United States experience with oxprenolol in hypertension

Double-blind, randomized, parallel-group studies have confirmed that oxprenolol, either alone or in combination with a thiazide, is effective in reducing elevated blood pressure. In 2 of 3 comparisons with placebo, the blood pressure reduction was significantly more effective with oxprenolol; in 1 study, even though the placebo response was pronounced, oxprenolol was still more effective than placebo. In 2 studies propranolol reduced blood pressure by about 2 mm Hg more than oxprenolol. In the larger, longer-term study this difference was significant at the end of the dose-titration period, but there were no significant differences between the 2 treatment groups at study end. Moreover, oxprenolol reduced heart rate less and was associated with fewer side effects. Oxprenolol effectively lowered blood pressure when given once daily and was well tolerated, even in large doses. Blood pressure was reduced less with oxprenolol than with hydrochlorothiazide, -14/-11 versus -20/-13 mm Hg. The mean reduction with oxprenolol was less for black patients than for white. In a 1-year safety study, 86% of the patients continued to have a diastolic pressure of less than 90 mm Hg at study end.     

Assessing duration of antihypertensive effects with whole-day blood pressure monitoring

The whole-day blood pressure response to once-daily and twice-daily administration of a combination of captopril and hydrochlorothiazide was measured in a study of elderly patients (aged 59 to 78 years) with mild to moderate hypertension. Whole-day automated ambulatory blood pressure profiles were obtained at baseline, after 8 weeks of therapy with a combination of 25 mg of captopril and 15 mg of hydrochlorothiazide twice daily, and again after 8 weeks of once-daily therapy with 50 mg of captopril and 25 mg of hydrochlorothiazide. Average systolic and diastolic whole-day blood pressures significantly decreased from baseline during both twice-daily treatment (mean +/- SEM change, 18 [+/- 3]/10 [+/- 2] mm Hg) and once-daily treatment (11 [+/- 2]/9 [+/- 1] mm Hg). While the decrease in systolic blood pressure during once-daily therapy was less than that during twice-daily therapy for the group as a whole, 16 of 19 patients achieved normal systolic (less than 140 mm Hg) and diastolic (less than 90 mm Hg) blood pressures throughout the day during the once-daily regimen. During once-daily therapy, the blood pressure reductions were sustained throughout the 24-hour period, and were not attenuated during the final 2 to 4 hours before the next dose. A subgroup of 5 patients were identified who appeared unresponsive to both twice-daily and once-daily antihypertensive treatment. Despite hypertensive office-measured blood pressures at entry to the study, 4 of these 5 patients actually had normotensive whole-day blood pressure averages at baseline (mean, 131 [+/- 7]/81 [+/- 4] mm Hg). Thus, whole-day ambulatory blood pressure monitoring is a valuable tool for testing treatment responses. It demonstrated that once-daily treatment with low doses of captopril and hydrochlorothiazide was as effective as twice-daily administration in decreasing diastolic pressures throughout the day, but was slightly less effective in decreasing systolic pressures. Additionally, the monitoring identified apparently normotensive patients in whom treatment may not be indicated.     

Dilevalol compared with propranolol and placebo for systemic hypertension

Dilevalol is a new antihypertensive agent that is both a vasodilator, through its beta 2-agonist action, and a nonselective beta antagonist. Two multicenter, double-blind studies were performed: study 1 compared dilevalol administered once-daily with either dilevalol or propranolol every 12 hours; study 2 compared dilevalol administered once daily with placebo. Both studies had a placebo run-in period to establish that the baseline supine diastolic blood pressures were consistent in the mild to moderate severity range (95 to 115 mm Hg) at 2 consecutive visits for study 1 and in the mild severity range (95 to 105 mm Hg) in study 2. Patients then were randomized to the double-blind titration phase, during which doses were titrated over a 9-week period to achieve a supine diastolic blood pressure of less than 90 mm Hg and a decrease from baseline of greater than or equal to 10 mm Hg. Patients were then maintained on a fixed dose for 2 months (study 1) or for 1 month (study 2). Dilevalol given once daily was as effective in reducing supine diastolic blood pressure as dilevalol every 12 hours and propranolol every 12 hours (study 1) and was superior to placebo (p less than 0.001) (study 2). In both studies, dilevalol given once daily was effective and well tolerated. The side-effect profile of dilevalol was similar to that of placebo and different from that of propranolol. Treatment with dilevalol resulted in significantly less fatigue (p less than 0.05), bradycardia (less than 50 beats/minute) and mental depression than with propranolol, but significantly (p less than 0.05) more diarrhea/loose stools.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bucindolol, a beta-adrenoceptor blocker with vasodilatory action: its effect in systemic hypertension

