Comparison in young and elderly patients of pharmacodynamics and disposition of labetalol in systemic hypertension

Pharmacodynamics and pharmacokinetics of labetalol, a combined alpha- and beta-adrenoceptor antagonist drug, were studied in elderly and young hypertensive patients. After receiving intravenous labetalol, elderly patients had a greater maximal mean decrease in systolic blood pressure (BP) (39 +/- 8 vs 25 +/- 13 mm Hg, p less than 0.02); however, maximal decrease in diastolic BP was similar in elderly (18 +/- 10 mm Hg) and young (17 +/- 6 mm Hg) patients. After receiving oral labetalol, elderly patients had a greater maximal decrease in standing systolic BP (41 +/- 16 vs 16 +/- 14 mm Hg, p less than 0.001) and similar decreases in standing diastolic BP (21 +/- 7 vs 17 +/- 9 mm Hg). Sitting maximal BP decreases after oral labetalol treatment were similar in elderly and young patients (12 +/- 16 vs 17 +/- 7 mm Hg systolic and 24 +/- 6 vs 12 +/- 7 diastolic). The decrease in heart rate was greater in young patients after intravenous labetalol administration. To evaluate labetalol pharmacodynamics, a linear model was used. Slope of labetalol concentration vs systolic BP for elderly vs young patients was 0.928 +/- 1.05 vs 0.326 +/- 0.490 ng/ml X mm Hg-1 (difference not significant). The slope of labetalol concentration vs heart rate for elderly vs young patients was 0.176 +/- 0.063 vs 0.406 +/- 0.303 ng/ml X beats/min-1 (p less than 0.05), with 2 elderly patients showing no decrease in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute and chronic studies of diltiazem in elderly versus young hypertensive patients

The pharmacodynamics, disposition and hormonal responses to acute intravenous and chronic oral diltiazem treatment were compared in young and elderly hypertensive patients. In elderly patients, supine diastolic blood pressure decreased significantly during the first week of treatment (baseline mean +/- standard error of the mean, 100 +/- 1 to 93 +/- 2 mm Hg) and decreased further during the study to 86 +/- 2 mm Hg at the end of the study. Diastolic blood pressure of the young patients decreased significantly by the third week of treatment (from 104 +/- 2 to 97 +/- 3 mm Hg) and decreased further during the study to 94 +/- 2 mm Hg at the end of the study. Baseline supine systolic blood pressure was greater in elderly than in young patients (167 +/- 5 vs 144 +/- 3 mm Hg; p less than 0.01) and was significantly reduced in the elderly by the fourth week (167 +/- 5 to 154 +/- 3 mm Hg; p less than 0.003), with a significantly reduction sustained throughout the 14-week period. Young patients had little change in systolic blood pressure. Supine heart rate tended to decrease in both groups during the 14-week period. Acute intravenous diltiazem pharmacokinetics determined at the beginning of the study showed that total diltiazem clearance was similar in elderly (13.3 +/- 1.0 ml/min/kg) and young (13.7 +/- 1.9 ml/min/kg) patients as was volume of distribution (4.2 +/- 0.3 vs 4.3 +/- 0.6 liters/kg) and elimination half-life (3.78 +/- 0.19 vs 3.69 +/- 0.23 hours).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of diltiazem and nifedipine on systemic and coronary hemodynamics and ischemic responses during transient coronary artery occlusion in patients

