Effects of disopyramide on systemic and coronary hemodynamics and myocardial metabolism in patients with coronary artery disease: Comparison with lidocaine

In two groups, each comprising 10 patients with advanced coronary artery disease, disopyramide, 2 mg/kg over a period of 5 minutes, or lidocaine, 100 mg as a bolus dose, was injected intravenously. Disopyramide increased diastolic and mean arterial pressures significantly because of its vasoconstrictive properties. Cardiac index decreased from 3.7 ± 0.3 to 3.2 ±0.1 liters/min per m² at 10 minutes and to 3.1 ± 0.2 30 minutes after the injection was begun. After lidocaine no changes in hemodynamic variables were observed.Disopyramide revealed potent coronary constrictive activity, whereas lidocaine was a mild coronary vasodilator. Coronary blood flow increased significantly from 68.2 ± 4.3 ml/min × 100 g to 74.8 ± 4.1 directly after injection of 100 mg lidocaine and to 75.5 ± 5.0 25 to 30 minutes later. Disopyramide decreased coronary blood flow significantly from 73.8 ± 3.8 to 67.8 ± 2.7 ml/min × 100 mg during the 5 minute period after drug infusion. Coronary vascular resistance increased very significantly from 0.94 ± 0.1 to 1.14 ± 0.1 units. Because of an extreme increase in the arterial-coronary sinus oxygen difference, myocardial oxygen consumption (MVO₂) increased at the same time from 9.9 ± 0.6 to 10.6 ± 0.5 ml/min × 100 g. At 25 to 30 minutes after the start of the dlsopyramide infusion MVO₂ increased significantly to 11.9 ± 0.6 because the coronary blood flow increased to 79.1 ± 2.8. However, the arterial-coronary sinus oxygen difference remained significantly elevated and coronary vascular resistance declined only moderately. Myocardial lactate extraction did not change. Apparently a metabolism-induced dilatation in coronary vasculature actually overcomes the vasoconstriction by disopyramide and prevents serious myocardial ischemia, but a vasoconstrictive effect of disopyramide is still present. The potent coronary constrictive activity of intravenous disopyramide in the presence of increased myocardial oxygen need may be hazardous in specific clinical situations.     

Systemic versus intracoronary streptokinase infusion in the treatment of acute myocardial infarction

Clinically encouraging results can be obtained with an intravenous high dose short-time infusion of streptokinase in patients with evolving myocardial infarction. The feasibility and efficacy of the intracoronary and the systemic approach of streptokinase therapy in acute myocardial infarction are discussed in this report and include topics such as infarct artery recanalization success rate, coronary thrombus lysis time, benefit for patients with subtotal coronary occlusion, reocclusion rate, the necessity of additional surgical interventions, salvage of ischemic myocardium and side effects. The value of high dose intravenous short-time streptokinase infusion needs to be assessed with properly designed clinical trials against the background afforded by the results observed with direct intracoronary streptokinase infusion.     

Alpha-receptor restriction of coronary blood flow during atrial fibrillation

The effects of atrial fibrillation (AF) on coronary circulation before and after alpha-receptor blockade were studied in 14 anesthetized, open-chest dogs. AF was induced by electrical stimulation of the left atrial appendage; identical rhythmic heart rates were adjusted by left atrial pacing. During atrial pacing, coronary vascular resistance (CVR) was 0.97 +/- 0.10 mm Hg X min X 100 g/ml (resistance units [RU]), coronary blood flow (CBF) 125 +/- 14 ml/min X 100 g, and oxygen saturation 30 +/- 2%; plasma epinephrine was 193 +/- 42 pg/ml and norepinephrine 584 +/- 111 pg/ml. During AF, CVR was higher (1.16 +/- 0.11 RU, p less than 0.0005), whereas CBF (92 +/- 9 ml/min X 100 g, p less than 0.001) and coronary sinus oxygen saturation (24 +/- 2%, p less than 0.0025) were lower than during atrial pacing. When AF was induced, epinephrine increased to 333 +/- 98 pg/ml (p less than 0.05) and norepinephrine to 1,005 +/- 214 pg/ml (p less than 0.005). The large increase in plasma catecholamines suggested an activation of the sympathoadrenal system during AF. In addition, the alpha-receptor blocker phenoxybenzamine (10 mg/kg, intravenously) abolished the differences in CVR, CBF and oxygen saturation between AF and atrial pacing. The data suggest that the decrease in CBF and increase in CVR during experimentally induced AF are caused by coronary vasoconstriction, mediated by sympathetic activation of alpha receptors in the coronary vascular bed.     

