Mechanism of antihypertensive effect of thiazide diuretics

Hemodynamic studies were carried out before and during 8 weeks of treatment with hydrochlorothiazide 50 mg. twice daily in 11 hypertensive patients. Forty-eight hours after beginning treatment there was a significant reduction in blood pressure, cardiac output, plasma volume, and extracellular fluid volume (thiocyanate space) while total peripheral resistance increased. After 6 and 8 weeks of treatment, the blood pressure and the plasma and extracellular volumes remained reduced. However, total peripheral resistance fell while cardiac output rose to control levels. These results were consistent with the “reverse autoregulation” theory of the action of the thiazides as proposed by Tobian. The present findings as well as other clinical and experimental evidence discussed below makes it appear unlikely that the thiazides have an important direct vasodilator effect.     

Inotropic properties of an isoquinoline derivative (NC 7197) in man

An isoquinoline derivative (NC 7197) was administered intravenously in a dose of 0.2 to 1.0 mg. per kilogram of body weight in four normal subjects and in 18 patients with shock or heart failure. An increase in cardiac output averaging 45 per cent in the normal subjects and 47 per cent in the patients was sustained for at least two hours. Heart rate was only slightly increased and stroke volume consistently rose. Arterial pressure was unchanged in normals but rose in the patients, although peripheral vascular resistance usually fell. Forearm blood flow rose only with the higher doses but renal and hepatic flow rose in the two patients studied. Norepinephrine-induced forearm vasoconstriction was not blocked during intra-arterial administration of NC 7197. Infusion into the left circumflex coronary artery of dogs led to a localized increase in myocardial contractility which was blocked by propranolol or pretreatment with reserpine. These data indicate that NC 7197 is a potent inotropic drug of prolonged duration of action which acts through an adrenergic mechanism and may be useful in the treatment of low output states.     

Day-to-day variation of the Frank electrocardiogram and vectorcardiogram in heart disease

Day-to-day variation of the Frank electrocardiogram and vectorcardiogram was studied in 20 patients with clinically stable hypertensive and/or coronary heart disease. Ten recordings were made on each patient during two consecutive five-day periods separated by a two-day weekend. Fifty-four selected measurements including durations, amplitudes, amplitude ratios, spatial magnitudes, and angles were computed on each of the records. Mean and maximal day-to-day variations of these measurements were compared with variations observed in 20 normal subjects reported in a previous study.Although considerable repeat variability was observed for several parameters, the magnitude of variability was not significantly different from that in normal subjects. However, abrupt and marked change in the electrocardiographic pattern seen in two patients suggests that sudden alterations in conduction may be common in patients with heart disease.The data presented can be helpful in assessing the significance of variations observed in serial electrocardiography in clinical practice.     

Leukocyte intracellular cations in hypertension: Effect of antihypertensive drugs

Leukocyte (WBC) cations were determined in 32 normotensive control subjects and in 47 agematched patients with uncomplicated hypertension. The intracellular concentration of sodium (Na⁺) which averaged 25.5 mEq./Kg. wet cell weight (wcw) in the hypertensive patients was significantly higher (P <.01) than in the control subjects (average 19.7 mEq./Kg. wcw). Elevated WBC Na⁺ was observed only in the hypertensive patients under age 50 years. WBC potassium, magnesium, and percentage water content were not significantly different in hypertensive patients as compared to the control subjects. The finding of an increased intracellular Na⁺ content in hypertensive patients is consistent with recent observations relating the extracellular/intracellular Na⁺ gradient to vascular smooth muscle tension and to the control of the peripheral vascular resistance.WBC cations also were determined after treatment with hydrochlorothiazide, hydralazine, reserpine, or alpha methyldopa. Hydrochlorothiazide was associated with a reduction in WBC sodium content (P < .01). Reserpine also was associated with a lesser fall in WBC sodium (P < .05). Cell water content decreased slightly after hydrochlorothiazide (P < .05), but increased slightly following reserpine (P < .05). Changes in WBC, sodium, or water were not significant following alpha methyldopa or hydralazine. None of the drugs were associated with changes in WBC potassium or magnesium, although serum potassium concentration decreased significantly (P < .05) with hydrochlorothiazide.     