Diltiazem and nifedipine improve coronary blood flow and reduce peripheral determinants of myocardial oxygen demand through activation of similar but distinct cellular mechanisms. To identify differences during myocardial ischemia, systemic and coronary hemodynamics were measured continuously before and during brief periods of left anterior descending coronary balloon occlusion in 23 patients undergoing single-vessel angioplasty. Data were compared for two matched ischemic periods, one control and one "drug" period. In 13 patients, diltiazem, 10 mg (intravenous bolus with continuous 500 mg/min infusion), was given; in 10 patients, nifedipine, 10 mg sublingual, was given and after 15 minutes, ischemia was reinduced. Both drugs significantly reduced systolic and mean arterial pressure (for diltiazem, 108 +/- 15 to 93 +/- 10 mm Hg; and for nifedipine, 117 +/- 20 to 96 +/- 8 mm Hg, both p less than 0.01). Diltiazem significantly reduced heart rate-pressure product (with heart rate unchanged), while both drugs maintained the resting great vein blood flow (for diltiazem, 97 +/- 25 to 91 +/- 34 ml/min; for nifedipine, 115 +/- 49 to 98 +/- 58 ml/min, p = ns) with reduced arterial pressure. Coronary flow during occlusion was unchanged (for control versus diltiazem, 63 +/- 21 versus 59 +/- 14 ml/min; for nifedipine, 66 +/- 33 versus 73 +/- 38 ml/min, both p = ns). Neither drug improved collateral hemodynamics or resistance index during ischemia. Both diltiazem and nifedipine prolonged the time to ischemic ST segment alteration (for diltiazem, 27 +/- 10 to 40 +/- 16 seconds, p less than 0.05; for nifedipine, 24 +/- 14 to 38 +/- 14 seconds, p = ns) during transient coronary occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of differences in the hemodynamic response to passive postural stress in healthy subjects greater than 70 years and less than 30 years of age

To test the hypothesis that age-related increases in arterial pressure alter the cardiovascular response to physiologic stress, 9 healthy elderly volunteers (74 +/- 2 years) and 7 young subjects (27 +/- 3 years) were subjected to a standard 60 degrees upright tilt. Cardiac volumes were measured with patients in the supine position and 5 minutes after they assumed an upright posture using radionuclide ventriculography, while heart rate, blood pressure and forearm cutaneous flow were recorded continuously and simultaneously. Only the expected age-related increase in mean arterial pressure (young subjects, 79 +/- 1 mm Hg; elderly subjects, 99 +/- 3 mm Hg; p less than 0.001) distinguished the 2 groups at baseline. However, during upright tilt, elderly subjects had significant decreases in stroke volume (supine [108 +/- 9 ml] vs upright [78 +/- 9 ml]; p less than 0.01) and cardiac index (supine [3.4 +/- 0.2 liters/min/m2] vs upright [2.8 +/- 0.2 liters/min/m2]; p less than 0.05) because of an inability to reduce end-systolic volume (supine, 44 +/- 6 ml; upright, 51 +/- 7 ml); however, mean arterial pressure was maintained through an increase in peripheral resistance. In contrast, the young relied solely on cardiac adaptations to postural stress by decreasing end-systolic volume (supine, 62 +/- 5 ml; upright, 39 +/- 5 ml; p less than 0.01) and increasing heart rate (57 +/- 2 min-1 to 71 +/- 3 min-1, p less than 0.01), whereby cardiac output and mean arterial pressure were maintained during tilt.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute hemodynamic effect of oral nifedipine in severe chronic congestive heart failure

