Catecholamine turnover in normotensive and hypertensive man: effects of antiadrenergic drugs.

Intravenous administration of tritium-labeled 3,4-dihydroxyphenylalanine (dopa) to human subjects resulted in the labeling of endogenous catecholamines and vanillylmandelic acid (VMA). Determination of the changes in specific activity of these compounds with time in fractional collections of urine and in cardiac biopsies from patients undergoing corrective cardiac surgery permitted estimation of apparent turnover rates. The average half-time of the exponential decline in specific activity of labeled urinary norepinephrine was about 8 hr and that of VMA was 11-16 hr in five normal subjects. No significant differences from normal were observed in eight patients with essential hypertension. The average half-life of norepinephrine was only 5 hr in cardiac patients undergoing surgery, and the levels and rate of decline of cardiac norepinephrine specific activity correlated well with the exponential phase of the urinary disappearance curve. There were significant effects of treatment with alpha-methyltyrosine, reserpine, and pargyline hydrochloride on the labeling and apparent turnover rates of norepinephrine and VMA; the effects noted were consistent with known actions of these three drugs. It is suggested that the technique used is a suitable means of assessing "over-all" catecholamine metabolism in man, particulary if combined with quantitative assay of urinary catecholamine metabolites.

Increased blood pressure and neural tone in the silent ischemia of hypertension: disparate effects of immediate release nifedipine.

OBJECTIVES: The aims of this study were 1) to evaluate the role of blood pressure and associated neural tonicity in ambient ischemia of a group of hypertensive patients with stable angina, and 2) to determine the efficacy of immediate release nifedipine therapy in controlling the total ischemic burden in both office-measured and ambulatory blood pressure. BACKGROUND: Low heart rate ischemia, as detected by Holter ambulatory electrocardiographic monitoring, suggests that reduced coronary flow is the major factor leading to ischemia. We previously found that 91% of the ischemic episodes in our hypertensive patients with stable angina were silent. METHODS: We measured plasma norepinephrine content during ischemic events from blood obtained from automatic pump withdrawal with the assistance of a real-time ST segment depression monitor. We then related the norepinephrine content to ischemic episodes assessed by 48-h Holter recording, blood pressure reading by ambulatory blood pressure monitoring and patients' diaries. Measurements were taken during the placebo period and immediate-release nifedipine therapy in 30 hypertensive patients (20 with and 10 without stable angina). RESULTS: More than half of the patients had ischemic episodes; 95% of these were silent. Ischemic episodes peaked in the early morning, and 55% occurred during routine sedentary activities. There was a 10% to 15% increase in heart rate at the onset of ischemia associated with a 30% higher plasma norepinephrine level. Seventy-five percent of patients had increased norepinephrine after nifedipine therapy. Nifedipine therapy controlled measured blood pressure but not 24-h ambulatory blood pressure. Ischemic episodes were reduced only in patients whose ambulatory blood pressure was controlled. CONCLUSIONS: The results suggest that increased neural tone at the time of the ischemic event may play a role in reducing coronary perfusion leading to silent ischemia. Nifedipine therapy (immediate release) was effective in control of ischemia only when both ambulatory and office-measured blood pressure were controlled.

Effect of beta-blockade on low heart rate-related ischemia during mental stress.

To explore the effect of beta-adrenergic blockade on low heart rate-related (mental stress) ischemia, 19 patients with coronary artery disease were randomized into a double-blind crossover trial of metoprolol, 100 mg twice daily, and underwent serial mental stress/bicycle exercise studies. Mental stress-induced wall motion abnormalities occurred at a lower heart rate than exercise-induced wall motion abnormalities during placebo administration (81 +/- 16 vs. 123 +/- 20 beats/min, p less than 0.05). Metoprolol reduced the mean magnitude of exercise-induced wall motion abnormalities (2.8 +/- 2.0 vs. 1.6 +/- 2.4, p = 0.003); improvement was related to the magnitude of hemodynamic beta-blockade effect. Metoprolol did not significantly reduce the mean magnitude of mental stress-induced wall motion abnormalities (3.0 +/- 2.2 vs. 2.6 +/- 2.2), although individual responses predominantly either improved (50%) or worsened (29%). Unlike exercise, the magnitude of hemodynamic beta-blockade did not predict mental stress response and metoprolol did not block mental stress-induced blood pressure elevations. Patients with abolition of exercise-induced ischemia were more likely to have reduction of mental stress-induced ischemia. Patients whose ischemia worsened with metoprolol during mental stress had more easily inducible ischemia, as assessed by exercise-induced placebo wall motion abnormality, chest pain and prior myocardial infarction. Beta-blockade was associated with a lowering of ischemia-related hemodynamic thresholds compared with placebo. These results suggest that beta-blockade has a variable effect on low heart rate-related ischemia that may be due to a lack of effect on mental stress-induced blood pressure elevation in patients with easily induced ischemia or to effects on coronary vasomotor tone, or both.

