Comparison of oral propranolol and verapamil for combined systemic hypertension and angina pectoris. A placebo-controlled double-blind randomized crossover trial

The relative efficacies of oral verapamil, a calcium-entry blocking drug, and propranolol, a beta-adrenergic blocking drug, were compared in 12 patients who had both stable angina pectoris and mild to moderate systemic hypertension, using a placebo-controlled, double-blind, randomized crossover protocol. Compared with placebo, both propranolol and verapamil decreased the frequency of anginal attacks and the number of nitroglycerin tablets consumed, and increased exercise duration and total work; there were no significant differences in the antianginal effect of the two drugs. Both verapamil and propranolol reduced the supine and standing systolic and diastolic blood pressure measured at rest; compared with propranolol, however, verapamil had greater effects on standing diastolic blood pressure (p less than 0.002). Resting heart rate was reduced from placebo baseline with large doses of both drugs; compared with verapamil, however, propranolol exerted greater effects on resting heart rate and rate-pressure product. Plasma renin activity was increased from placebo baseline with verapamil (p less than 0.05), but was reduced with propranolol (p less than 0.05); no significant change in plasma aldosterone was seen with either drug. Verapamil appears to be a safe and effective treatment alternative to propranolol for relieving anginal symptoms, improving exercise tolerance, and reducing elevated systemic blood pressure in patients with both angina pectoris and mild to moderate systemic hypertension.     

Single and combined therapy for systemic hypertension with propranolol, hydralazine and hydrochlorothiazide: hemodynamic and neuroendocrine mechanisms of action

The antihypertensive mechanisms of single and combined therapy with a beta-adrenergic antagonist (propranolol) and a vasodilator (hydralazine) were investigated in 9 patients with moderately severe hypertension, who were receiving maintenance diuretic (hydrochlorothiazide) treatment. Hemodynamic and neuroendocrine responses were determined at rest and during lower body negative pressure, and dynamic and static exercise stress after the chronic administration of propranolol and hydralazine, given alone or in combination. All 3 drug regimens, each administered for at least 10 weeks, reduced blood pressure (p less than 0.05) compared with diuretic-only therapy in patients at rest, in both the supine and standing position, and during lower body negative pressure and dynamic exercise. There was a significant additive antihypertensive effect when propranolol and hydralazine were combined. Only combination therapy effectively lowered pressure during static exercise. The regimens produced divergent effects on the supine cardiac output: a decrease with propranolol (p less than 0.05), no change with combination therapy and an increase with hydralazine (p less than 0.05). Both hydralazine and combination therapy significantly reduced supine total peripheral resistance (p less than 0.05), whereas propranolol produced no change. All 3 drug treatments significantly reduced total peripheral resistance during upright rest and dynamic exercise (p less than 0.05), without changing cardiac output or maximal exercise capacity. During exercise, cardiac output was maintained in patients treated with propranolol and in those treated with combined therapy by increases in stroke volume (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

The possible importance of aldosterone as well as renin in the long-term antihypertensive action of propranolol

In 50 patients with essential hypertension, propranolol produced a significant decrease in blood pressure. The decrease in mean pressure was greatest in patients classified by a renin sodium nomogram as having high renin hypertension. In turn, blood pressure decreased more in patients with normal renin than in those with low renin levels. Indeed, a net increase in diastolic pressure occurred in the low renin subgroup. These findings confirm the value of pretreatment plasma renin measurements for predicting blood pressure responses to propranolol.Over-all, seven of the 50 patients exhibited increases in mean blood pressure during propranolol treatment. Presumably, this occurred because the minimal suppression of renin-angiotensinmediated vasoconstriction in these patients was insufficient to compensate for the unopposed alpha-sympathetic vasoconstriction unmasked by peripheral vascular beta-blockade. Within this group of patients, there was a significant inverse correlation between control renin values and the amplitude of the pressor response.The decrements in plasma renin were slightly greater in patients classified as responders (decrease in mean blood pressure ≥ 10 per cent) than in nonresponders. However, when the propranolol-induced decrements in aldosterone excretion were taken into account, responders to treatment exhibited far greater decreases than non-responders. Thus, higher levels of aldosterone during treatment may operate to oppose the antihypertensive action of propranolol. Ultimately, this dependency of the blood pressure response upon aldosterone levels is at least partly coordinated with propranolol-induced inhibition of renin release, since we found a significant correlation between changes in these hormones during treatment.     