Bucindolol is a newly developed, nonselective beta-adrenergic blocking agent with intrinsic sympathomimetic activity and direct vasodilator properties. In 14 patients with mild to moderate essential hypertension, the effects of bucindolol, hydrochlorothiazide and their combination on blood pressure (BP), heart rate (HR) and parameters of the renin-aldosterone system were compared with those after placebo. Bucindolol's antihypertensive effect was evident within the first hour after drug administration, maximal at 2 to 3 hours, and lasted for as long as 12 hours. Compared with placebo values (108 +/- 5 mm Hg), both bucindolol (97 +/- 9 mm Hg) and hydrochlorothiazide (99 +/- 10 mm Hg) alone significantly and comparably reduced the 12-hour averaged standing diastolic BP, with the combination resulting in approximately additive effects (91 +/- 9 mm Hg). Although bucindolol alone did not affect HR, it attenuated the hydrochlorothiazide-induced increase in HR. There was a tendency for bucindolol to decrease plasma renin activity. Except for transient postural hypotension in 2 patients, bucindolol was well tolerated.     

Monotherapy in mild to moderate hypertension: Comparison of hydrochlorothiazide,propranolol and prazosin

There has been recent interest in using nondiuretic drugs as initial antihypertensive therapy. Therefore, a study was designed to compare the efficacy and the effects on left ventricular function of hydrochlorothiazide, propranolol and prazosin in 13 patients with mild to moderate hypertension. After a 4-week washout period, patients were treated serially with each drug in a randomized order for 2 months each. Dosages were titrated until the patient showed a sitting diastolic blood pressure ≤90 mm Hg or to a maximum dosage of 100 mg/day of hydrochlorothiazide, 320 mg of propranolol and 20 mg of prazosin. Blood pressure was measured, plasma catecholamine concentrations were assayed and radionuclide determinations of rest and exercise left ventricular function and volume were made at the end of each period as well as after a second 1-month washout period at the end.In the sitting and standing positions, systolic and diastolic blood pressure control was equivalent for all 3 drugs. Goal blood pressure was achieved in 10 of 13 patients receiving hydrochlorothiazide, in 8 of 12 receiving propranolol and in 9 of 13 on prazosin. Importantly, 3 of 4 patients not controlled with prazosin, 5 of 6 uncontrolled with propranolol and 2 of 3 whose blood pressure was not reduced by hydrochlorothiazide were controlled when receiving 1 of the other medications. None of the drugs changed rest or exercise ejection fraction or volume, and side effects were minimal. These findings indicate that as single agents, all 3 drugs produce similar effects on blood pressure, have few symptomatic side effects and can effectively be substituted for each other when there is a lack of efficacy or contraindication to 1 drug.     

Prazosin versus propranolol plus prazosin: a comparison in diuretic-treated hypertensive patients

The antihypertensive efficacy of prazosin was compared with that of a combination of prazosin and propranolol in 14 patients with essential hypertension. All patients had sitting diastolic blood pressures greater than or equal to 95 mm Hg despite daily therapy with 50 mg of hydrochlorothiazide and 240 mg of propranolol. After a 4-week monitoring period, patients were divided randomly into 2 groups in whom either (1) propranolol was reduced to 120 mg/day (to avoid potential hypotension) and prazosin was added, starting with an initial dose of 1 mg twice daily, or (2) propranolol was tapered and discontinued as prazosin was added. The average doses of prazosin were 7.4 and 7.6 mg/day, respectively. After 12 weeks of therapy, blood pressure was reduced in both groups, and there was no significant difference in the reduction of blood pressure or dose of prazosin in the 2 groups. Mean heart rate increased significantly in both groups (p less than 0.01), but more so in the group of patients who discontinued propranolol therapy. Thus, when a combination of 50 mg/day of hydrochlorothiazide and 240 mg/day of propranolol is insufficient to control hypertension, the addition of prazosin is shown to decrease blood pressure whether or not propranolol is continued.     