Reliability of echocardiographic assessment of left ventricular structure and function: the PRESERVE study. Prospective Randomized Study Evaluating Regression of Ventricular Enlargement.

OBJECTIVES: The study was done to evaluate reliability of echocardiographic left ventricular (LV) mass. BACKGROUND: Echocardiographic estimation of LV mass is affected by several sources of variability. METHODS: We assessed intrapatient reliability of LV mass measurements in 183 hypertensive patients (68% men, 65 +/- 9 years) enrolled in the Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement (PRESERVE) trial after a screening echocardiogram (ECHO) showed LV hypertrophy. A second ECHO was repeated at randomization (45 +/- 25 days later). Two-dimensional (2D)-guided M-mode or 2D linear measurements of LV cavity and wall dimensions were verified by one experienced reader. RESULTS: Mean LV mass was similar at first and second ECHO (243 +/- 53 vs. 241 +/- 54 g) and showed high reliability as estimated by intraclass correlation coefficient (RHO) = 0.93. Within-patient 5th, 10th, 90th and 95th percentiles of between-study difference in LV mass were -32 g, -28 g, +25 g and +35 g. Mean LV mass fell less from the first to the second ECHO than expected from a formula to predict regression to the mean (2 +/- 19 vs. 17 +/- 12 g, p < 0.001). Reliability was also high for LV internal diameter (RHO = 0.87), septal (RHO = 0.85) and posterior wall thickness (RHO = 0.83). Substantial or moderate reliability was observed for measures of LV systolic function and diastolic filling (RHO from 0.71 to 0.57). CONCLUSIONS: Left ventricular mass had high reliability and little regression to the mean; between-study LV mass change of +/-35 g or +/-17 g had > or = 95% or > or = 80% likelihood of being true change.

Effects of antihypertensive agents on circadian blood pressure and heart rate patterns. Review.

Blood pressure and heart rate exhibit a circadian rhythm, with both rising rapidly during the morning hours and then decreasing throughout the day to a nadir around 3 AM. Current evidence suggests a possible link between cardiovascular events, such as myocardial infarction and sudden cardiac death, which have been shown to occur most frequently during the morning hours, and the rapid rise in blood pressure and heart rate during this same time period. We review data from ambulatory blood pressure studies to ascertain which antihypertensive agents provide the most satisfactory control of blood pressure and heart rate during the hours of 6 AM to 12 noon. Of the forms of drug therapy studied, labetalol, a combined alpha- and beta-blocker, and two calcium channel blockers, nifedipine and verapamil, appear to be the most effective in blunting the rise in arterial blood pressure during these critical morning hours.

A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide.

BACKGROUND: The safety and effectiveness of different dosages and combinations of antihypertensive agents can be efficiently studied using a multifactorial trial design. In consultation with the Cardio-Renal Division of the Food and Drug Administration, we conducted a randomized, double-blind, placebo-controlled, 3 x 4 factorial trial of bisoprolol, a beta 1-selective adrenergic blocking agent, and hydrochlorothiazide. METHODS: A total of 512 patients with mild to moderate essential hypertension were randomized to once-daily treatment with bisoprolol (0, 2.5, 10, or 40 mg), hydrochlorothiazide (0, 6.25, or 25 mg), and all possible combinations. Diastolic and systolic blood pressures were monitored during this 12-week trial. RESULTS: The effects of bisoprolol and hydrochlorothiazide were additive with respect to reductions in diastolic and systolic blood pressures over the dosage ranges studied. The addition of hydrochlorothiazide (or bisoprolol) to therapy with bisoprolol (or hydrochlorothiazide) produced an incremental reduction in blood pressure. Dosages of hydrochlorothiazide as low as 6.25 mg/d contributed a significant antihypertensive effect. A hydrochlorothiazide dosage of 6.25 mg/d produced significantly less hypokalemia and less of an increase in uric acid levels than a dosage of 25 mg/d. The low-dose combination of bisoprolol, 2.5 mg/d, and hydrochlorothiazide, 6.25 mg/d, reduced diastolic blood pressure to lower than 90 mm Hg in 61% of patients and demonstrated a safety profile that compared favorably with that of placebo. CONCLUSIONS: The utility of factorial design trials to characterize dose-response relationships and to test the potential interactions between various antihypertensive agents has been demonstrated. The combination of low dosages of bisoprolol and hydrochlorothiazide may be a rational alternative to conventional stepped-care therapy for the initial treatment of patients with mild to moderate hypertension.