Review of major intervention studies in hypertension and hyperlipidemia: Focus on coronary heart disease

The ultimate aim in treating hypertension and hyperlipidemia is to reduce cardiovascular mortality and morbidity, especially strokes and coronary events, for example, fatal and nonfatal myocardial infarction and sudden death. Extensive intervention studies in moderate-to-severe hypertension have revealed the significance of antihypertensive therapy in reducing total cardiovascular mortality and morbidity, particularly from cerebrovascular causes. However, the reduction of coronary events has not been equally successful. The situation in mild-to-moderate hypertension is even more disappointing: recent studies, such as the Medical Research Council hypertension trial, the International Prospective Primary Prevention Study in Hypertension, and the Heart Attack Primary Prevention in Hypertensives trial could not demonstrate any benefit from antihypertensive treatment with β-blockers or diuretics in the prevention of coronary heart disease. The reasons for these negative results are not obvious. However, metabolic side effects associated with certain antihypertensive drugs, which counteract the beneficial effects of blood pressure reduction, are one topic of discussion. For the genesis of atherosclerosis of the coronary vasculature, hyperlipoproteinemia appears to be of greater importance than hypertension and has to be treated simultaneously. Two extensive intervention studies, the Lipid Research Clinics coronary primary prevention trial and the Helsinki Heart Study, showed a significant reduction of coronary events with lipid-lowering treatments with cholestyramine and gemfibrozil, respectively. These findings are in agreement with the results of a recent secondary prevention study, which showed a regression of atherosclerosis in coronary arteries and aortocoronary bypass grafts. Moreover, antihypertensive treatment aimed at a reduction in coronary heart disease has to focus on serum lipids, especially in mild hypertension. Blood pressure reduction disregarding hyperlipidemia and other coronary risk factors seems to be inadequate.     

Prevalence of late potentials in patients with and without ventricular tachycardia: Correlation with angiographic findings

Late potentials occurring at the end of or after the QRS complex were searched for from the body surface using high gain amplification and signal averaging techniques with filter settings between 100 and 300 hertz. The number of repetitions of the averaging process ranged between 150 and 300. Two hundred thirty-six patients were studied. In 27 control subjects, no late potentials were recorded. Among 146 patients without ventricular tachycardia or fibrillation, late potentials were present in 49 (34 percent). The mean duration of late potentials was 31 ± 15.3 ms (median 25). Of 63 patients with documented ventricular tachycardia or fibrillation, 45 (71 percent) had late potentials (mean duration 51 ± 31.5 ms; median 50) (probability [p] < 0.001). There was a close correlation between the detection of late potentials and left ventricular function. Late potentials occurred more frequently in patients with than in those without ventricular akinesia or aneurysm and in patients with than in those without ventricular tachycardia or fibrillation.

In conclusion, late potentials are a frequent finding in patients with regional contraction abnormalities, both in patients with and in those without documented ventricular tachycardia. The greater prevalence and longer duration of these signals in patients with ventricular tachycardia or fibrillation might be responsible for the greater susceptibility to ventricular tachycardia. Long-term follow-up studies will be necessary to assess the possible prognostic significance of late potentials in patients without previously documented ventricular tachycardia or fibrillation.     

Renin and aldosterone secretion in pheochromocytoma. Effect of chronic alpha-adrenergic receptor blockade.

Patients suffering from pheochromocytoma characterized by an exclusive or almost exclusive excess of norepinephrine showed no (one patient) or only a moderate increase (two patients) in renin and aldosterone secretion. In those three patients with concomitant distinct hypersecretion of epinephrine, renin release (and aldosterone secretion except in one patient) was markedly enhanced. Similar results were obtained in a patient with excess norepinephrine and dopamine secretion. Renin release was markedly reduced in all patients during preoperative long-term alpha-adrenergic receptor blockade. With the exception of one patient, increased renin and aldosterone secretion was abolished. The results indicate that augmentation in renin release depends on the ratio of the different catecholamines secreted by the pheochromocytoma and their different effe-tiveness in stimulating beta-adrenergic receptors. Even in the presence of excess catecholamine secretion, there is evidence that renin secretion is predominantly mediated by beta receptors rather than by renal vascular alpha-adrenergic receptors. Normalization of catecholamine-induced enhanced renin release in patients with pheochromocytoma during chronic alpha-adrenergic receptor blockade supports the assumption that (alpha-) adrenergic blocking agents inhibit renin secretion distal to their blockade of specific adrenergic receptors. However, contrary to beta-adrenergic blockade, circadian rhythm of renin release seems to remain intact during alpha-adrenergic blockade.     

