifedipine I and nifedipine II periods as compared with the placebo I period (2.4 +/- 2.2 vs. 25.7 +/- 12.3, p less than 0.01; and 0.1 +/- 0.1 vs. 25.7 +/- 12.3, p less than 0.01, respectively). The total duration of episodes of ST-segment elevation per 48 hours decreased significantly during the nifedipine I period and the nifedipine II period as compared with the placebo I period (2.4 +/- 2.2 vs. 87.6 +/- 30.2 minutes, p less than 0.01; and 0.3 +/- 0.3 vs. 87.6 +/- 30.2 minutes, p less than 0.01, respectively). The total duration of the episodes also decreased significantly during the nifedipine II period as compared with the placebo II period (0.3 +/- 0.3 vs. 31.6 +/- 20.1 minutes, p less than 0.05). We concluded that 20-mg slow-release nifedipine given once a day at 10:00 p.m., or twice a day at 10:00 p.m. and 6:00 a.m., is highly effective in suppressing ischemic episodes in patients with variant angina.

Long-term therapy with slow-release nifedipine in essential hypertension

The purpose of this study, designed as an open multicenter trial, was to test the antihypertensive efficacy, patient acceptability, and side effects of long-term treatment with slow-release nifedipine in a large population. The drug was studied in 330 outpatients with essential hypertension, WHO stage 1-2, recruited in 20 hospital centers. After washout period was completed, nifedipine (20 mg bid) was given for 1 month (phase 1). Then, the treatment was extended for 4 months (phase 2) with variable doses (range 20-80 mg daily). No other antihypertensive drugs were administered during phase 1. However diuretics, beta blockers, or captopril were added to nifedipine during phase 2 in 11 patients. Seventy patients did not meet criteria for inclusion at washout. During phase 1 and 2, 66 additional patients were excluded due to side effects, the need of other antihypertensive drugs, or non-compliance. Systolic blood pressure significantly lowered (10% or more) in 84% patients in phase 1 and in 76% in phase 2. No responders were 6.1% and 3.6%, respectively. Diastolic blood pressure was normalized in 60% of patients after 5 months of therapy. Effects on blood pressure were equal in young patients and in the elderly, but a minimal rise in heart rate was recorded in younger patients. At least one side effect occurred in 46.6% patients, mainly headache (15.4%), hot flashes (13.3%), ankle edema (12.8%), or palpitation (6.6%). Sixteen patients (8.2%) were obliged to stop nifedipine treatment due to the severity of the side effects. This trial confirms the efficacy of nifedipine in hypertension, both in young and in aged patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute effects of nifedipine versus isosorbide dinitrate on exercise tolerance in patients with isolated coronary artery occlusion and collaterals

The acute effects of slow-release nifedipine and isosorbide dinitrate on exercise tolerance were compared in nine patients with isolated total coronary artery occlusion showing retrograde filling via collaterals. All patients had a reproducible positive exercise stress test off medication before the study. Each patient was randomized to 10 mg slow-release nifedipine and 5 mg isosorbide dinitrate in a single-blind, cross-over study. The exercise stress test was performed 30 minutes after drug administration. After nifedipine, three patients had a negative exercise stress test, whereas the test was negative after isosorbide dinitrate only in one patient. A significantly higher exercise tolerance was detected at peak exercise after nifedipine than after isosorbide dinitrate, as shown by a longer exercise time (380 +/- 44 vs. 295 +/- 41 seconds, p less than 0.001), a more increased maximum work load (355 +/- 89 vs. 255 +/- 55 W x min, p less than 0.02), and a higher rate-pressure product (30,300 +/- 2,500 vs. 26,100 +/- 2,700, p less than 0.01). In conclusion, these results seem to suggest that nifedipine may have a vasomotor effect on collaterals, since it elevated the threshold of ischemia more than isosorbide dinitrate did in patients with isolated coronary artery occlusion, showing retrograde filling via collaterals.

The combination of slow-release nifedipine and atenolol for stable angina

Beta-adrenoceptor antagonists, such as atenolol and the dihydropyridine calcium antagonist nifedipine, have antianginal actions that should prove complementary when the drugs are used in combination. Atenolol acts primarily by reducing myocardial oxygen demand, while the vasodilator effects of nifedipine can both reduce demand and increase oxygen supply. The slow-release tablet formulation of nifedipine (Nifedipine Retard) provides more persistent plasma concentrations than the conventional capsule formulation, which may prolong the duration of action. There is increasing evidence that the plasma nifedipine concentration is closely related to efficacy, although the absolute concentration required to improve exercise tolerance in patients with angina varies between individuals. Clinical studies indicate that for many patients the duration of action of slow-release nifedipine, particularly when added to atenolol, is less than 12 hours. This reflects the extensive but variable first-pass metabolism of nifedipine, leading to subtherapeutic trough concentrations. To achieve 24-hour symptom relief, slow-release nifedipine will often need to be given three times daily to patients with angina.

Effects of short- and long-term administration of nifedipine on serum lipoprotein metabolism in patients with mild hypertension

The effects of short- and long-term administration of nifedipine on serum lipids, lipoproteins, and apolipoproteins (apo) were studied. Administration of nifedipine capsule for 4 months significantly decreased triglycerides and increased the HDL2 cholesterol and the HDL2/HDL3 cholesterol ratio. No significant changes in serum lipids and lipoproteins were observed during short-term therapy with slow-release nifedipine tablets. Following administration of tablets for 24 months, the LDL/HDL cholesterol ratio, apo B, and apo B/apo A-I ratio increased at 12 months, but reverted to baseline values at 24 months. Apo E levels were decreased significantly at 24 months. No significant changes were noted in total cholesterol, triglyceride, HDL cholesterol, HDL2,3 cholesterol, apo A-I, apo A-II, apo C-II, or apo C-III levels during long-term therapy with slow-release nifedipine tablets. These results indicate that nifedipine has a neutral or even favorable effect on lipoprotein metabolism. However, a prospective well-controlled study would be required to finally establish this effect. This finding strengthens the indications for using nifedipine as a first-line drug in the long-term treatment of hypertension.