Elevated blood pressure in subjects with lipodystrophy.

OBJECTIVES: To assess the prevalence of elevated blood pressure in patients with lipodystrophy. DESIGN: Case-control study. PARTICIPANTS: Forty-two patients with abnormal body fat (100%) and serum lipids (86%) (HIV-positive cohort) were matched by age and sex to 42 HIV-positive controls without previously diagnosed lipodystrophy and to 13 HIV-negative controls. SETTING: Tertiary care, university-based, fully dedicated HIV clinic. MAIN OUTCOME MEASURES: Frequency and magnitude of elevated blood pressure during highly active antiretroviral therapy. RESULTS: There were 23 +/- 16 and 22 +/- 12 blood pressure measurements recorded per subject over 21 +/- 11 and 22 +/- 11 months for the HIV-positive cohort and HIV-positive controls, respectively. Three or more elevated readings occurred in 74% of the cohort and in 48% of the HIV-positive controls (P = 0.01) and accounted for 38 +/- 25% versus 22 +/- 26% (P = 0.01) of the total readings, respectively. The average of the three highest systolic readings (153 +/- 17 versus 144 +/- 15 mmHg; P = 0.01) and diastolic readings (92 +/- 10 versus 87 +/- 9 mmHg; P = 0.01) was greater for the cohort than for the HIV-positive controls. Family history of hypertension was more common in the cohort than in the controls but accounted for only 13% of the log odds ratio value for elevated blood pressure in the cohort. Systolic blood pressure was correlated with waist-to-hip ratios in the cohort (r = 0.45; P = 0.003) but not in the HIV controls (r = 0.06; P = 0.68) and tended to be related to fasting triglycerides (r = 0.34; P = 0.052) in subjects with HIV. CONCLUSIONS: Elevated blood pressure may be linked to the metabolic disorders occurring in patients with HIV, as in the dysmetabolic syndrome.

The relationships of free to conjugated normetanephrine in plasma and spinal fluid of hypertensive patients.

The concentrations of free and total normetanephrine (NMN) were determined in the plasma of normotensives and patients with primary hypertension and pheochromocytoma. NMN values were measured in the cerebrospinal fluid (CSF) of patients. Free and conjugated NMN, the latter after acid hydrolysis, were assayed using S-adenosylmethionine in the presence of phenylethanolamine-N-methyltransferase to form labeled metanephrine. The conjugates of NMN were present in plasma as sulfates principally, as they were also liberated with arylsulfatase. Free and conjugated NMN levels were 117 +/- 10 and 1417 +/- 109 ng/liter, respectively in plasma of normotensives. The mean ratio of the content of conjugated to free NMN was 14.9 +/- 1.8 (mean +/- SEM). The contents of free and conjugated NMN were 155 +/- 33 and 1670 +/- 320 ng/liter in primary hypertensives, respectively, and the ratio of conjugated to free NMN was 18.5 +/- 3.3. These values did not differ significantly from those in normotensives. The contents of free and total NMN in the plasma of patients with pheochromocytoma were 50- to 60-fold greater than values in normotensive and primary hypertensives. The mean ratio of conjugated to free NMN in the plasma of patients with pheochromocytoma was similar to those in normotensives and primary hypertensives. The contents of free and conjugated NMN in the CSF of patients with pheochromocytoma exceeded those in primary hypertensives (P less than 0.01 and P less than 0.001). Further, the ratio of conjugated to free NMN in CSF was increased in patients with pheochromocytoma (33.9 +/- 8.1) compared to that primary hypertensives (8.3 +/- 2.3; P less than 0.001). The measurement of NMN in plasma and CSF may help characterize sympathetic nerve tone in patients with primary hypertension to elucidate the pathophysiology of the elevated blood pressure.