Minoxidil in severe hypertension with renal failure. Effect of its addition to conventional antihypertensive drugs

Minoxidil, a new vasodilator antihypertensive compound, was given to 9 uremic patients with severe hypertension uncontrollable with currently available drugs. Addition of minoxidil in doses of 5 to 10 mg twice daily to their prior therapy, resulted in satisfactory control of blood pressure in all patients. Supine blood pressure fell from a control value of 200 ± 6/124 ± 3 to 164 ± 5/91 ± 2 mm Hg (mean and standard error) after administration of minoxidil, and no patient experienced orthostatic hypotension. Tachyphylaxis has not been seen during a follow-up period averaging 26 weeks. Side effects resulting from minoxidil have been limited to mild hypertrichosis in 2 patients, nausea in another 2 and fluid retention, which was readily controlled by either hemodialysis or furosemide. Minoxidil appears, therefore, to provide a means for controlling blood pressure in patients with severe hypertension resistant to all other antihypertensive drugs.     

Computer analysis of the orthogonal electrocardiogram and vectorcardiogram in 939 cases with hypertensive cardiovascular disease

Orthogonal ECG's (Frank system) were recorded from 939 male patients with hypertensive cardiovascular disease (HCVD) and were compared with records from 229 normal subjects, matched for age, race, and sex. The hypertensive subjects were divided into three clinical groups: (1) patients without cardiac enlargement by chest x-ray and no history of congestive heart failure (CHF), (2) patients with cardiac enlargement but without past or present CHF, and (3) patients with cardiac enlargement and one or more episodes of CHF. A sustained blood pressure level of $\text{150}\text{90}\text{mm. Hg}$ or more was present in all cases.First an attempt was made to identify optimal scalar and vectorial ECG measurements for discriminating between HCVD and normal, testing a total of 333 variables. With four scalar measurements at a specificity level of 95 per cent, 24 per cent of Group 1, 37 per cent of Group 2, and 44 per cent of Group 3 could be correctly classified. Vector measurements were found mostly redundant.Using linear discriminant function analysis and a likelihood ratio test with 13 different ECG variables at a level of specificity of 95 per cent, it was possible to identify correctly 53 per cent, 75 per cent, and 87 per cent of Groups 1, 2, and 3, respectively.Comparison of results with other reports on ECG changes caused by left ventricular overload (LVO) suggested that the degree of LVO in HCVD, even in the most advanced Group 3, was considerably less than that reported in patients with valvular heart disease with the only exception of terminal cases with HCVD who had come to autopsy. Antihypertensive therapy was considered as one factor which might have contributed to this finding.Multivariate ECG analysis was found an efficient means for diagnostic classification, leading to results which equalled those reported for multiple dipole analysis. As compared to scalar or vector measurements, either used individually or in combination, the multivariate technique exceeded all of these methods for LVO diagnosis by a wide margin when specificity was kept at a constant level.     

Predominant right ventricular dysfunction after right ventricular destruction in the dog

Right and left ventricular function was assessed by observing the response to rapid blood volume expansion before and after extensive cauterization of the right ventricle in open chest dogs. In the control period, left ventricular end-diastolic pressure surpassed right ventricular end-diastolic pressure by an average of 11.5 mm Hg after volume expansion whereas, after destruction of the right ventricle, pressure in this chamber surpassed pressure in the left ventricle by an average of 4 mm Hg. In contrast, after left ventricular damage, left ventricular end-diastolic pressure averaged 25 mm Hg more than right ventricular end-diastolic pressure. Despite extensive damage to the right ventricular free wall, the right ventricle continued to generate a near normal pressure and aortic flow could be increased above control levels by volume expansion. We conclude that, in contrast to previous evidence, damage to the right ventricle produces a syndrome of predominant right ventricular dysfunction. However, cauterization of the entire free wall of the right ventricle does not reproduce the more profound right ventricular dysfunction noted in infarction of the right ventricle in man.     