Fosenopril,an angiotensin-converting enzyme inhibitor,and propranolol: Comparative effects at rest and exercise on blood pressure,hormonal variables,and plasma potassium in essential hypertension

Summary Fosenopril sodium, a prodrug, is converted to its active diacid during and after intestinal absorption. Its excretion is equally divided between hepatic and renal routes. This placebo-controlled, randomized, double-blind, parallel group study evaluated the efficacy and safety of fosenopril compared to propranolol, at rest and during exercise, on blood pressure, plasma potassium, plasma renin activity, and plasma aldosterone. Exercise testing utilized bicycle ergometry, and individual subjects underwent an identical exercise protocol on placebo and on active treatment. The fosenopril group comprised nine subjects who were matched to nine subjects on propranolol. Blood pressure fell significantly and equally at rest (fosenopril-157/103 to 141/95 mmHg, p<0.005; propranolol-159/100 to 149/90 mmHg p<0.005) and during exercise in both groups. Plasma potassium fell significantly at rest (4.25 to 3.98 mmol/l, p<0.05) and during exercise (5.18 to 4.87 mmol/l, p<0.05) on fosenopril, but rose in subjects on propranolol during exercise (4.99 to 5.44 mmol/l, p<0.01). Plasma renin activity rose on fosenopril and fell on propranolol. Plasma aldosterone was uninfluenced by either drug. Fosenopril was well tolerated and its antihypertensive profile is similar to that of beta blockers and other ACE inhibitors.     

Acute hemodynamic effects of propranolol, glycerylnitrate, and exercise in coronary patients with left ventricular dysfunction

Some adverse effects of beta-blockers in heart failure are counteracted by glycerylnitrate. However, the hemodynamics in this condition after giving both drugs are not well known. We examined the drug combination in exercising coronary patients with left ventricular dysfunction. Elevated left ventricular end-diastolic pressure was a measure of dysfunction. A right-heart catheterization with three successive exercise stress tests was done in 40 patients. At repeated exercise without drugs a "warming up" phenomenon was observed, consisting of small but statistically significant reductions in pulmonary capillary wedge pressure, and heart rate. At exercise propranolol reduced heart rate, cardiac output, systemic blood pressure, left ventricular work, and increased arteriovenous oxygen difference. Glycerylnitrate reduced pulmonary capillary wedge pressure at exercise, but, contrary to the findings at rest, it did not increase heart rate or reduce cardiac output. The drug combination resulted in hemodynamics that were similar to those after propranolol alone, except for a lower pulmonary capillary wedge pressure. The drug combination allowed the patients to exercise with the benefits of the beta-blocker, but at a lower ventricular filling pressure. Thus, the potential hazard of giving beta-blockers to patients with left ventricular dysfunction may be reduced by adding glycerylnitrate.     

Effects of Felodipine, Metoprolol and Their Combination on Blood Pressure at Rest and During Exercise and on Volume Regulatory Hormones in Hypertensive Patients

The effects on blood pressure (BP) and heart rate (HR), at rest and during bicycle exercise, of the vascular selective calcium antagonist felodipine, the cardio-selective beta-blocker metoprolol, and of the two drugs in combination, were assessed in a double-blind, three-way cross-over study comprising 23 patients with essential, mild to moderate hypertension. All three treatment regimens were given to each patient in randomised order for 4 weeks after a 4 week placebo run-in period. Felodipine 10-20 mg daily, metoprolol 100-200 mg daily and the combination of felodipine 10-20 mg plus metoprolol 100 mg daily were all effective antihypertensive treatments both at rest and during exercise. The two drugs seemed to have additive effects and the effect on BP of the combination was greater than that of either drug given as monotherapy. The mean sitting BP was 148/ 103 mmHg at randomisation, after 4 weeks of placebo treatment, and 134/88, 134/94 and 121/84 mmHg, respectively, after 4 weeks' treatment with felodipine, metoprolol and the combination. Maximal exercise capacity was similar irrespective of treatment regimen, and the normal response to exercise of BP and HR was maintained during all active treatments. Changes observed in volume regulatory hormones (PRA, aldosterone and ANP) were consistent with a direct tubular natriuretic-diuretic effect of felodipine and of beta-blocker attenuated release of renin. All treatment regimens were well tolerated and adverse events reported were usually mild and transient.     