The temporal hemodynamic effects of oral nifedipine after a single dose of 20 to 40 mg were evaluated in 11 patients with severe chronic congestive heart failure (left ventricular ejection fraction 0.22 +/- 0.7 [mean +/- standard deviation]). Nifedipine significantly reduced systemic vascular resistance, from 1,850 +/- 493 to 1,315 +/- 398 dynes s cm-5 at 1 hour (29%), to 1,410 +/- 246 at 3 hours and to 1,523 +/- 286 at 6 hours (p less than 0.05). Cardiac index increased 21%, from 2.07 +/- 0.46 to 2.51 +/- 0.83 liters/min/m2 at 1 hour, to 2.38 +/- 0.53 liters/min/m2 at 3 hours (p less than 0.05) and to 2.24 +/- 0.41 liters/min/m2 at 6 hours. The group response of stroke volume to nifedipine was smaller. A peak increase of 17% was seen 3 hours after initiation of therapy (22.6 +/- 7.2 versus 25.5 +/- 6.1 ml/m2). This difference did not reach statistical significance. Mean blood pressure declined significantly, from 94 +/- 20 to 80 +/- 13 mm Hg at 1 hour, to 83 +/- 15 mm Hg at 3 hours and to 86 +/- 17 mm Hg at 6 hours (p less than 0.05) and was associated with no significant change in heart rate. The marked decrease in blood pressure resulted in a decrease in rate-pressure product from 12,272 +/- 4,230 to 10,500 +/- 2,074 mm Hg/min at 1 hour, to 10,374 +/- 2,735 mm Hg/min at 3 hours and to 11,047 +/- 3,813 mm Hg/min at 6 hours (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of sublingual nifedipine on hemodynamics and systolic and diastolic function in patients with hypertrophic cardiomyopathy

The hemodynamic effects of sublingual nifedipine were examined in 36 patients with hypertrophic cardiomyopathy. Twenty-one patients were initially given 20 mg and 15 patients were given 10 mg of the drug; 30 min after this first dose 26 patients received 10 mg and one patient 20 mg as a second dose. Hemodynamic findings in patients who received different doses of the drug were similar. Peak effects included an increase in heart rate from 79 +/- 12 to 91 +/- 14 (mean +/- 1 SD) beats/min (p less than .01), and a decrease in mean blood pressure from 89 +/- 12 to 77 +/- 10 mm Hg (p less than .01). Cardiac index increased after nifedipine (2.8 +/- 0.6 to 3.3 +/- 0.8 liters/min/m2; p less than .01); stroke volume index, however, did not change (36 +/- 7 to 36 +/- 8 ml/beat/m2; NS). Peripheral vascular resistance index fell significantly from 822 +/- 261 to 610 +/- 197 dynes X sec X cm-5 (p less than .01). Overall, left ventricular outflow tract gradient (LVOTG) did not change in patients with significant (greater than or equal to 30 mm Hg) basal LVOTG (75 +/- 22 to 83 +/- 22 mm Hg; NS), but it increased significantly in those six patients in whom peripheral vascular resistance fell by 25% or more (73 +/- 28 to 99 +/- 22 mm Hg; p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Beneficial hemodynamic effects of intravenous and oral diltiazem in severe congestive heart failure

Concern persists about the potential negative inotropic effects of calcium channel blockers in patients with severely depressed myocardial function. Therefore, intravenous diltiazem (100 to 200 micrograms/kg per min infusion) was administered for 40 minutes followed by oral diltiazem (90 to 120 mg/8 hours) for 24 hours to patients with advanced congestive heart failure (New York Heart Association class III to IV, mean ejection fraction 26 +/- 4 [SD]). Intravenous diltiazem (eight patients) increased cardiac index 20% (2.05 +/- 0.8 to 2.47 +/- 0.8 liters/min per m2, p less than 0.01), stroke volume index 50% (22 +/- 9 to 33 +/- 12 ml/m2, p less than 0.001) and stroke work index 27% (19 +/- 10 to 24 +/- 10 g-m/m2, p less than 0.05); while reducing heart rate 23% (97 +/- 18 to 75 +/- 11 beats/min, p less than 0.01), mean arterial pressure 18% (95 +/- 13 to 78 +/- 7 mm Hg) and pulmonary wedge pressure 34% (29 +/- 9 to 19 +/- 7 mm Hg), without altering maximal first derivative of left ventricular pressure (dP/dtmax). Oral diltiazem (seven patients) produced equivalent hemodynamic effects. Transient junctional arrhythmias were observed in three of eight patients with intravenous diltiazem and one of seven patients with oral diltiazem. It is concluded that intravenous and short-term oral diltiazem improve left ventricular performance and reduce myocardial oxygen demand by heart rate and afterload reduction without significantly depressing contractile function in severe congestive heart failure. Caution should be exercised to avoid potential adverse, drug-induced electrophysiologic effects in such patients.     