Percutaneous myocardial and pericardial biopsy with the Menghini needle

A simple, safe method of obtaining myocardial or pericardial tissue for analysis by light or electron microscopy or for culture has obvious application. The Menghini needle has been demonstrated to be a safe and effective instrument for the aspiration biopsy of liver and kidney. Therefore, application of aspiration biopsy with a 17 gauge Menghini needle to the heart by means of the left ventricular apical percutaneous approach has been evaluated in humans in 27 myocardial and 8 pericardial biopsies. Adequate tissue was obtained in all except one pericardial and two myocardial biopsy attempts. Of the eight pericardial biopsies, the diagnosis of tuberculous pericarditis was made in two cases and carcinomatous invasion of the pericardium was made in another two cases. Three cases showed nonspecific pericarditis. Of the 27 myocardial biopsies, 6 were examined by light microscopy and 21 were examined by electron microscopy. Light microscopy revealed no specific findings. However, electron microscopy showed moderate to severe intracellular abnormalities, the significance of which remains to be determined. Biopsy procedure takes 5 minutes or less under local anesthesia following mild premedication. Pneumothorax occurred in two patients and transient mild pleuritic chest pain occurred in four patients. Both complications were well tolerated. The technique seems effective and safe. Its utility and application remain to be determined.     

Right ventricular infarction. Clinical and hemodynamic features

Six patients with acute myocardial infarction presented with hemodynamic evidence of predominant right ventricular failure, characterized by a mean right atrial pressure averaging 20.2 mm Hg and left ventricular filling pressure averaging 16.3 mm Hg. Autopsy in two cases revealed extensive involvement of the right as well as the left ventricle. Clinically the patients usually had evidence of diaphragmatic wall infarction, distended neck veins, hypotension and heart block. Pressure contours and mean pressure often showed no significant change as the catheter was advanced from the right atrium to the pulmonary artery. Shock in three patients was effectively treated with plasma volume expansion, to increase further right-sided pressure, or the administration of sodium nitroprusside, to reduce left-sided filling pressure. It is suggested that when right ventricular infarction accompanies left ventricular infarction, a unique clinical and hemodynamic syndrome occurs because the ability of the right ventricle to maintain adequate left ventricular filling is impaired. Recognition of this syndrome is vital if appropriate therapy is to be instituted.     

Evaluation of frontal plane QRS loop rotation in vectorcardiographic diagnosis

The diagnostic usefulness of frontal plane QRS loop rotation in the Frank vectorcardiogram (VCG) was evaluated in a series of 598 normal subjects, 301 patients with postero-diaphragmatic myocardial infarction (PDMI), 84 with lateral myocardial infarction (LMI), 844 with left ventricular hypertrophy (LVH), and 190 with right ventricular hypertrophy (RVH). In normals 62% showed clockwise (CW) rotation of the QRS loops; 28%, figure-of-eight; and 10%, counterclockwise (CCW). The respective distributions were 68%, 23%, and 9% in PDMI; and 23%, 40%, and 37% in LMI. In normals the superior and inferior limits (96% range) of the maximal QRS vector angles were +15° and +79° in VCGs with CW rotation, +12° and +62° in VCGs with figure-of-eight, and −4° and +58° in VCGs with CCW rotation. Based on these limits, approximately half of PDMI cases (with 2% false positives) and a little over two-thirds of LMI cases (with 4% false positives) could be separated from normal. In LVH and RVH groups without clinical evidence of ischemic heart disease, the superior and inferior limits (96% range) of the maximal QRS vector angles differed from those of normal. In LVH such limits were +1° and +86° in VCGs with CW rotation, +12° and +62° in VCGs with figure-of-eight, and −86° and +48° in VCGs with CCW rotation. The respective limits in RVH were +13° and −160°, −3° and +76°, and −30° and +65°. Thus, when LVH or RVH is present, the foregoing limits separating PDMI or LMI from normal need to be modified accordingly.Results of the study demonstrate the diagnostic significance of QRS rotation analysis in the frontal plane VCG. These findings should prove useful as the standard of reference for clinical interpretation of the Frank VCG.     