Labetalol blunts morning pressor surge in systolic hypertension.

Twenty-four-hour ambulatory blood pressure, including the acceleration phase, and left ventricular mass were evaluated in 16 patients with isolated systolic hypertension (standing blood pressure greater than or equal to 160 mm Hg systolic and less than or equal to 95 mm Hg diastolic). After a 4-week, single-blind, placebo period, each patient underwent 24-hour ambulatory blood pressure monitoring and echocardiography. Labetalol therapy was then initiated at 100 mg twice a day in a single-blind manner and increased weekly by 100 mg twice a day until blood pressure control was obtained or a maximum dosage of 400 mg twice a day was reached. Blood pressure control was achieved at a mean daily dose of 363 +/- 46 mg of labetalol. Measurements were repeated at the end of an 8-week maintenance phase. Labetalol therapy significantly reduced the mean 24-hour systolic ambulatory blood pressure from 154 +/- 8 (mean +/- SEM) mm Hg at baseline to 142 +/- 6 mm Hg (p greater than 0.01) and controlled the early morning surge in systolic ambulatory blood pressure. Minor reductions in diastolic blood pressure and heart rate were statistically but not clinically significant. Left ventricular mass was not changed. Labetalol monotherapy provides effective 24-hour control of systolic blood pressure, including the acceleration phase, in patients with isolated systolic hypertension.

Childhood familial pheochromocytoma. Conflicting results of localization techniques.

Childhood familial pheochromocytoma was investigated in four patients by abdominal computed tomographic scan, [131I]metaiodobenzylguanidine scan, and vena caval catecholamine sampling. Results conflicted with surgical findings. Computed tomographic scan identified all four adrenal tumors but missed two midline tumors in one patient. [131I]metaiodobenzylguanidine scan identified two of three adrenal tumors but also suggested extra-adrenal tumors not confirmed at operation in two of three patients. Vena caval sampling for catecholamines confirmed all adrenal tumors but suggested additional tumors not verified at operation in two of three patients. All patients are asymptomatic and have normal urinary catecholamines 15 to 51 months after operation. Because of the frequency of multiple tumors in familial pheochromocytoma, different diagnostic techniques were employed. False-positive results were more frequent with [131I]metaiodobenzylguanidine and vena caval sampling. Reinterpretation of the [131I]metaiodobenzylguanidine scans at a later date led to less false-positive interpretation, although the false-negative rate remained unchanged. More pediatric experience with [131I]metaiodobenzylguanidine scans and vena caval sampling in familial pheochromocytoma is needed. Confirmation of tumor and its localization rest with meticulous surgical exploration.

Anxiety, anger, and neurogenic tone at rest and in stress in patients with primary hypertension.

To determine whether basal blood pressure or pressor responses to stress are related to sympathetic nerve tone or to psychological factors in hypertensives, 15 hypertensives and 13 normotensives were studied by mean of a self-administered questionnaire, isometric handgrip exercise (IHE), and the mental stress of serial subtraction. Plasma norepinephrine (NE), epinephrine (E), blood pressure (BP) and heart rate (HR) were measured before and at the end of IHE and mental stress. A greater number of hypertensives had suppressed anger (p less than 0.01) and scored higher on anxiety trait (p less than 0.01) and depression (p less than 0.05). Prestress (IHE and mental) BP and NE values were significantly greater in hypertensives (all p less than 0.01). During IHE, both groups had a significant increase of BP, HR, and NE (all p less than 0.01) but E rose in hypertensives only (p less than 0.05). The percentage change of BP, HR, NE, and E during IHE was similar in both groups. The changes of BP and HR were not related to NE or E. During mental stress, HR (p less than 0.01) and E (p less than 0.05) increased in both groups. However, BP (systolic and diastolic) increased in normotensives only (p less than 0.01). Plasma NE contents were unchanged in both groups. There were significant positive correlations of anxiety trait with systolic BP (p less than 0.05), diastolic BP (p less than 0.05), and NE (p less than 0.05) and E (p less than 0.05). Although hypertensives had increased neurogenic tone related perhaps to inward anger and anxiety, the percentage responses of neurogenic tone and BP to IHE were equivalent to those of normotensives. The challenge of serial subtraction did not elicit further noradrenergic or pressor responses in hypertensives. Suppressed anger and anxiety, via increased basal neurogenic tone, may be pathogenic factors in some patients with primary hypertension.