Antihypertensive efficacy of once daily MK-521, a new nonsulfhydryl angiotensin-converting enzyme inhibitor

The effects of the new nonsulfhydryl-containing oral converting-enzyme inhibitor MK-521 on blood pressure, heart rate, angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration were assessed in 10 hypertensive patients. After a 2-week no-treatment period, patients received placebo and then 14 days each: MK-521 20 mg once daily, hydrochlorothiazide 50 mg once daily and the latter 2 in combination. During the last day of each treatment, the mean (+/- standard deviation) time-averaged (1- to 12-hour) standing diastolic blood pressure decreased from 106 +/- 8 (placebo) to 95 +/- 10 mm Hg with MK-521, 95 +/- 13 mm Hg with hydrochlorothiazide (p less than 0.05 vs placebo) and 88 +/- 11 mm Hg with the combination (p less than 0.05 vs all other treatments). The antihypertensive effect of MK-521 was maintained 24 hours after dosing. Heart rate did not change significantly after MK-521 treatment. MK-521 caused a marked suppression of converting enzyme activity for over 24 hours; plasma renin activity increased significantly after each active treatment and MK-521 significantly decreased the hydrochlorothiazide-induced elevation of plasma aldosterone concentration. In this short-term trial, MK-521 was well tolerated.     

Comparative double-blind study of ramipril and captopril in mild to moderate essential hypertension

The angiotensin converting enzyme inhibitors ramipril and captopril were administered in doses of 10 mg once daily and 50 mg twice daily, respectively, to patients with mild to moderate essential hypertension. After a 4-week single-blind placebo washout period, patients were treated for 12 weeks with 1 of the drugs under double-blind conditions. Patients who did not respond after 6 weeks of treatment were given 50 mg hydrochlorothiazide concomitantly. The ramipril group showed greater decreases in blood pressure compared with baseline values: 20.1/14.9 mm Hg (ramipril) compared with 16.5/13.5 mm Hg (captopril). A further 6 weeks of treatment lowered the blood pressure even more: 22.5/20.0 mm Hg (ramipril) compared with 20.5/18.6 mm Hg (captopril). Concomitant hydrochlorothiazide given to nonresponders reduced the blood pressure levels in 24 of 40 patients in the ramipril group and in 20 of 36 patients in the captopril group. At the end of the study the overall response to treatment with ramipril alone and ramipril plus hydrochlorothiazide was 77.1%. The overall response rate in the captopril group was 82.7%. No clinically relevant adverse reaction occurred in any patient. Ramipril given once daily was as effective as captopril given twice daily in lowering blood pressure. Both drugs proved to be safe during treatment for 12 weeks.     

Treatment of essential hypertension with PN 200-110 (isradipine)

The safety and antihypertensive efficacy of PN 200-110 (isradipine), a novel calcium antagonist, are discussed in a preliminary report of double-blind, multicenter, controlled, phase III clinical trials for essential hypertension. Patients who qualified for entry after a 3 week placebo-washout period were enrolled in 1 of 5 studies; 2 studies were placebo controlled; 3 studies evaluated PN 200-110 against 1 of 3 active controls: hydrochlorothiazide (HCTZ) propranolol or prazosin. A separate study assessing the effects of PN 200-110 in combination with HCTZ versus propranolol plus HCTZ is also discussed. Compared with placebo, PN 200-110 decreased mean supine systolic and diastolic blood pressures by 20/16 mm Hg versus 4/6 mm Hg. Compared with placebo and active control drugs, PN 200-110 normalized supine diastolic blood pressure to less than or equal to 90 mm Hg in 72% of patients, versus 13% in the placebo group, 74% in the HCTZ group, 45% in the propranolol group and 69% in the prazosin group. In the ability to decrease diastolic blood pressure by greater than or equal to 10 mm Hg, PN 200-110 compared favorably to prazosin (81% vs 81%), and was superior to HCTZ (81% vs 61%) and propranolol (81% vs 36%). In combination with HCTZ, PN 200-110 exerted as great an antihypertensive effect as propranolol plus HCTZ. Long-term therapy with PN 200-110 was also effective. Supine systolic and diastolic blood pressures decreased a mean of 15/13 mm Hg at 3 months, and 18/20 mm Hg at 12 months. PN 200-110 is well tolerated with relatively few adverse effects reported.     