Contrasting effects of acute beta blockade with propranolol on plasma catecholamines and renin in essential hypertension: a possible basis for the delayed antihypertensive response.

Blood pressure, heart rate, plasma renin activity, plasma norepinephrine and plasma epinephrine were determined in 11 patients with essential hypertension at rest before and 15, 30, 45, and 60 minutes after an intravenous infusion of 0.12 mg./Kg. propranolol given over five minutes. After propranolol mean blood pressure was unchanged; heart rate decreased by 14 per cent within 15 minutes and showed no further changes. Plasma renin activity decreased progressively by 48 per cent 60 minutes after propranolol, whereas plasma norepinephrine and epinephrine were always higher after propranolol than control values. Increases in norepinephrine were statistically significant at 30, 45, and 60 minutes (respectively 49, 39, and 45 per cent, P less than 0.005 at least) and those of epinephrine even at 15 minutes (respectively 60, 82, 62, and 94 per cent P less than 0.01 for all). These results indicate that acute beta blockade with propranolol incudes increases in circulating plasma norepinephrine and epinephrine which might be consequent to rapidly induced hemodynamic changes. This augmented sympathetic activity might explain why propranolol, when acutely infused, does not decrease blood pressure despite effective cardiac and renin blockade.     

Comparison of celiprolol and propranolol in stable angina pectoris. Celiprolol International Angina Study Group.

The comparative antianginal effects and safety of propranolol and celiprolol, a highly beta 1-selective adrenoceptor blocker with selective partial beta 2-adrenoceptor agonist activity, were assessed in an international multicenter, placebo run-in, active control, double-blind, randomized, titration-to-effect study of 140 patients with stable, exercise-induced angina pectoris. At baseline, all patients received placebo for 2 weeks, then titrated doses of once-daily celiprolol (200, 400, 600 mg) or twice-daily propranolol (total daily dose 80, 160, 320 mg) over 4 weeks, followed by a 2-week maintenance period. Heart rate and blood pressure, at rest and with exercise, weekly anginal attack frequency, nitroglycerin consumption and symptom-limited treadmill exercise times (modified Bruce protocol) were assessed. Compared with their respective baselines, both celiprolol and propranolol reduced anginal attack and nitroglycerin consumption rates to a comparable degree, while improving exercise tolerance (p less than 0.05). Treatment with propranolol compared with celiprolol, however, was associated with a significantly lower heart rate at rest (p less than 0.01). The double-product at the conclusion of exercise testing was significantly reduced by both drugs. Celiprolol and propranolol had similar effects on blood pressure, and were well tolerated. More symptomatic bradycardia occurred with propranolol. Despite the differences in their hemodynamic actions, once-daily celiprolol is as effective as twice-daily propranolol in the treatment of patients with stable angina pectoris.     

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.     

Effects of intravenous infusion of esmolol and propranolol on biventricular performance at rest and during exercise as assessed by quantitative radionuclide angiography