Pathophysiologic and pharmacokinetic determinants of the antihypertensive response to propranolol.

The tendency for patients with essential hypertension to differ markedly in antihypertensive response to propranolol could arise from pathophysiologic or pharmacokinetic differences between them. This possibility was investigated in 23 men with mild to moderately severe essential hypertension. At each of three propranolol doses, 40 mg, 80 mg, and 320 mg daily, approximately a 20-fold range in steady-state plasma propranolol concentrations was observed. Clinical response however was unrelated to plasma propranolol: oral dose ratio, since patients with higher plasma levels were less sensitive to the existing plasma drug concentration. When falls in blood pressure and plasma propranolol concentration were compared overall, a biphasic dose-response relationship was noted, with a first component at plasma propranolol concentrations of 3 to 30 ng/ml and a second at concentrations above 30 ng/ml. Only patients with increased sympathetic nervous system activity and high plasma renin activity (PRA) had substantial falls in pressure at propranolol levels of 3 to 30 ng/ml. Cardiac beta adrenergic receptor blockade, not suppression of PRA, seemed to be the antihypertensive mechanism. This relation of pretreatment sympathetic nervous activity and PRA to antihypertensive response existed only at lower plasma propranolol concentrations. With a propranolol dose of 320 mg daily, both plasma norepinephrine concentration and PRA were unrelated to the clinical response.

The impact of ethnicity on response to antihypertensive therapy.

The aim of this review is to assess the prevalence of complications and responses to various antihypertensive drug therapies in ethnic minority groups in the United States. In some instances, these comments are extended to responses of citizens in their countries of origin. The incidence of hypertension, mortality from hypertensive heart disease, stroke, and hypertensive renal disease are higher in African Americans. Although some Hispanic Americans have a lesser risk for hypertension, they have a greater risk for other risk factors such as diabetes and dyslipidemia. There is a similar association between income and mortality for both African Americans and Hispanic Americans. When compared to European Americans and other ethnic minorities, African Americans respond less favorably to beta blockers and angiotensin-converting enzyme (ACE) inhibitors. Nevertheless, the observed response in African Americans to ACE inhibitors and beta blockers is clinically significant. The available literature indicates that Asian American responses to calcium antagonists seem to be more favorable than responses to ACE inhibitors and equivalent to their responses to diuretic and beta blocker therapy. Although there are few published studies of drug efficacy in Hispanic Americans, there appears to be no hierarchy in response to the various antihypertensive drug classes. Ethnicity is not an accurate criterion for predicting poor response to any class of antihypertensive therapy. Thus, there is little justification to use racial profiling as a criterion for the avoidance of selected drug classes because of presumed lack of efficacy. Observed differences in the incidence of hypertension and its poor outcomes have led some investigators to postulate that the etiology of hypertension in ethnic minority groups is intrinsically different from whites. Awareness of racial differences in hypertension outcomes evolved in the United States within a historical context that does not fully appreciate that race is often a surrogate for many social and economic factors that influence health status and healthcare delivery. Poor outcomes in ethnic minority groups occur in many diseases, not only hypertension. The goal of ethnicity-related research should be to describe the diversity of disease expression in humans and to target at-risk groups for prevention and early intervention. The use of racial descriptors to explain genetic differences in ethnic groups should take a lesser priority.

Comparison of labetalol versus enalapril as monotherapy in elderly patients with hypertension: results of 24-hour ambulatory blood pressure monitoring.