Electrophysiologic effects of lorcainide on the accessory pathway in the Wolff-Parkinson-White syndrome

The electrophysiologic effects of lorcainide, a class I antiarrhythmic agent with local anesthetic properties, were studied in 20 patients with the Wolff-Parkinson-White syndrome. After intravenous administration of lorcainide (2 mg/kg), the sinus cycle length decreased in all patients from 705 ± 117 to 636 ± 94 ms (p < 0.001). The atrioventricular conduction time lengthened from 84 ± 22 to 94 ± 22 ms (p < 3.01) and the QRS duration increased from 92 ± 19 to 120 ± 29 ms (p < 0.001). The effective refractory period of the atrium increased from 230 ± 27 to 243 ± 35 ms (p < 0.05), whereas the ventricular refractoriness was unaffected. Retrograde conduction over the accessory pathway was blocked in 5 of 18 patients after lorcainide; in the remaining 13 patients a prolongation from 107 ± 32 to 162 ± 57 ms (p < 0.001) was found. Anterograde conduction over the accessory pathway was blocked in 6 patients, and in all other patients it increased considerably. Circus movement tachycardia could be induced in 14 patients before and in 10 patients after the drug. The shortest R-R interval during tachycardia lengthened from 326 ± 40 to 364 ± 67 ms (p < 0.05). The tachycardia zone was unaffected by lorcainide. In 15 patients atrial fibrillation was induced. After lorcainide anterograde conduction during atrial fibrillation was blocked (n = 5). The shortest R-R interval over the accessory pathway during induced atrial fibrillation increased from 228 ± 35 to 304 ± 103 ms (p < 0.05). Intravenous administration of lorcainide produced a pronounced negative dromotropic effect on the conduction properties of the accessory pathway. Lorcainide appears to be a promising new antiarrhythmic agent in patients with the Wolff-Parkinson-White syndrome.     

Intracoronary thrombolysis in acute myocardial infarction: An attempt to quantitate its effect by comparison of enzymatic estimate of myocardial necrosis with left ventricular ejection fraction

The quantity of myocardium was estimated that can be salvaged by reperfusion of acute transmural myocardial infarction (MI). Serial analysis of serum creatine kinase (CK) activity was carried out in 41 consecutive patients with acute MI who underwent intracoronary thrombolysis. Enzymatic estimate of MI size was calculated using an average (method A) and an individually determined elimination constant (method B). Left ventricular ejection fraction 4 weeks after successful thrombolysis (cineangiogram) correlated inversely with MI size (method A: r = −0.85, method B: r = -0.76; both p < 0.001). Patients with recanalization within 4 hours after the onset of symptoms were assembled in group A₁ (n = 13, early reperfusion), and patients with successful recanalization after 4 hours in group A₂ (n = 16, late reperfusion). Group B consisted of 12 patients without reperfusion. MI size in group A₁ was 21 CK-g-Eq (method A) and 23 CK-g-Eq (method B), in group A₂ 50 CK-g-Eq (method A) and 54 CK-g-Eq (method B), and in group B 73 CK-g-Eq (method A) and 63 CK-g-Eq (method B). Mean values in group A₁ were lower than in group A₂ and group B (p < 0.05). It is concluded that MI size was significantly reduced to about one third after early reperfusion as compared with no reperfusion. In contrast, MI size was not significantly reduced after late reperfusion.     