This double-blind, randomized, crossover study examined the effects of intravenous infusion of esmolol (a new ultra-short-acting beta-receptor blocking agent) and propranolol on cardiovascular performance at rest and during peak upright exercise in 15 patients. Biventricular function was assessed by means of first-pass radionuclide ventriculography with a computerized multicrystal camera. At rest, significant treatment differences between esmolol and propranolol vs baseline were found for the heart rate, systolic blood pressure, double product, left ventricular ejection fraction (EF), systolic blood pressure to end-systolic volume ratio, cardiac index and right ventricular EF. During exercise, significant treatment differences were also found for the heart rate, systolic blood pressure, double product, right ventricular EF and cardiac index. The mean baseline measurements were higher than the mean treatment measurements, but no significant differences were found between mean esmolol and mean propranolol measurements at rest and during exercise except for the exercise systolic blood pressure, which was lower during esmolol infusion. The magnitude of drug effect was greater at the time of exercise than at rest. The blood level of esmolol decreased markedly by 30 minutes after infusion. Esmolol was well tolerated, with no important local, systemic or laboratory abnormalities. Thus, the effects of esmolol on cardiovascular performance at rest and exercise are similar to those of propranolol.     

The effect of practolol, propranolol and strophanthin compared with placebo on exercise tolerance and a postural test in patients with hypertrophic cardiomyopathy

A double-blind randomized crossover study was performed in 10patients with hypertrophic cardiomyopathy. [Two females andeight males, mean age 38-2 years (range 19–64)]. The aimof the study was to compare the effects of strophanthin (0.5mg), practolol (10 mg) and propranolol (4 mg) on exercise tolerancewith those of placebo. Exercise was performed as graded submaximalbicycle ergomelry. A postural test was performed with and withoutdrug. The response to 6 min standing was similar after placebo anddigitalis, with a mean increase in heart rate of 18 beats/min.A significantly diminished increase in heart rate on standingwas seen after ß-blockers. No change in blood pressureresponse was observed. Practolol and propranolol significantlyreduced heart rate at rest, and during and after exercise comparedto placebo on strophanthin. No change in blood pressure wasobserved between medications. Total work was not increased byany drug for the group as a whole but marked intraindividualresponses to drugs were observed. Two brothers had similar reactionsto drugs. One patient with LBBB tolerated both strophanthinand ß-blockers. A fall in blood pressure on increasingwork load was seen in two patients both after practolol andafter propranolol. The present investigation demonstrates that the response todrugs in hypertrophic cardiomyopathy is individual and probablydependent on complex pathophysiological mechanisms. Furthermore,digitalis is usually well tolerated without any adverse reactions,and may be of benefit in individual patients with this disorder     

Effects of esmolol on cardiac function: evaluation by noninvasive techniques

In a double-blind, randomized, crossover study, the effects of esmolol and propranolol were examined at rest and during peak upright exercise in 15 patients. At rest, both esmolol and propranolol significantly decreased heart rate, systolic blood pressure, rate-pressure product, left ventricular ejection fraction, cardiac index and right ventricular ejection fraction. During exercise, significant decreases were also found in heart rate, systolic blood pressure and cardiac index in both treatment groups. No significant differences were found between mean esmolol and mean propranolol measurements at rest and during exercise, except for the exercise systolic blood pressure, which was lower during esmolol infusion. Blood levels of esmolol decreased markedly by 30 minutes postinfusion, as did its beta-blocking action. Esmolol was well tolerated with no important local, systemic or laboratory abnormalities. Thus, the effects of esmolol on cardiovascular performance at rest and during exercise are similar to those of propranolol.     

Comparison of nifedipine and isosorbide dinitrate when added to maximal propranolol therapy in stable angina pectoris

A study was performed to compare isosorbide dinitrate and nifedipine as adjunctive therapy in 14 patients with coronary artery disease and stable angina pectoris taking maximal beta-blocking drugs. Drug titration phases ensured maximal therapy of propranolol, isosorbide or nifedipine. The combination of nifedipine and propranolol was more effective than the combination of isosorbide and propranolol in reducing angina and increasing exercise capacity (323 vs 416 seconds, p less than 0.005) during exercise treadmill testing. Nifedipine produced a greater reduction in systolic blood pressure at submaximal exercise than isosorbide. Global and regional ejection fraction at rest and exercise was assessed with radionuclide ventriculography. The substitution of nifedipine for isosorbide depressed the global ejection fraction at rest (0.61 to 0.56 p less than 0.05) and produced a slight improvement in exercise ejection fraction (0.47 to 0.51, difference not significant). The decrease in ejection fraction from rest to exercise was 0.14 to 0.04 with nifedipine (p less than 0.005). The benefit of nifedipine compared with isosorbide occurred in regions with marked exercise-induced ischemia. In patients treated with maximal beta-blocking therapy, nifedipine is an effective alternative to isosorbide as a combination agent with propranolol. The salutary effects of nifedipine included afterload reduction with exercise and possible improvements in coronary blood supply.     