The antihypertensive efficacy of the combination of irbesartan and hydrochlorothiazide assessed by 24-hour ambulatory blood pressure monitoring. Irbesartan Multicenter Study Group

In a multicenter, double-blind, randomized trial, 178 patients with ambulatory diastolic blood pressure (BP) > or =85 mm Hg and seated diastolic BP (SeDBP) 95-110 mm Hg received either once-daily irbesartan 75 mg/hydrochlorothiazide (HCTZ) 12.5 mg, irbesartan 150 mg/HCTZ 12.5 mg, or placebo for 8 weeks to assess reductions in 24-hour ambulatory BP and office BP. Safety and tolerability of all treatment regimens were also evaluated. BP results and therapeutic response (trough SeDBP normalized to <90 mm Hg) were expressed as change from baseline to Week 8. Mean reductions in 24-hour ambulatory BP and office seated BP for irbesartan/HCTZ combinations were significantly greater compared with placebo (all, p<0.01). More patients were normalized with irbesartan/HCTZ (65%-69%) than placebo (24%, p<0.01). The frequency of adverse events was similar in all groups. Irbesartan/HCTZ given once-daily appears to be a well-tolerated, safe, and effective antihypertensive treatment.     

Twice-daily administration of oral verapamil in the treatment of essential hypertension

The antihypertensive effect of twice-daily administration of verapamil hydrochloride was evaluated in 21 adult patients with mild to moderate essential hypertension. Following four weeks of placebo therapy, verapamil was given for four weeks with a treatment goal of sitting diastolic blood pressure (BP) of less than 90 mm Hg, or to a maximum dose of 160 mg twice daily. Sitting and standing BPs, heart rate, and verapamil plasma levels were determined weekly, ten to 12 hours post dose. At the maximal dose (mean, 154 +/- 19.2 mg), heart rate was not affected, side effects were minimal, and sitting diastolic BP was significantly reduced from placebo baseline, with 12 of 21 patients having a fall in sitting diastolic BP of 10 mm Hg or more or less than 90 mm Hg. A trough verapamil plasma level of greater than 80 ng/mL was associated with a good hypotensive response. These data indicate the safety and utility of twice-daily verapamil administration for the treatment of essential hypertension and suggest the value of obtaining verapamil plasma levels as a guide to dosage determination.     

Isradipine vs propranolol in hydrochlorothiazide-treated hypertensives. A multicenter evaluation

A randomized, parallel, controlled study was conducted to evaluate the safety and efficacy of isradipine, 2.5 to 10 mg orally twice a day, compared with propranolol hydrochloride, 60 to 240 mg orally twice a day, in 78 hypertensives whose supine diastolic blood pressure was greater than 95 mm Hg while receiving 50 mg/d or more of hydrochlorothiazide. Isradipine or propranolol was titrated during a 10-week double-blind phase to achieve a supine diastolic blood pressure below 90 mm Hg while a fixed dose of hydrochlorothiazide was maintained. Supine diastolic blood pressure was reduced by 10 mm Hg in 88% of the isradipine/hydrochlorothiazide-treated and 83% of the propranolol/hydrochlorothiazide-treated groups and to less than 90 mm Hg in 55% of the isradipine/hydrochlorothiazide-treated and 69% of the propranolol/hydrochlorothiazide-treated patients. There was no significant difference in supine blood pressure reduction between either group, but there was a 3-to 4-beats per minute increase in supine heart rate in isradipine-treated patients and an expected 15- to 20-beats per minute decrease in heart rate in propranolol-treated patients. Five of 7 patients in the isradipine-treated group and 8 of 9 patients in the propranolol-treated group discontinued the therapy because of adverse reactions or treatment failure. Using Fisher's Exact Test, we found no significant difference in the relative frequency of individual adverse reactions between groups, although the absolute adverse reaction frequency was significantly higher with isradipine. This study demonstrates the effectiveness and safety of supplemental isradipine in the treatment of hypertension not controlled by hydrochlorothiazide alone.     