PURPOSE: This study compared the safety and efficacy of labetalol and enalapril as antihypertensive therapy for elderly patients. PATIENTS AND METHODS: A randomized, open-label, parallel controlled trial was conducted. After completing a 4-week placebo phase, 79 elderly (65 years or older) patients with an average standing diastolic blood pressure (BP) 95 mm Hg or above and 114 mm Hg or less were randomized to receive a 12-week course of either labetalol or enalapril in an open-label design. The patients' BP and heart rate were evaluated biweekly by trained observers unaware of the treatment status, and drug dosage was titrated (up to 400 mg twice a day of labetalol or 40 mg daily of enalapril) to achieve a standing diastolic BP of less than 90 mm Hg and a decrease of 10 mm Hg from baseline. Patients underwent 24-hour ambulatory BP monitoring (ABPM) at the end of the placebo phase and again after 8 weeks of active treatment. RESULTS: The treatment groups were comparable in their reduction of supine diastolic BP, with no significant differences between the two treatments. Labetalol demonstrated a significantly greater reduction (p less than 0.05) in standing diastolic BP at the end of the titration period compared to enalapril, but this difference was not significant by the end of the study period. Based on 24-hour ABPM readings, labetalol reduced mean 24-hour diastolic BP (p less than 0.05) and mean heart rate (p less than 0.05) more than enalapril. The labetalol-treated patients were significantly less often above their diastolic BP goal throughout the 24-hour ABPM period (p less than 0.01). The two treatments were equally well tolerated. CONCLUSIONS: The results indicate that labetalol and enalapril are equally effective in lowering supine diastolic BP in the elderly, but labetalol is more effective in lowering ambulatory BP and heart rate throughout the day.

Imaging of medullary thyroid carcinoma and hyperfunctioning adrenal medulla using iodine-131 metaiodobenzylguanidine.

Scintigraphy with radiolabeled metaiodobenzylguanidine was performed in a patient with MEN Type IIa having a pheochromocytoma of the right adrenal gland, adrenomedullary hyperplasia of the left adrenal gland and a primary medullary thyroid carcinoma. The scintigraphic findings demonstrate visualization of all the above mentioned pathologies.

Effects of celiprolol on plasma renin, aldosterone, norepinephrine and epinephrine in primary hypertension.

Celiprolol is a newly developed cardioselective beta-blocking agent with mild beta 2-agonist and weak alpha 2-antagonist properties. To evaluate the acute (2.5 hours) and chronic (2 weeks) effects of celiprolol (400 mg once a day) on plasma renin, aldosterone, norepinephrine and epinephrine, 20 patients with mild to moderate primary hypertension were studied in a double-blind placebo-controlled crossover trial. Two and one-half hours after the first dose of both placebo and celiprolol, supine and standing measurements of blood pressure showed a significant reduction, whereas plasma norepinephrine increases were comparable with baseline values. Placebo and celiprolol produced similar changes on supine blood pressure and plasma norepinephrine. In 9 patients celiprolol decreased plasma renin (from a mean +/- standard deviation of 1.09 +/- 0.35 to 0.77 +/- 0.52 ng/ml/hr, p less than 0.05) and aldosterone (from 9.2 +/- 3.7 to 6.7 +/- 3.9 ng/dl, p less than 0.05) acutely both supine and standing, but placebo did not change these parameters. Celiprolol increased pulse rate supine (but not standing) as compared with baseline values. After 2 weeks of celiprolol therapy, blood pressure was decreased both supine and standing compared with placebo in 18 patients (140 +/- 18/88 +/- 8 vs 149 +/- 18/94 +/- 7, 136 +/- 18/91 +/- 6 vs 142 +/- 20/97 +/- 9 mm Hg, respectively, each p less than 0.05), without a change of pulse rate when supine and with a reduction when standing. There were no significant changes of plasma renin, aldosterone, norepinephrine and epinephrine levels during chronic therapy compared with placebo.

Increased plasma catecholamines in high renin hypertension.

Plasma catecholamines, indexes of sympathetic nervous tonicity, were measured simultaneously with renin both supine and after standing plus furosemide in patients with primary hypertension and normotensive volunteers. Seventy percent of hypertensive patients with high renin levels had increased catecholamines compared with a 14% incidence in the combined group with low and normal renin (P less than 0.001). Basal catecholamines were related directly to renin in the hypertensive patients and to blood pressure in the normal (P less than 0.05), but not in the high and low renin subgroups, and inversely to percent increase of catecholamines after standing plus furosemide in hypertensive and normotensive patients (P less than 0.01). Sympathetic nervous hypertonicity may be responsible for the elevation of blood pressure and for the activation of the renin-angiotensin system in patients with high renin hypertension.

Additional antianginal and anti-ischemic efficacy of mibefradil in patients pretreated with a beta blocker for chronic stable angina pectoris.