Doppler echocardiographic evaluation of cardiac performance in infants on prolonged extracorporeal membrane oxygenation

Cardiac performance was evaluated by Doppler echocardiography in 19 infants with persistent pulmonary hypertension before, during and after prolonged extracorporeal membrane oxygenation (ECMO). Systemic arterial pressure was normal before ECMO (67 +/- 12 mm Hg), increased during ECMO (78 +/- 13 mm Hg) and decreased to baseline after ECMO (p less than or equal to 0.01). Heart rate was normal before ECMO and did not change during or after ECMO. The left ventricular shortening fraction was normal before ECMO (37 +/- 11%), decreased after beginning ECMO (25 +/- 11%) and returned to baseline 72 hours after beginning ECMO (p less than or equal to 0.01). Pulmonary arterial and aortic blood flow velocities were normal before ECMO, decreased 30 to 50% during ECMO and increased to baseline 72 hours after beginning ECMO (p less than or equal to 0.01). Stroke volume had an identical trend (p less than or equal to 0.01). Left ventricular velocity of circumferential shortening--an index of contractility--decreased after beginning ECMO (p less than or equal to 0.05). Left ventricular systolic wall stress--an index of systemic afterload--increased after beginning ECMO (p less than or equal to 0.01). A patent ductus arteriosus was present in 13 of 19 infants before ECMO, 16 of 19 infants during ECMO and in none of 19 infants after ECMO. Pulmonary arterial systolic pressure was high before ECMO (72 +/- 25 mm Hg), began to decrease after 48 hours on ECMO (59 +/- 24 mm Hg) and was normal after ECMO (38 +/- 18 mm Hg), p less than or equal to 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of diltiazem on regional coronary hemodynamics during atrial pacing in patients with stable exertional angina: implications for mechanism of action

To investigate the mechanism of the antianginal action of diltiazem in stress-induced myocardial ischemia, we studied 12 patients with stable exertional angina and disease of the proximal left anterior descending artery by measuring great cardiac vein flow (GVCF) and calculating anterior regional coronary resistance (ARCR) during myocardial ischemia induced by atrial pacing before and after intravenous administration of diltiazem (0.25 mg/kg in a bolus dose followed by continuous infusion of 0.005 mg/kg/min). Diltiazem increased the pacing time to angina from 6.9 +/- 3.5 to 10.7 +/- 4 min (p less than .001). At peak pacing heart rate was increased after diltiazem (from 128 +/- 17 to 145 +/- 17 beats/min, p less than .005), while mean arterial pressure was decreased (from 131 +/- 19 to 113 +/- 17 mm Hg, p less than .025), leaving the double product unaltered. At peak pacing no changes were observed in GCVF (from 115 +/- 46 to 119 +/- 46 ml/min, p = NS), ARCR (from 1.3 +/- 0.4 to 1.1 +/- 0.4 mm Hg/ml/min), or myocardial oxygen consumption of the anterior region (from 14.5 +/- 4.2 to 13.4 +/- 4.7 ml/min). Reduction of myocardial oxygen demand plays a major role in the antianginal action of diltiazem in patients with stress-induced myocardial ischemia.     

Relation between serum nifedipine concentration and hemodynamic effects in nonobstructive hypertrophic cardiomyopathy