"Maximal" drug therapy is not necessarily optimal in chronic angina pectoris

Beta-adrenergic blocking agents, nitrates and calcium channel antagonists are effective in treating angina pectoris, but much remains unknown about how they act in combination. Consequently, treadmill exercise was used to assess the relative efficacy of nifedipine or isosorbide dinitrate, or both, in 19 patients with stable angina receiving propranolol. Propranolol therapy was continued and either placebo, nifedipine (20 mg), isosorbide dinitrate (20 mg) or both drugs were given randomly 1 1/2 hours before exercise in a double-blind trial. In 16 patients who completed the protocol, heart rate at rest during propranolol therapy was 53.7 +/- 1.9 beats/min (mean +/- standard error of the mean); it increased 4.6 +/- 1.2 beats/min with the addition of nifedipine (p less than 0.01), but was unchanged with isosorbide dinitrate or both combined. Compared with values during treatment with propranolol alone, systolic blood pressure at rest decreased with each vasodilator individually and when combined. Rate-pressure product at maximal exercise was the same with all combinations. Exercise duration was 467 +/- 50 seconds with propranolol, increased to 556 +/- 47 seconds with isosorbide dinitrate (p less than 0.05) and to 636 +/- 50 seconds with nifedipine (p less than 0.001). Exercise duration with all three drugs was 597 +/- 47 seconds (p less than 0.01 compared with propranolol alone). The improvement with nifedipine was greater than with isosorbide dinitrate (p less than 0.05) but exercise duration was not significantly different with the combination of these drugs than when either drug was used alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of selective (beta 1) and nonselective (beta 1 and beta 2) beta-adrenergic blockade on systemic and coronary hemodynamic findings in angina pectoris

To investigate the influence of selective beta 1-adrenergic blockade, in contrast to beta 1- and beta 2-adrenergic blockade, systemic and coronary hemodynamics were studied. Measurements were made at rest and during exercise in 23 patients with suspected coronary artery disease (CAD) before and after either metoprolol or propranolol, given in doses to provide comparable beta 1-receptor blockade. Quantitative coronary angiography was performed at rest. Using a randomized, double-blind protocol, either beta 1 and beta 2 blockade was produced by propranolol (0.1 mg/kg intravenously), or selective beta 1 blockade was produced by metoprolol (0.15 mg/kg intravenously). As expected, at these doses both drugs produced a comparable decrease in heart rate at rest and during exercise, averaging 9% and 14% after propranolol and 10% and 16% after metoprolol. Exercise duration to ischemia was prolonged in most patients with severe CAD after either propranolol (5 of 7) or metoprolol (6 of 10) treatment. The effects of these 2 beta-blocking drugs on systemic hemodynamic values at rest and during exercise were similar. Additionally, coronary sinus flow was usually unchanged by both drugs at rest (-5% after propranolol and -4% after metoprolol, differences not significant) and decreased a similar amount during exercise (-15% after propranolol and -9% after metoprolol, both p less than 0.05). Coronary resistance did not change significantly with either drug (0% after propranolol and 3% after metoprolol), and during exercise (11% after propranolol and 3% after metoprolol), suggesting that decreases in flow were secondary to reduced demand. Furthermore, neither drug produced detectable changes in coronary artery size.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adaptation of hypertensives to treatment with cardioselective and non-selective beta-blockers. Absence of correlation between bradycardia and blood pressure control, and reduction in slope of the QT/RR relation.