Onset and reversibility of changes in secretory function and composition of isolated rat pancreatic islets following long-term administration of high or low tolbutamide doses

Chronic administration of a high tolbutamide dose to rats induces islet hypertrophy associated with a decreased insulin content per islet and with a diminished insulin release in response to a glucose or leucine stimulus. These changes are reversible after discontinuation of tolbutamide. Chronic administration of a low tolbutamide dose (effective dose 30%) has no effect on islet size, on insulin content per islet, or on leucine-induced insulin release. In contrast, the glucose-induced insulin release is impaired. However, glucose-induced insulin release is normal in the presence of glucagon (5 μg/ml) or theophylline (5 mM). Since islet hypertrophy occurs following admin-istration of high tolbutamide doses only and is associated with hypofunction rather than with hyperfunction, it seems hardly conceivable that the therapeutic principle of tolbutamide is based on a beta-cytotrophic effect. B-cell hypofunction seems to be due to at least three factors: the decrease in the insulin content per islet, an impairment in secretory signal recognition, and an interference with the process of signal transmission.     

Prevalence and clinical significance of the repetitive ventricular response during sinus rhythm in coronary disease patients

The prevalence of the repetitive ventricular response (RVR) after single and double premature stimulation during sinus rhythm or a paced supraventricular rhythm at a rate of 85 bpm was assessed in 343 patients (group 1: 237 patients studied prospectively who were referred for coronary arteriography and ventriculography; group 2: 44 patients after recent acute myocardial infarction; group 3: 61 patients with documented ventricular tachycardia and/or fibrillation). In group 1 patients, RVR testing was performed from both the right ventricular apex (n = 237) and outflow tract (n = 190), whereas in the remaining patients only the apex was stimulated. In group 1, RVR after a single premature stimulus occurred in 21.9% and after two stimuli in 63.2%. In patients with normal left ventricular (LV) function (n = 63) the prevalence of RVR after a single stimulus was significantly less (9.5%) than in those with LV dysfunction (n = 174;26.4%,p < 0.01). However, after double stimulation, there was no longer any difference. In group 2, the prevalence of RVR was 25% after one and 34.1% after two premature stimuli. In group 3 patients, RVR was observed in only 14.8% after one and in 41% of patients after two premature stimuli. Ventricular tachycardia (≥ 10 QRS) was induced in nine patients during a supraventricular rhythm. Two hundred thirty-seven patients of group 1, who were prospectively studied in order to assess the prognostic significance of the RVR, were followed for a mean period of 27.2 ± 10.7 months. No prognostic significance of the RVR could be shown in this group of patients, 160 of whom had chronic coronary artery disease. In conclusion, premature ventricular stimulation during sinus rhythm with the use of single and double stimuli was not able to provide a clinically useful differentiation between various groups of patients. It had no predictive value for the dentification of patients prone to sudden death or ventricular tachycardia in patients with chronic coronary artery disease.     

Effects of antihypertensives on plasma lipids and lipoprotein metabolism

There is good epidemiologic evidence that hypertension is associated with a high risk of cardiovascular disease. However, primary intervention trials have failed to demonstrate that a reduction in blood pressure in hypertensive patients reduces morbidity and mortality from cardiac events. Since various antihypertensive drugs adversely affect lipoprotein metabolism, these drugs may increase associated coronary risk and offset the beneficial effects of lowering blood pressure. This article reviews the effects of various antihypertensive drugs on plasma lipids, lipoproteins, and apolipoproteins. They can be summarized as follows: thiazide-type diuretics cause a marked elevation of plasma triglycerides and very low-density lipoprotein (VLDL) and minor increases in total cholesterol and low-density lipoprotein (LDL), but have little effects on high-density lipoprotein (HDL). The nonselective β-blockers do not significantly affect total cholesterol and LDL, but increase total triglycerides and VLDL and decrease HDL. The changes in plasma lipids and lipoproteins caused by cardioselective β-blockers and β-blockers with intrinsic sympathomimetic activity are qualitatively similar but less pronounced. Calcium antagonists and angiotensin-converting enzyme inhibitors appear to have no significant effects on plasma lipids. α₁-inhibitors reduce total triglycerides, total cholesterol, VLDL, and LDL and increase HDL. The possible mechanisms by which antihypertensive drugs affect cellular lipid metabolism (e.g., LDL receptor, lipid synthesis, lipoprotein lipase, lecithin cholesteryl acyltransferase, acylcholesteryl acyltransferase, and cholesteryl ester hydrolase) are described. The clinical significance of changes in blood lipids and cellular lipid metabolism caused by antihypertensive drugs is not yet totally clear. Nevertheless, before antihypertensive drug treatment is initiated, blood lipid levels should be measured to identify preexisting hyperlipidemia. Blood lipoprotein levels should be monitored during long-term antihypertensive therapy to reconsider the therapeutic regimen if adverse lipid changes are observed.     