Azilsartan medoxomil plus chlorthalidone reduces blood pressure more effectively than olmesartan plus hydrochlorothiazide in stage 2 systolic hypertension

Azilsartan medoxomil, an effective, long-acting angiotensin II receptor blocker, is a new treatment for hypertension that is also being developed in fixed-dose combinations with chlorthalidone, a potent, long-acting thiazide-like diuretic. We compared once-daily fixed-dose combinations of azilsartan medoxomil/chlorthalidone force titrated to a high dose of either 40/25 mg or 80/25 mg with a fixed-dose combination of the angiotensin II receptor blocker olmesartan medoxomil plus the thiazide diuretic hydrochlorothiazide force titrated to 40/25 mg. The design was a randomized, 3-arm, double-blind, 12-week study of 1071 participants with baseline clinic systolic blood pressure 160 to 190 mm Hg and diastolic blood pressure ≤119 mm Hg. Patients had a mean age of 57 years; 59% were men, 73% were white, and 22% were black. At baseline, mean clinic blood pressure was 165/96 mm Hg and 24-hour mean blood pressure was 150/88 mm Hg. Changes in clinic (primary end point) and ambulatory systolic blood pressures at week 12 were significantly greater in both azilsartan medoxomil/chlorthalidone arms than in the olmesartan/hydrochlorothiazide arm (P<0.001). Changes in clinic systolic blood pressure (mean±SE) were -42.5±0.8, -44.0±0.8, and -37.1±0.8 mm Hg, respectively. Changes in 24-hour ambulatory systolic blood pressure were -33.9±0.8, -36.3±0.8, and -27.5±0.8 mm Hg, respectively. Adverse events leading to permanent drug discontinuation occurred in 7.9%, 14.5%, and 7.1% of the groups given azilsartan medoxomil/chlorthalidone 40/25 mg, azilsartan medoxomil/chlorthalidone 80/25 mg, and olmesartan/hydrochlorothiazide 40/25 mg, respectively. This large, forced-titration study has demonstrated superior antihypertensive efficacy of azilsartan medoxomil/chlorthalidone fixed-dose combinations compared with the maximum approved dose of olmesartan/hydrochlorothiazide.     

Usefulness of bevantolol for chronic, stable angina pectoris

An objective assessment of the efficacy of bevantolol was performed in 21 patients with chronic, stable angina using computer-assisted exercise testing and ambulatory ST-segment monitoring. Given once daily, 200 mg of bevantolol was compared with 200 mg of bevantolol given twice daily and with placebo, using a double-blind crossover technique. The mean exercise time with placebo was 7.4 +/- 0.6 minutes; this increased to 10.6 +/- 0.9 minutes (p less than 0.001) with once-daily bevantolol and to 9.4 +/- 0.9 minutes (p less than 0.001) with twice-daily bevantolol. The mean heart rate at rest was 80 +/- 3 beats/min with placebo; it decreased to 63 +/- 2 beats/min (p less than 0.001) with once-daily bevantolol and to 66 +/- 2 beats/min (p less than 0.001) with twice-daily bevantolol. The maximum exercise heart rate of 118 +/- 6 beats/min with placebo was reduced to 99 +/- 4 beats/min (p less than 0.001) on once-daily and 101 +/- 4 beats/min (p less than 0.001) on twice-daily bevantolol. There was a corresponding decrease in the rate-pressure product. The corrected maximum ST-segment depression was reduced from 0.3 +/- 0.06 mm min-1 with placebo to 0.2 +/- 0.03 mm min-1 (p less than 0.02) with once-daily and 0.2 +/- 0.04 mm min-1 (p less than 0.05) with twice-daily bevantolol. The mean hourly ambulatory heart rate was significantly reduced for 21 hours with once-daily and 22 hours with twice-daily bevantolol. The lowest mean minimum heart rate was 55 beats/min during twice-daily treatment. The mean number of episodes of ST depression over 24 hours in lead CM5 was decreased from 6.89 +/- 1.7 with placebo to 2.50 +/- 0.6 (p less than 0.001) with once-daily and to 3.72 +/- 1.3 (p less than 0.001) with twice-daily bevantolol. Three patients were withdrawn during the once-daily bevantolol regimen due to adverse experiences, and another patient was admitted for coronary artery bypass surgery after 25 days.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcium entry blockers for systemic hypertension