The relation between nifedipine concentration and hemodynamic effects after sublingual administration of 10 or 20 mg was examined in 13 patients with nonobstructive hypertrophic cardiomyopathy (HC). Serum nifedipine concentrations were determined by gas chromatography and were not related to dose. Peripheral vascular resistance decreased as a function of nifedipine concentration (r = -0.63, p less than 0.001); this was associated with a concentration-related increase in heart rate (r = 0.56, p less than 0.001) and in cardiac index (r = 0.50, p less than 0.001). However, evidence for a pure vasodilator effect of nifedipine was inconsistent, in that the change in stroke volume index with nifedipine was not significant. Although stroke volume index increased at nifedipine concentrations between 60 and 120 ng/ml (38 +/- 6 to 42 +/- 4 ml/m2, p less than 0.01), it decreased at concentrations greater than 120 ng/ml (40 +/- 3 to 38 +/- 4 ml/m2, p less than 0.01). Moreover, pulmonary artery wedge pressure increased at nifedipine concentrations greater than 120 ng/ml (11 +/- 2 to 16 +/- 4 mm Hg, p less than 0.001), suggesting either depressed left ventricular (LV) systolic function or reduced LV filling. To investigate these possible mechanisms, LV systolic and diastolic function was studied during catheterization with a nonimaging scintillation probe in 6 of the 13 patients. In these subjects, heart rate was held constant by atrial pacing.(ABSTRACT TRUNCATED AT 250 WORDS)     

Spectral analysis of heart rate dynamics in elderly persons with postprandial hypotension.

Prior studies suggest that postprandial hypotension in elderly persons may be due to defective sympathetic nervous system activation. We examined autonomic control of heart rate (HR) after a meal using spectral analysis of HR data in 13 old (89 +/- 6 years) and 7 young (24 +/- 4 years) subjects. Total spectral power, an index of overall HR variability, was calculated for the frequency band between 0.01 and 0.40 Hz. Relatively low-frequency power, associated with sympathetic nervous system and baroreflex activation, was calculated for the 0.01 to 0.15 Hz band. High-frequency power, representing parasympathetic influences on HR, was calculated for the 0.15 to 0.40 Hz band. Mean arterial blood pressure declined 27 +/- 8 mm Hg by 60 minutes after the meal in elderly subjects, compared with 9 +/- 8 mm Hg in young subjects (p less than or equal to 0.0001, young vs old). The mean change in low-frequency HR power from 30 to 50 minutes after the meal was +19.4 +/- 25.3 U in young subjects versus -0.1 +/- 1.5 U in old subjects (p less than or equal to 0.02). Mean change in total power was also greater in young (19.0 +/- 26.6 U) subjects compared with old subjects (0.0 +/- 1.6 U, p greater than or equal to 0.02). Mean ratio of low:high-frequency power increased 3.1 +/- 3.3 U in young subjects vs 0.5 +/- 2.7 U in old subjects (p less than or equal to 0.01). The increase in low-frequency HR power and in the low:high frequency band ratio in young subjects is consistent with sympathetic activation in the postprandial period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of diltiazem and long-term beta 1-adrenergic blockade on hemodynamics and blood flow during exercise in patients with stable angina pectoris

The short-term effects of oral diltiazem on hemodynamics and distribution of cardiac output at rest and during semiupright bicycle exercise were evaluated in eight patients with stable effort angina on long-term beta 1-adrenergic blockade. Cardiac output and iliofemoral blood flow were measured using thermodilution. The patients were exercised to the same work load on a bicycle before and 2 h after oral diltiazem (60 mg in two patients and 120 mg in six). At maximal exercise, diltiazem reduced heart rate from 94 +/- 5 to 88 +/- 6 beats/min (p less than 0.01), mean arterial pressure from 139 +/- 5 to 127 +/- 4 mm Hg (p less than 0.01) and systemic vascular resistance from 9.7 +/- 0.7 to 8.4 +/- 0.4 x 10(2) dynes.s.cm-5 (p less than 0.05) compared with control. During exercise, cardiac output, iliofemoral blood flow, mean pulmonary wedge pressure and mean right atrial pressure were not altered, but stroke volume increased from 119 +/- 11 to 131 +/- 10 ml (p less than 0.05). Maximal ST segment depression during exercise was decreased and angina was less. Diltiazem does not alter the distribution of the cardiac output during exercise but improves ischemia.     