Thirty mild hypertensives were treated for more than two months with either cardioselective (atenolol or metoprolol) or non-selective (propranolol or pindolol) beta-blockers; the patients were assigned to the drugs in a double-blind manner. A procedure was designed to distinguish between the effects of the drugs themselves while treatment continued, and the development of adaptive changes which would persist when the drugs had been eliminated from the body. Though individual responses to treatment varied in both groups, the mean effect of the cardioselective and non-selective drugs in the control of hypertension was similar. There was no evidence of the development of supersensitivity or "rebound". On the contrary, an adaptive bradycardia (that is a fall of not less than 10% in heart rate persisting 52 hours after stopping treatment) was observed at rest in 17/30 patients, and peak heart rates and blood pressures during exercise were lower in both groups than before treatment. Cardioselective drugs induced a significantly greater bradycardia at rest than non-selective, but on exercise increases in heart rate were reduced more by the non-selective drugs, so that the same peak heart rates were reached on exercise in both groups. Adaptation also affected QT. The results suggest that two factors govern the shortening of QT by increases in heart rate, a "metabolic" effect, determined by sympathetic drive, and a "biophysical" effect determined by heart rate. The adrenergic effect is attenuated by acute beta-blockade, or by adaptation to prolonged blockade, leaving a shallow, rate-determined, slope to the QT/RR regression.     

Adaptation of hypertensives to treatment with cardioselective and non-selective beta-blockers. Absence of correlation between bradycardia and blood pressure control, and reduction in slope of the QT/RR relation

Thirty mild hypertensives were treated for more than two months with either cardioselective (atenolol or metoprolol) or non-selective (propranolol or pindolol) beta-blockers; the patients were assigned to the drugs in a double-blind manner. A procedure was designed to distinguish between the effects of the drugs themselves while treatment continued, and the development of adaptive changes which would persist when the drugs had been eliminated from the body. Though individual responses to treatment varied in both groups, the mean effect of the cardioselective and non-selective drugs in the control of hypertension was similar. There was no evidence of the development of supersensitivity or "rebound". On the contrary, an adaptive bradycardia (that is a fall of not less than 10% in heart rate persisting 52 hours after stopping treatment) was observed at rest in 17/30 patients, and peak heart rates and blood pressures during exercise were lower in both groups than before treatment. Cardioselective drugs induced a significantly greater bradycardia at rest than non-selective, but on exercise increases in heart rate were reduced more by the non-selective drugs, so that the same peak heart rates were reached on exercise in both groups. Adaptation also affected QT. The results suggest that two factors govern the shortening of QT by increases in heart rate, a "metabolic" effect, determined by sympathetic drive, and a "biophysical" effect determined by heart rate. The adrenergic effect is attenuated by acute beta-blockade, or by adaptation to prolonged blockade, leaving a shallow, rate-determined, slope to the QT/RR regression.     

Modern system for treating high blood pressure based on renin profiling and vasoconstriction-volume analysis: a primary role for beta blocking drugs such as propranolol.

A new system is proposed for treating the spectrum of patients with high blood pressure. It is based on studies of the renin axis using renin profiling, pharmacologic probes and our bipolar vasoconstriction-volume hypothesis. The new system does not require renin profiling, pharmacologic testing or a vasoconstriction-volume analysis for widespread application. But these procedures, whenever available, will make treatment more efficient and more certain, and at the same time provide better base line definition. In the new system, all patients, except the elderly and those with congestive heart failure, bradycardia or a history of asthma, are treated first with propranolol alone, a procedure which will diminish or normalize blood pressure in many patients with high and noraml renin levels. For nonresponders, diuretic therapy is then superimposed. Subsequently, a propranolol subtraction trial picks out the low-renin patients who will usually respond to a diuretic alone. This program is likely to be fully effective in possible up to 85 per cent of patients. For the residual smaller fraction, drugs such as hydralazine, methyl DOPA, clonidine, reserpine or guanethidine are then added in traditional trial and error fashion. The proposed system has the theoretic attraction for long-term commitment, implicit in antihypertensive therapy, of achieving blood pressure control in large fractions with one drug instead of two or with two drugs instead of three or more. Moreover, the large groups who respond to therapy with propranolol alone (most high-renin and normal-renin patients) or to diuretics alone (most low-renin patients) gain the advantage of simple, more specific, long-term (i.e., antirenin or antivolume) therapy. The use of propranolol alone has practical and theoretic advantages over diuretics. Control may be achieved with even fewer side effects and without hypokalemia and chronic dehydration with its possibly adverse consequences (hyperuricemia, azotemia, hyperlipidemia, hyperreninemia, increased blood viscosity). Also, propranolol provides more direct control of the increased peripheral resistance and of neurogenically-induced swings in blood pressure. At the same time, the new system efficiently exploits the long-term use of diuretic therapy alone in low-renin patients in whom volume excess seems a causal factor. And it tends to avoid the use of diuretics in high-renin patients and of beta-blockers in low-renin patients in whom these drug types may be contraindicated.     