Calcium entry blockers appear to be effective antihypertensive agents in both young and older patients. Studies comparing diltiazem and placebo, diltiazem and propranolol, and diltiazem and hydrochlorothiazide indicate that this calcium entry blocker is more effective than placebo, equally effective as the beta-adrenergic inhibitors at least in short-term studies, but not as effective in lowering systolic blood pressure (BP) when compared with hydrochlorothiazide (diastolic BP -11.5 mm Hg with diltiazem vs -12.2 mm Hg with hydrochlorothiazide; systolic BP -12.2 mm Hg with diltiazem vs -20.0 mm Hg with hydrochlorothiazide). Combination therapy with diltiazem and hydrochlorothiazide proved effective in a high percentage of mono-therapy nonresponders. The most common adverse reactions to diltiazem included headaches, dizziness and edema. The exact place of calcium entry blockers in therapy as initial or step-2 therapy with a diuretic in hypertension must be determined by additional long-term experience in large numbers of patients.     

Efficacy of candesartan cilexetil alone or in combination with amlodipine and hydrochlorothiazide in moderate-to-severe hypertension. UK and Israel Candesartan Investigators

This multicenter study evaluated the efficacy of candesartan cilexetil, an angiotensin II type 1 receptor antagonist, used alone or in combination with amlodipine or in combination with amlodipine and hydrochlorothiazide in the treatment of patients with moderate-to-severe essential hypertension. After a 2-week, single-blind, placebo run-in period, patients entered a 12-week, open-label, dose-titration period. The candesartan cilexetil dose was increased from 8 to 16 mg once daily; amlodipine (5 mg once daily), hydrochlorothiazide (25 mg once daily), and additional medication were also added sequentially if necessary. Patients then entered a final 4-week, parallel-group, double-blind, randomized, placebo-controlled withdrawal period of candesartan alone. A total of 216 patients were recruited. After a 2-week run-in period on placebo tablets, mean sitting blood pressure (BP) was 175/108 mm Hg. At the end of the 12-week dose-titration/maintenance period, mean sitting BP fell to 141/88 mm Hg. In 67 patients who were randomized to placebo and had their candesartan withdrawn, there was a highly significant increase in mean systolic/diastolic BP (13/6 mm Hg) compared with those patients who continued with candesartan (ANCOVA, P:<0.0001). In conclusion, candesartan cilexetil is an effective BP-lowering drug when used alone or in combination with amlodipine or amlodipine plus hydrochlorothiazide in the treatment of moderate-to-severe essential hypertension. The drug was well tolerated throughout the investigation period.     

Pulse pressure changes with six classes of antihypertensive agents in a randomized, controlled trial

Pulse pressure has been more strongly associated with cardiovascular outcomes, especially myocardial infarction and heart failure, than has systolic, diastolic, or mean arterial pressure in a variety of populations. Little is known, however, of the comparative effects of various classes of antihypertensive agents on pulse pressure. In retrospective analyses of the Veterans Affairs Single-Drug Therapy for Hypertension Study, we compared changes in pulse pressure with 6 classes of antihypertensive agents: 1292 men with diastolic blood pressure of 95 to 109 mm Hg on placebo were randomized to receive hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem, prazosin, or placebo. Drug doses were titrated to achieve a goal diastolic blood pressure of <90 mm Hg during a 4- to 8-week medication titration phase. Pulse pressure change (placebo subtracted) was assessed from baseline to the end of the 3-month titration and 1-year maintenance. Mean baseline systolic, diastolic, and pulse pressures were 152, 99, and 53 mm Hg, respectively. Reductions in pulse pressure during titration were greater (P<0.001) with clonidine (6.7 mm Hg) and hydrochlorothiazide (6.2 mm Hg) than with captopril (2.5 mm Hg), diltiazem (1.6 mm Hg), and atenolol (1.4 mm Hg); reduction with prazosin (3.9 mm Hg) was similar to all but clonidine. After 1 year, pulse pressure was reduced significantly more (P<0.001) with hydrochlorothiazide (8.6 mm Hg) than with captopril and atenolol (4.1 mm Hg with both); clonidine (6.3 mm Hg), diltiazem (5.5 mm Hg), and prazosin (5.0 mm Hg) were intermediate. These data show that classes of antihypertensive agents differ in their ability to reduce pulse pressure. Whether these differences affect rates of cardiovascular events remains to be determined.     

Comparative efficacy of two different beta-blockers on 24-hour blood pressure control.