Effects of intravenous verapamil on left ventricular relaxation and filling in stable angina pectoris

Left ventricular (LV) diastolic function is often impaired in coronary artery disease (CAD). To assess whether verapamil could improve LV diastolic properties, 12 patients with CAD undergoing right- and left-sided cardiac catheterization, as well as simultaneous radionuclide angiography, were studied before and during intravenous administration of verapamil (0.1 mg/kg as a bolus followed by 0.007 mg/kg/min). The heart rate was kept constant by atrial pacing in both studies. LV pressure-volume relations were obtained. Verapamil decreased LV systolic pressure (130 +/- 22 to 117 +/- 16 mm Hg, p less than 0.01) and the end-systolic pressure/volume ratio (2.4 +/- 1.3 to 1.6 +/- 0.5 mm Hg/ml, p less than 0.05), and increased LV end-diastolic (13 +/- 4 to 16 +/- 4 mm Hg, p less than 0.02) and pulmonary capillary pressures (10 +/- 5 to 12 +/- 5 mm Hg, p less than 0.005). Despite such negative inotropic effects, cardiac index increased (3.4 +/- 0.7 to 3.9 +/- 0.6 liters/min/m2, p less than 0.02). The time constant of isovolumic relaxation shortened (63 +/- 14 to 47 +/- 9 ms, p less than 0.02); peak filling rate increased (370 +/- 155 to 519 +/- 184 ml/s, p less than 0.001; 2.6 +/- 1.1 to 3.3 +/- 0.9 end-diastolic counts/s, p less than 0.02; and 4.1 +/- 1.6 to 5.5 +/- 1.5 stroke counts/s, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of calcium administration on the short-term hemodynamic and anti-ischemic effects of nifedipine

This prospective study investigated whether pretreatment with intravenously administered calcium would influence the effect of nifedipine on rest hemodynamics and treadmill performance in patients with ischemic heart disease. Seventeen patients were studied after undergoing a qualifying treadmill exercise test that revealed ST segment depression indicative of ischemic heart disease. Study subjects performed three additional treadmill tests as part of the protocol. One treadmill test was obtained from each patient to provide baseline measurements without a preceding intravenous infusion and in the absence of all antianginal drugs including nifedipine; two additional exercise tests were preceded by an infusion and 10 mg of bite-and-swallow nifedipine. The infusions, administered in a randomized, double-blind, crossover fashion, consisted of either 10 ml of 10% calcium chloride (13.6 mEq) in 50 ml of 5% dextrose in water or 5% dextrose in water alone. Rest systolic blood pressure (134 +/- 4.6 mm Hg) was unchanged after placebo infusion (135 +/- 4.6 mm Hg) but decreased to 124 +/- 4.1 mm Hg (p less than 0.01) 25 min after nifedipine administration. Rest systolic blood pressure increased after calcium infusion (from 139 +/- 4.3 to 148 +/- 4.8 mm Hg, p less than 0.01) and then decreased significantly 25 min after nifedipine administration to 135 +/- 4.2 mm Hg (p less than 0.01). Despite a decrease at the time of peak nifedipine effect after either infusion, systolic blood pressure was significantly lower after administration of nifedipine alone than after administration of calcium and nifedipine (124 +/- 4.1 vs. 135 +/- 4.2 mm Hg, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of diltiazem and nifedipine for both angina pectoris and systemic hypertension