Diltiazem versus propranolol in essential hypertension: responses of rest and exercise blood pressure and effects on exercise capacity

Both beta-blocking and calcium channel-blocking drugs are being used with increasing frequency as initial therapy for essential hypertension. The present study was designed to compare the antihypertensive effects of a beta-blocking drug, propranolol, with a calcium channel-blocking drug, diltiazem, at rest and during upright bicycle exercise and to determine whether exercise capacity is altered by these therapies. Twenty-one patients with uncomplicated systemic hypertension and a diastolic blood pressure (BP) of 95 to 110 mm Hg without medication were randomly assigned to propranolol or diltiazem therapy in a double-blind manner. The total daily dosages were titrated as needed, from 160 to 480 mg of propranolol (mean 371 mg) and 120 to 360 mg of diltiazem (mean 307 mg) over 12 weeks, and the titrated dose was maintained for 4 additional weeks. Both drugs significantly reduced supine BP (from 149 +/- 14/101 +/- 4 to 136 +/- 17/89 +/- 10 mm Hg with propranolol and from 157 +/- 14/103 +/- 4 to 144 +/- 13/93 +/- 8 with diltiazem. Only diltiazem reduced BP during submaximal exercise, but both agents produced significant responses during maximal exercise. Diltiazem had no effect on maximal heart rate, exercise duration or O2 uptake, whereas propranolol reduced maximal VO2 from 27 +/- 6 to 22 +/- 6 ml/min/kg (p less than 0.01) and also shortened duration of exercise. Propranolol, despite its effects on heart rate, maintained the workload VO2 relation at submaximal loads, suggesting an increased oxygen delivery. However, these adaptive mechanisms appear to be insufficient during maximal effort.     

Effects of propranolol and timolol on left ventricular volumes during exercise in patients with coronary artery disease

The hemodynamic effects of beta-receptor blocking agents on the ejection fraction of patients with coronary artery disease during exercise have been studied previously using radionuclide techniques. Left ventricular volume measurements and the peak systolic pressure/end-systolic volume (PSP/ESV) index have been shown to be variables of left ventricular function that are less influenced by preload and afterload than is ejection fraction. Left ventricular volumes and PSP/ESV were therefore measured in 18 patients with proven coronary artery disease in the control state and after 2 weeks of daily maintenance therapy with either 240 mg propranolol or 60 mg timolol. Values at rest and during symptom-limited upright exercise were compared using the first pass technique and a multicrystal scintillation camera. Left ventricular volumes were measured by the area-length method. Because there was no difference between the propranolol and timolol groups, the results for both groups were combined. The ejection fraction at rest after beta-receptor blocker treatment was not significantly different from pretreatment measurements because of an increase in both end-diastolic and end-systolic volumes (p less than 0.01). However, the value for peak systolic pressure/end-systolic volume (PSP/ESV) index at rest was lower after treatment. The exercise ejection fraction was greater after treatment (p less than 0.01), owing to an increase in end-diastolic volume and unchanged end-systolic volume. In addition, there was a significant improvement in the directional change in the PSP/ESV ratio between rest and exercise from pretreatment to treatment (-1.1 +/- 2.5 to +0.2 +/- 1.2, p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)