This study assessed the safety, tolerability, and efficacy of mibefradil when added to beta-blocker monotherapy in patients with chronic stable angina pectoris. Two hundred five patients were randomized to receive double-blind treatment with either placebo (n = 70), mibefradil 25 mg (n = 67), or mibefradil 50 mg (n = 68) for 2 weeks. Exercise tolerance tests (ETTs) were performed at the end of the run-in (baseline) and double-blind treatment periods, and patients maintained an anginal diary. Compared with placebo, treatment with mibefradil 50 mg resulted in significant increases in exercise duration (36 +/- 51 seconds; p = 0.036), time to onset of angina (48 +/- 65 seconds; p = 0.002), and time to persistent 1-mm ST-segment depression (47 +/- 77 seconds; p = 0.004). Greater reductions in heart rate, blood pressure, and the rate-pressure product were more apparent at each stage of the ETT in the 50-mg mibefradil group than in the placebo group. Daily treatment with mibefradil 50 mg was associated with a significant decrease in the number of weekly anginal attacks (-2.1 +/- 4.0, p = 0.020) compared with placebo. The addition of mibefradil to existing beta-blocker therapy was well tolerated. Dizziness was the most frequently reported adverse event in the mibefradil 50-mg dose, and occurred with an incidence of 4.4%. The addition of mibefradil 50 mg, administered once daily, to patients on stable beta-blocker therapy produced additive antianginal and anti-ischemic effects and was well tolerated.

Effects of exercise on blood pressure, plasma catecholamines, potassium and the electrocardiogram after diuretic and neural-blocking therapy for moderate hypertension.

Blood pressure control in mild and moderate hypertension may reduce morbidity and mortality. On the other hand, antihypertensive drugs may cause adverse metabolic, electrolyte, neural and hemodynamic alterations that detract from their effectiveness. The effect of hydrochlorothiazide (HCTZ) on some of these factors was compared with that of HCTZ and a sympatholytic drug in 20 hypertensive patients with left ventricular hypertrophy and retinopathy. HCTZ controlled blood pressure at rest and during maximum treadmill exercise (-12 mm Hg systolic and diastolic pressure (p less than 0.05), reduced left ventricular mass by 7% (p less than 0.05) and lessened aerobic impairment at maximum treadmill exercise by 45% (p less than 0.05). These effects were further improved after "neural blockade." A potential adverse effect of HCTZ--hypokalemia (-0.6 mEq/liter, p less than 0.01)--and the associated incidence of ectopy during effort (50%) were lessened after neutralizing neural tone. Combination therapy with low-dose diuretic and sympatholytic drugs was effective and well tolerated in patients with cardiac and vascular sequelae of moderately severe hypertension.

Efficacy of bucindolol in systemic hypertension.

The hemodynamic effects of oral bucindolol, a non-selective beta-adrenergic blocking agent with intrinsic sympathomimetic activity and direct vasodilating properties, were studied at rest and during handgrip exercise with a flotation-directed pulmonary artery catheter in 12 patients with mild to moderate essential hypertension. After the initial dose of 150 mg of bucindolol, blood pressure (BP) was significantly reduced and cardiac output was increased (from 5.9 +/- 0.8 to 6.8 +/- 1.6 liters/min) in the supine position and during exercise (p less than 0.05). Systemic vascular resistance was reduced (from 1,555 +/- 339 to 1,311 +/- 467 dynes s cm-5, p less than 0.01) at rest and without significant changes during exercise. There were increases in heart rate (13 +/- 13%, p less than 0.01) and right atrial (69 +/- 77%, p less than 0.05), pulmonary arterial (38 +/- 24 %, p less than 0.001) and pulmonary artery wedge pressures (62 +/- 46%, p less than 0.001) during exercise. Bucindolol did not change these variables at rest or during exercise. Bucindolol increased plasma norepinephrine levels both at rest (from 330 +/- 151 to 588 +/- 320 ng/liter, p less than 0.01) and during exercise (from 468 +/- 220 to 685 +/- 390 ng/liter, p less than 0.05). After 4 weeks of bucindolol with doses of 50 to 200 mg 3 times daily, BP was reduced in both supine and standing positions (mean arterial BP of 11 +/- 7% [p less than 0.001] and 11 +/- 6% [p less than 0.001], respectively), without changes in cardiac output, systemic vascular resistance or plasma norepinephrine level.(ABSTRACT TRUNCATED AT 250 WORDS)