In a randomized, double-blind, placebo-controlled crossover trial, diltiazem and nifedipine were compared in 10 patients with stable angina pectoris and mild to moderate hypertension (supine diastolic blood pressure greater than or equal to 90 mm Hg). Patients received placebo for 2 weeks, then increasing doses of diltiazem (90 to 360 mg/day) or nifedipine (30 to 120 mg/day) in 3 daily divided doses over 2 weeks, followed by 1 week of therapy at the maximal dose, a 1-week placebo "washout," then crossover to the other drug. Heart rate and blood pressure at rest and during exercise, anginal frequency, nitroglycerin consumption and treadmill exercise tolerance were assessed. Compared with placebo, anginal frequency and nitroglycerin consumption were reduced with both diltiazem and nifedipine (p less than 0.01) and exercise tolerance was increased with both drugs (p less than 0.01). Standing blood pressure at rest was reduced by diltiazem and nifedipine (146.6 +/- 11.4/97.7 +/- 5.3 mm Hg at placebo, baseline reduced to 129.6 +/- 15.2/79.5 +/- 13.7 mm Hg with diltiazem, and to 122.2 +/- 9.9/82.0 +/- 7.1 with nifedipine, p less than 0.01 for both). Compared with placebo, diltiazem and nifedipine also reduced exercise diastolic blood pressure (p less than 0.01), but not systolic blood pressure. Diltiazem lowered the heart rate at rest from 88.5 +/- 14.4 beats/min at placebo baseline to 79.7 +/- 17.9 beats/min (p less than 0.01); the heart rate with diltiazem was 11 beats/min lower than that with nifedipine (p less than 0.05). Both diltiazem and nifedipine had similar effects on the heart rate-blood pressure product at rest and during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of nifedipine on hemodynamics and cardiac function in patients with normal left ventricular ejection fraction already treated with propranolol

The interaction between nifedipine and propranolol on cardiac hemodynamics and function was investigated in 9 patients with normal left ventricular (LV) function who were undergoing cardiac catheterization for complaints of chest pain. Only 2 patients had angiographic evidence of significant coronary artery disease but no patient had clinical evidence of ischemia during the study. All patients were pre-treated with propranolol, 30 to 320 mg/day (mean +/- standard deviation 210 +/- 122); the propranolol serum level ranged from 43 to 246 ng/ml (mean 203 +/- 62). The administration of nifedipine resulted in a decrease in blood pressure (from 94 +/- 11 to 85 +/- 13 mm Hg, p less than 0.05), increase in heart rate (from 59 +/- 6 to 65 +/- 7 beats/min, p less than 0.05), and an increase in both mean right atrial and mean pulmonary artery wedge pressures (from 8 +/- 3 to 9 +/- 3 mm Hg and from 13 +/- 3 to 14 +/- 4 mm Hg, respectively, both p less than 0.05). Cardiac index increased (from 2.3 +/- 0.3 to 2.7 +/- 0.2 liters/min/m2, p less than 0.01). Stroke volume index also increased significantly (from 39 +/- 5 to 43 +/- 6 ml/m2) and systemic vascular resistance decreased (from 1,715 +/- 369 to 1,255 +/- 271 dynes s cm-5, p less than 0.01). No significant change was noted in pulmonary vascular resistance (148 +/- 94 vs 140 +/- 62 dynes s cm-5), LV stroke work index (44 +/- 9 vs 42 +/- 10 g-m/m2), LV end-diastolic pressure (15 +/- 2 vs 16 +/- 2 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Diuretics versus calcium-channel blockers in systemic hypertension: a preliminary multicenter experience with hydrochlorothiazide and sustained-release diltiazem