Coronary dilatory capacity in idiopathic dilated cardiomyopathy: Analysis of 16 patients

Hemodynamic function and overall coronary blood flow (argon technique) were measured in 16 patients with idiopathic dilated cardiomyopathy (IDC) and in 12 patients without detectable heart disease (control subjects) referred for precordial pain. In patients with IDC, coronary blood flow was normal at rest (78 ± 17 ml/100 g·min versus 78 ± 9 in control subjects). During maximal inducible coronary vasodilation (dipyridamole, 0.5 mg/kg), coronary blood flow was significantly reduced (142 ± 38 ml/100 g · min versus 301 ± 64 in control subjects; p < 0.001). Consequently, obtainable minimal coronary resistance was increased in IDC (0.54 ± 0.20 mm Hg/ml/100 g · min versus 0.23 ± 0.04 in control subjects; p < 0.001). In patients with IDC, left ventricular (LV) end-diastolic pressure was significantly increased (19 ± 11 mm Hg versus 6 ± 3 in control subjects; p < 0.005), and the LV ejection fraction was diminished (36 ± 11% versus 72 ± 3% in control subjects; p < 0.001). In patients with IDC, LV end-diastolic pressure correlated significantly with the obtained minimal coronary resistance after application of dipyridamole (r = 0.85; p < 0.001). LV catheter biopsy specimens revealed no alterations in myocardial microvasculature. Thus, coronary dilatory capacity is impaired in patients with IDC, due partially to an increase in extravascular component of coronary resistance.     

Diagnosis of increased pulmonary blood flow by suprasternal M-mode echocardiography in atrial septal defect

The right pulmonary artery (PA) was quantitatively assessed by Suprasternal M-mode echocardiography in 25 patients in whom an atrial septal defect (ASD) was suspected clinically. In 10 patients an ASD was excluded (Group 1) and in 15 it was confirmed (Group 2). The smallest diameter of the right PA at end-diastole in Group 1 was 8.8 ± 1.5 mm/m² body surface area and in Group 2 14.8 ± 3.6 mm/m² (p < 0.001). The greatest diameter of the right PA during systole was also much smaller in Group 1 (11.3 ± 1.2 mm/m²) than in Group 2 (17.7 ± 3.5 mm/m²) (p < 0.001). The absolute and percent systolic expansion of the right PA did not differ in the 2 groups (2.7 ± 0.5 mm [29.1 ± 10.8%] in Group 1 and 2.9 ± 0.8 mm [20.8 ± 9.8%] in Group 2). No correlation was found between measured and derived echocardiographic variables of the right PA and the magnitude of the left-to-right shunt. Patients in Group 2, who had an additional pressure elevation in the PA, showed, on average, a larger right PA and a smaller percent systolic expansion. The study demonstrates characteristic alterations in the wall motion pattern of the right PA in patients with ASD, indicating increased pulmonary blood flow.     

Immune reactions in tuberculous and chronic constrictive pericarditis: Clinical data and diagnostic significance of antimyocardial antibodies

Humoral immune reactions were analyzed in 12 patients with exudative tuberculous pericarditis, 10 patients with constrictive pericarditis due to former tuberculosis, 10 patients with viral pericarditis, 20 patients with pulmonary tuberculosis and 98 healthy donors. Pericarditis occurred in 12.5% of the patients with tuberculosis, whereas the incidence of tuberculosis in the 149 patients with pericarditis was 8%. Repeated pericardial puncture and pericardial effusions of greater than 500 ml with impending cardiac tamponade had to be performed in 4 patients. Clinical data indicated probable myocardial involvement in 4 of 12 patients.Antimyolemmal antibodies, which are a muscle-specific subtype of antisarcolemmal antibodies, were found in all patients with exudative tuberculous pericarditis and viral perimyocarditis, in only 1 of 12 patients with constrictive pericarditis and in no patient with pulmonary tuberculosis. Antifibrillary antibodies—primarily of the antimyosin type—were missed in patients with viral heart disease but were demonstrated in 75% of patients with tuberculous pericarditis.Only sera with complement-fixing antimyolemmal antibodies of the IgG type in liters greater than 1:40 induced cytolysis of vital adult heterologous cardiocytes isolated and enriched by silica sol gradient centrifugation. These findings suggest not only that antimyolemmal antibodies are diagnostic indicators of perimyocardial involvement in tuberculous pericarditis, but also that they may play a significant role in its pathogenesis.     