Left ventricular relaxation,mitral valve prolapse,and intracardiac conduction in myotonia atrophica: Assessment by digitized echocardiography and noninvasive His bundle recording

Myotonia atrophica, a neuromuscular disease marked by autosomal dominant transmission and delayed relaxation of skeletal muscle, has been associated with cardiac failure, conduction abnormality, and mitral prolapse (MVP). In order to determine the relaxation rate of cardiac muscle, left ventricular (LV) size and function, and the presence of MVP, 30 patients with myotonia atrophica were studied using digitized M-mode echocardiography (MME). Intracardiac conduction intervals were determined by noninvasive His bundle recording (HBR) from surface electrodes using a high-resolution, R-wave triggered, signal averaging computer. Neurologically unaffected first-degree relatives of the patients with myotonia atropica were also studied to determine if cardiac abnormalities may be present in the absence of neurologic manifestations of the disease. Peak normalized diastolic endocardial velocity in patients with myotonia atrophica (3.7 ± 0.8 sec^?1) did not differ from unaffected first-degree relatives (3.8 ± 0.8 sec^?1) or normal subjects (3.6 ± 0.8 sec^?1). Systolic LV function and LV dimensions on MME were normal in both groups. However, MVP was present in 7 or 24 (29%) of patients who could be evaluated, but not in unaffected first-degree relatives. Despite normal LV systolic and diastolic function, infranodal intracardiac conduction was prolonged in patients with myotonia atrophica (average HV interval 50 ± 5 SD msec) but not in neurologically unaffected relatives (average HV interval 40 ± 5 msec). Delay in proximal intracardiac conduction was also found in patients with myotonia atrophica (average PH interval 140 ± 20 msec) but not in neurologically unaffected relatives (average PH interval 115 ± 6 msec). Hence cardiac findings in myotonia atrophica include proximal and distal conduction delay by external HBR even in the absence of abnormality of the standard 12-lead ECG. There may also be an increased frequency of MVP; however, early diastolic relaxation of the LV is unimpaired, and cardiac manifestations of myotonia are not transmitted independently of neurologic abnormality.     

Clinical application of a second generation electrocardiographic computer program

An electrocardiographic computer program based on multivariate analysis of orthogonal leads (Frank) was applied to records transmitted daily by telephone from the Veterans Administration Hospital, West Roxbury, Mass., to the Veterans Administration Hospital, Washington, D.C. A Bayesian classification procedure was used to compute probabilities for all diagnostic categories that might be encountered in a given record. Computer results were compared with interpretations of conventional 12 lead tracings. Of 1,663 records transmitted, 1,192 were selected for the study because the clinical diagnosis in these cases could be firmly established on the basis of independent, nonelectrocardiographic information. Twenty-one percent of the records were obtained from patients without evidence of cardiac disease and 79 percent from patients with various cardiovascular illnesses. Diagnostic electrocardiographic classifications were considered correct when in agreement with documented clinical diagnoses. Of the total sample of 1,192 recordings, 86 percent were classified correctly by computer as compared with 68 percent by conventional 12 lead electrocardiographic analysis. Improvement in diagnostic recognition by computer was most striking in patients with hypertensive cardiovascular disease or chronic obstructive lung disease. The multivariate classification scheme functioned most efficiently when a problem-oriented approach to diagnosis was simulated. This was accomplished by a simple method of adjusting prior probabilities according to the diagnostic problem under consideration.     