The safety and efficacy of sustained-release diltiazem 120 to 180 mg, 2 times a day, were compared with hydrochlorothiazide 25 to 50 mg, 2 times a day, and the combination of diltiazem and hydrochlorothiazide in 56 patients with mild to moderate hypertension (supine diastolic blood pressure between 95 and 114 mm Hg) using a placebo-controlled, parallel-design protocol. Data from an additional 21 patients were evaluated for safety only. The data reported herein represent the preliminary experience from a larger 200-patient multicenter study. All patients received placebo for 4 weeks, followed by either hydrochlorothiazide or diltiazem titrated to achieve a diastolic blood pressure reduction of greater than or equal to 10 mm Hg to reach a goal supine diastolic blood pressure of less than 90 mm Hg. Patients not achieving the treatment goal received hydrochlorothiazide plus diltiazem. At week 14, on maintenance monotherapy, diltiazem and hydrochlorothiazide produced comparable reductions in blood pressure from placebo baseline (160.3 +/- 24.3/101.7 +/- 5.5 to 145.2 +/- 24.1/89.8 +/- 7.4 mm Hg with diltiazem, 156.0 +/- 15.6/103.7 +/- 4.7 to 134.1 +/- 12.5/89.2 +/- 9.5 mm Hg with hydrochlorothiazide, p less than 0.001 for both). Diltiazem and hydrochlorothiazide achieved goal blood pressure in 42% and 45% of patients, respectively. The effects in responders were sustained for 6 months. In patients who did not achieve the treatment goal, 63% responded to diltiazem plus hydrochlorothiazide.No clinically significant postural hypotension was observed on any regimen. Heart rate was slightly lower with diltiazem than with hydrochlorothiazide. Adverse effects were minimal with diltiazem, hydrochlorothiazide and diltiazem plus hydrochlorothiazide but more hypokalemia occurred with hydrochlorothiazide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intravenous and intrapulmonary recombinant tissue-type plasminogen activator in the treatment of acute massive pulmonary embolism

Eight centers participated in a study in which intrapulmonary and intravenous administration of recombinant tissue-type plasminogen activator (rt-PA) were compared in 34 patients with acute massive pulmonary embolism. All patients received intravenous heparin in a bolus of 5,000 IU followed by 1,000 IU/hr. After 50 mg rt-PA given over 2 hr the severity of embolism, determined from pulmonary angiograms, declined by 12% in the intrapulmonary drug group (p less than .005) and 15% in the intravenous drug group (p less than .005); mean pulmonary arterial pressure fell from 31 +/- 7 to 22 +/- 6 mm Hg (p less than .005) and from 31 +/- 12 to 21 +/- 9 mm Hg (p less than .005) in the respective groups. After a further 50 mg given over 5 hr (22 patients), the angiographically determined severity of embolism had decreased by 38% from baseline in the intrapulmonary drug group and by 38% in the intravenous drug group. The mean pulmonary arterial pressure further declined to 18 +/- 7 and 12 +/- 5 mm Hg in the respective groups. Fibrinogen levels dropped to 48% of baseline after 50 mg and to 36% of baseline after 100 mg rt-PA. Some degree of bleeding at puncture and/or operation sites was noted in 16 patients, including four who required a transfusion of two or more units of blood and had been operated on an average of 7.5 days (range 2 to 13) before thrombolytic treatment was started.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of skin site on bioavailability of nitroglycerin ointment in congestive heart failure

Nitroglycerin ointment (12.5 to 50 mg) was administered in randomized fashion to three skin sites, arm, chest, or thigh, to compare the hemodynamic effects and bioavailability in nine patients with severe congestive heart failure. Hemodynamic parameters and arterial nitroglycerin concentrations were measured frequently for 12 hours after each application and for 90 minutes after removal of the ointment. During the study, left ventricular filling pressures decreased from control values of 25.0 +/- 8.6 mm Hg (arm), 25.7 +/- 10.9 mm Hg (chest), and 23.7 +/- 8.4 mm Hg (thigh) to 20.4 +/- 8.6 mm Hg, 20.4 +/- 8.5 mm Hg, and 20.0 +/- 7.5 mm Hg; p less than 0.05, less than 0.01, and difference not significant respectively. Peak nitroglycerin concentrations were 5.1 +/- 4.3 ng/ml (arm), 6.2 +/- 6.0 ng/ml (chest), and 4.1 +/- 6.3 ng/ml (thigh). No significant difference was observed in mean arterial pressure, left ventricular filling pressure, right atrial pressure, or nitroglycerin concentration among the sites. These data show that nitroglycerin ointment has similar bioavailability on the arm, chest, or thigh and therefore can be used interchangeably on these skin sites.