Effect of sublingually administered nitroglycerin on regional myocardial blood flow in patients with coronary artery disease.

The effect of sublingually administered nitroglycerin on regional myocardial specific blood flow (in ml/min per 100 g tissue) was evaluated with a xenon-133 washout technique in 31 patients in a resting nonstressed state. Eight patients had normal coronary arteriograms (Group 1), 12 had coronary artery disease without collateral vessels (Group 2) and 11 had coronary artery disease with collateral vessels (Group 3). Although nitroglycerin caused a similar decrease in mean arterial blood pressure and blood pressure-heart rate product in all three groups, the decrease in regional myocardial blood flow was significantly less in Group 3 (-8+/-6% [mean+/-standard error of the mean]) than in Group 1 (-31+/-5%), P less than 0.05); an intermediary decrease occurred in Group 2 (-23+/-5%). Within Group 3, there was a mean increase in regional myocardial blood flow after nitroglycerin in the five patients whose collateral vessels were of a higher angiographic grade and arose from non-stenosed coronary arteries, whereas a reduction was observed in the six patients with none or only one of these findings (+10+/-7% versus -23+/-3%, P less than 0.001). This study suggests that even in the resting state, in some patients with coronary artery disease enhancement of regional myocardial blood flow can occur after sublingual administration of nitroglycerin and is probably mediated through well functioning collateral vessels. It is possible that the drug's effects on both the coronary and systemic circulation may relieve angina in some patients with coronary artery disease.     

Influence of insulin on blood levels of branched chain keto and amino acids in man

Branched chain keto acids, their corresponding amino acids, glucose, glucagon, growth hormone, C-peptide and gastric inhibitory polypeptide were determined in 8 healthy subjects after an intravenous bolus injection of 0.1 U/kg insulin. Branched chain keto acids declined within 60 min, the corresponding amino acids within 20 min or later. Amino acids tended to return towards normal earlier than their keto acids. Blood glucose levels were normal 2 hr after insulin injection while keto and amino acids remained diminished for more than 3 hr. In 8 healthy controls, given physiological saline instead of insulin, the branched chain keto acids did not decline throughout the test. It is suggested that insulin diminishes blood levels of branched chain keto acids, that the intraorgan flux of branched chain keto acids is different from the flux of branched chain amino acids and that branched chain keto acids may serve to correct for hypoglycemia.     

Alpha and beta adrenergic blockade with orally administered labetalol in hypertension. Studies on blood volume, plasma renin and aldosterone and catecholamine excretion.

Patients with essential hypertension were treated for 6 weeks with the alpha and beta adrenoceptor blocking agent labetalol alone (no. = 18) or in combination with the diuretic agent chlorthalidone (no. = 11). Maximal doses of labetalol during these trials averaged 1,460 and 650 mg/day, respectively. Significant (P < 0.05) changes during therapy with labetalol alone included a transient decrease in supine blood pressure reaching a maximum of 11 percent, persistent reduction in upright blood pressure, pulse rate (20 percent) and plasma renin activity (40 percent), a gain of 1.7 percent in body weight and of 17 percent in blood volume, a sevenfold rise in epinephrine excretion rate and a mild increase in plasma potassium; plasma aldosterone and norepinephrine excretion rate remained unaltered. After 6 weeks of combination therapy, blood pressure reduction was greater (P < 0.02) than after labetalol alone in both the supine (14.4 versus 4.3 percent) and upright (18.6 versus 11.6 percent) positions; blood volume and plasma potassium were decreased (P < 0.05), plasma renin was doubled (P < 0.02) and plasma aldosterone was unchanged. Orthostatic hypotension and several other side effects were common with large doses of labetalol but infrequent at doses used during combination therapy; moreover, these effects were often transient. These data indicate that combined alpha and beta adrenoceptor blockade with labetalol may effectively reduce blood pressure in patients with essential hypertension, with a somewhat more pronounced effect in the upright position. Extracell fluid retention may reduce the sensitivity of supine blood pressure to treatment, but this effect is avoided with concomitant diuretic therapy. Labetalol's antihypertensive action appears to be renin-independent and is associated with a marked increase in epinephrine excretion.