Blood pressure and cardiac performance

The factors which control the performance of the left ventricle include the determinants of myocardial function (preload, afterload, contractility and heart rate) and peripheral vascular function (capacitance and impedance). Arterial pressure represents an interaction of myocardial and vascular factors. When left ventricular function becomes impaired, impedance to left ventricular ejection becomes increasingly important in determining cardiac performance. Increases in impedance may result from the influence on arteries of neural, humoral or structural changes which can occur in response to a fall in cardiac output or an impairment of cardiac reserve. This increased impedance may further reduce cardiac output while myocardial oxygen consumption is increased. Alterations in the peripheral vascular bed therefore probably play an important role in the hemodynamic and metabolic events which usually are attributed to progressive impairment of the heart. Pharmacologie reduction of impedance with vasodilator drugs could become an important adjunct in the management of heart failure of diverse etiologies.     

Methionine metabolism in mammals: the biochemical basis for homocystinuria

Three genetic disorders result in “homo-cystinuria”. Of these, cystathionine synthase deficiency is the most common. Impairment of N⁵-methyltetrahydrofolate-homocysteine methyltransferase, due to either deficient coenzyme synthesis (derangement of B₁₂ metabolism) or to reduced substrate availability (methylenetetrahydrofolate reductase deficiency), is the basis for the other two forms. Analyses of the pathobiochemistry caused by these defects is essential for the development of rational and appropriate therapy. Such studies have the additional benefit of illuminating the pattern of methionine metabolism in the normal human.     

Marrow granulocyte reserves in black Americans. Hydrocortisone-induced granulocytosis in the "benign" neutropenia of the black.

The bone marrow granulocyte reserves of nine black patients with "benign" neutropenia were estimated by measuring the maximum neutrophil increment after the administration of hydrocortisone. Thirty control subjects, including 16 black and 14 white adults, were also studied. The mean neutrophil increment in the black patients with neutropenia was significantly less than that in the control subjects. The mean increment in the black control was also significantly less than that in the white control subjects. Four of the 16 black control subjects had neutrophil counts below 2,000/microliter; if these four are excluded from the analysis, the difference between the black and white control subjects is no longer significant. These data suggest that there is a subpopulation of healthy black adults with neutrophil counts below 2,000/microliter with reduced marrow granulocyte reserves as tested by corticosteroids. Bone marrow aspirates in four of the neutropenic patients showed normal cellularity and myeloid maturation suggesting that the lower increments are due to a difference in granulocyte release rather than to a difference in granulocyte production.     

Sea-blue histiocytes in a patient with lymphoma.

A middle-aged man with lymphocytic lymphoma had numerous sea-blue histiocytes in his bone marrow, splenomegaly and thrombocytopenia. Thus, his illness mimicked that of patients with the primary syndrome of the sea-blue histiocyte. However, the paucity of sea-blue histiocytes in his spleen, the absence of neurologic disease, his age and the ultrastructure of his abnormal histiocytes were all evidence for the presence of the acquired syndrome. The pathogenesis of sea-blue histiocytosis and the relationship between acquired cases and the primary syndrome are discussed.     

Chronic intrahepatic cholestasis of sarcoidosis.

The development of the syndrome of chronic intrahepatic cholestasis in five young, black men who had systemic granulomatous disease and clinical features consistent with those of sarcoidosis is described. Clinical and biochemical aspects, similar to those of primary biliary cirrhosis, included pruritus, jaundice, hepatomegaly and striking elevations of serum levels of alkaline phosphatase and cholesterol. (One patient had skin xanthomas.) Mitochondrial antibodies were not found; and survival of the patients (7 to 18 years) exceeded the usual survival of patients with primary biliary cirrhosis. The histologic abnormalities included noncaseating granulomas, chronic intrahepatic cholestasis, increased copper in hepatocytes, progressive diminution in number of interiobular bile ducts, periportal fibrosis and the eventual development of a micronodular "biliary" cirrhosis. The histologic evolution of the disease suggests a slow, progressive destruction of the bile ducts by granulomas. Although the end stage of this syndrome resembles primary biliary cirrhosis, the characteristic nonsuppurative, destructive cholangitis of primary biliary cirrhosis was not present.     

Bacteremia due to gram-positive cocci in patients with neoplastic disease.