Atenolol and metoprolol succinate, dosed once daily, have different pharmacokinetic profiles. This study tests the hypothesis that differences that are especially noted in the early morning period, when cardiovascular risk is highest, in 24-hour blood pressure (BP) control exist between these 2 beta-blockers. This was a small, randomized open-label study with blinded end point evaluation in 36 hypertensive patients. All participants received hydrochlorothiazide 12.5 mg for 2 weeks before randomization to either 50 mg atenolol or metoprolol succinate given every morning; both treatments were force-titrated to 100 mg/d at 4 weeks. The primary end point was the change in early morning ambulatory systolic BP. Early morning (12 AM-6 AM) systolic BP differences were 3+/-14 mm Hg with atenolol vs -7+/-8 mm Hg with metoprolol succinate (P=.03). The overall 24-hour changes in systolic BP were 1+/-15 mm Hg with atenolol vs -9+/-11 mm Hg with metoprolol (P=.03). In conclusion, metoprolol succinate was more effective in sustaining 24-hour and early morning BP reductions compared with atenolol in a small group of hypertensive patients also treated with once-daily low-dose hydrochlorothiazide. It is possible that differences in outcome between atenolol-based and other therapies may be the result of inadequate dosing of atenolol, a medication that may not be effective for the entire 24-hour period.     

Double-blind comparison of captopril and enalapril in mild to moderate hypertension

To compare the antihypertensive and humoral effects of the angiotensin-converting enzyme inhibitors captopril and enalapril, 20 patients with essential hypertension, not receiving treatment for 2 weeks and consuming a prescribed sodium ion intake, were randomly assigned to two parallel, double-blind treatment groups with stratification based on race and untreated seated diastolic blood pressure. These groups received a placebo (day -1) followed by either captopril, 200 mg every 12 hours (n = 9), or enalapril maleate, 20 mg every 12 hours (n = 11), alone (days 1 to 14) and then with hydrochlorothiazide, 25 mg every 12 hours (days 16 to 28). Captopril and enalapril were coadministered alone (day 15) and with hydrochlorothiazide (day 29) to assess whether further decreases in blood pressure would occur. Captopril and enalapril alone caused comparable decreases (p less than 0.05) in the mean 12 hour time-averaged seated diastolic blood pressure from values on day -1 (placebo), on day 1 (11 and 9 mm Hg, respectively) and day 14 (8 and 7 mm Hg, respectively). The addition of hydrochlorothiazide further decreased (p less than 0.05) blood pressure in each group (7 and 8 mm Hg, respectively) from values on day 14. Combined use of captopril and enalapril did not result in further reduction. Coupled with the comparable changes observed in each treatment group in serum angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration, these data support the view that captopril and enalapril have similar antihypertensive effects and mechanisms.     

Controlled treatment of primary hypertension with propranolol and spironolactone: A crossover study with special reference to initial plasma renin activity

Twenty-seven patients with hypertension were randomly allocated to a 10 month crossover study. Treatment consisted of spironolactone (200 mg/day for 2 months), propranolol (320 mg/day for 2 months) and combined administration of both drugs at half the dosage. Between treatment periods placebo was given for 2 months. Fourteen patients were previously untreated. The average pretreatment blood pressure for the entire group was 188/114 ± 16/7 (mean ± standard deviation) mm Hg supine and 188/118 ± 20/9 mm Hg standing. Both spironolactone and propranolol reduced blood pressure significantly in both the supine and standing positions.Upright plasma renin activity was determined by radioimmunoassay of angiotensin I. The average initial level was 1.9 ± 1.2 (range 0.4 to 5.0) ng/ml/hr. There was a close correlation between plasma renin activity and the effects of the drugs: With increasing renin level the response to propranolol was better whereas the opposite was true for spironolactone. The combination of spironolactone and propranolol decreased the blood pressure still further in the supine and standing positions, irrespective of initial plasma renin activity. All patients achieved a normal supine pressure. Blood pressure and plasma renin activity returned toward pretreatment values during placebo administration. It is concluded that pretreatment levels of plasma renin activity can predict the antihypertensive response to propranolol and spironolactone. The combination of the two drugs, which have different modes of action, will effectively reduce blood pressure in hypertension. The results support the concept that the renin-angiotensin-aldosterone system may be involved in primary hypertension.