Fifty-seven bacteremias caused by gram-positive cocci were observed over a four and a half year period in patients with a wide variety of malignant diseases. All patients had two or more positive antemortem blood cultures with the same microorganism. The number of bacteremic episodes were divided between Streptococcus pneumoniae (14), other streptococci (17) and Staphylococcus aureus (26). Seventy per cent, including 50 per cent of the pneumococcal bacteremias, were nosocomial. An identifiable portal of bacterial entry in the skin or the gastrointestinal or respiratory tract mucosa was present in 95 per cent, fever in 81 per cent and a prebacteremic performance status of less than 2 in 53 per cent. Granulocytopenia was present in only 18 per cent of the cases at the onset of the bacteremia. These bacteremias appeared to be responsive to antimicrobial therapy with an over-all immediate mortality rate of 23 per cent; 16 per cent in adequately treated patients. Poor outcome was associated with a prebacteremic performance status of 3 or 4, other than optimal antimicrobial therapy, a neutrophil count of less than 1,000/mm³ at the onset of the infection, and bacteremia due to Strep, pneumoniae. Hospitalized cancer patients, especially those with a poor performance status, should be monitored closely for breaks in the mucocutaneous host defense barriers and, if these are present in the face of suspected systemic infection, initial antimicrobial therapy should include drugs appropriate for the treatment of gram-positive coccal microorganisms.     

Is submaxillary gland immunoreactive glucagon important in carbohydrate homeostasis?

Previous investigators have shown rat submaxillary gland extracts to contain large amounts of material immunologically similar to pancreatic glucagon (SM-IRG). The present studies were designed to assess any physiologic contribution of this material to plasma immunoreactive glucagon (IRG) levels and to overall carbohydrate homeostasis in the rat. Bilateral submaxillary glandectomy or sham surgery was performed on adult male rats. After 2–4 wk, these animals were subjected to arginine or epinephrine infusion, fasting, insulin-induced hypoglycemia, or oral glucose loads. No measurable differences could be found between animals with or without submaxillary glands with respect to basal plasma levels of IRG, immunoreactive insulin (IRI), blood glucose (BG), or to the response of these parameters to any of the conditions tested. Furthermore, when eviscerated animals (without gastrointestinal tract or pancreas, but with intact liver and kidneys) were studied with or without submaxillary glands, no significant differences were found in either basal or stimulated levels of plasma IRG and BG. We conclude that SM-IRG makes no significant contribution to either plasma IRG or the metabolism of carbohydrates in the rat, even when other known sources of IRG have been surgically removed. While being unable to document any apparent role for SM-IRG in the maintenance of carbohydrate homestasis, we did observe dynamic changes in the glandular content of SM-IRG that occurred with the onset of puberty in both male and female weanling rats. The possibility, thus, remains that SM-IRG may be physiologically important, but in areas not necessarily related to carbohydrate metabolism.     

Early changes in plasma and urinary potassium in diuretic-treated patients with systemic hypertension

Two groups of patients with uncomplicated systemic hypertension were studied. Group 1 included 11 patients who had overt hypokalemia with diuretic drug treatment, and group 2 included 11 patients who remained normokalemic. After baseline studies without treatment were performed, both groups received hydrochlorothiazide, 50 mg twice daily. Plasma potassium (PK) was significantly reduced within the first day of treatment and stabilized by day 7 in both groups. The average decrease in PK was 1.0 +/- 0.1 mEq/liter (p less than 0.01) in the first group and 0.6 +/- 0.2 mEq/liter (p less than 0.01) in the second group. Cumulative losses of K were approximately 200 mEq in the hypokalemic group and were minimal in the normokalemic group as assessed by 24-hour urinary collections. Patients in the hypokalemic group also had a greater reduction in body weight and blood pressure. Supplementation with KCl, 96 mEq/day, or triamterene, 200 mg/day, in 9 hypokalemic patients resulted in an increase of PK to approximately 3.5 mEq/liter leveling off by day 7, and a cumulative K retention of approximately 200 mEq. Thus, overt thiazide-induced hypokalemia was associated with small and biologically unimportant losses of K from body stores. With replacement therapy the estimated amount of retained K was also small.