John F. Williams

Treatment of Congestive Heart Failure with Glucagon

Abstract The effectiveness of glucagon, 5 mg, subcutaneously, every 4 hr or 1 or 4 mg/hr by intravenous infusion, in the treatment of congestive heart failure was determined in 18 patients. Duratio...

The Effect of Pulmonary Emphysema upon Cardiopulmonary Hemodynamics at Rest and During Exercise

Excerpt The aberration in cardiopulmonary hemodynamics occurring in emphysematous subjects at rest is well-known, although there is no clear resolution of the question of the level of the cardiac o...

Experimental studyStudies on digitalis: XI. Effects of digitoxin on the development of cardiac hypertrophy in the rat subjected to aortic constriction

Abstract Two hundred male Sprague-Dawley rats were divided into four groups of 50 animals each. Group A served as controls; group B received 0.1 mg. of digitoxin/100 gm. body weight daily for six days of each week; group C underwent subdiaphragmatic suprarenal aortic constriction but did not receive digitoxin; and group D received doses of digitoxin similar to those given to group B, beginning five to seven days prior to aortic constriction. After suitable corrections for differences in body weight among the different groups, it became clear that digitoxin alone had no effect on the ventricular weight of the rats in group B. Although the rats in both groups C and D had ventricular weights significantly greater than control, the administration of digitoxin resulted in the development of significantly lesser degrees of myocardial hypertrophy and decreased the incidence of fatal congestive heart failure. While the development of hypertrophy represents a fundamental adaptive mechanism to a chronic pressure load placed on the ventricle, the usefulness of this adaptive mechanism may well be limited. By reducing the development of myocardial hypertrophy, digitoxin permits the ventricle to sustain an excessive hemodynamic burden with less encroachment on this fundamental reserve mechanism, thus favorably influencing cardiac function.

Glucagon and the Cardiovascular System

Excerpt In 1960 Farah and Tuttle (1) reported that crystalline glucagon exerted positive inotropic and chronotropic effects on isolated hearts of the dog, the rat, the guinea pig, and the cat. Surp...

Hydroxyproline and passive stiffness of pressure-induced hypertrophied kitten myocardium.

Passive stiffness and hydroxyproline content of myocardium hypertrophied by pressure-loading were determined in kittens 2, 8-16, and 24-52 wk after pulmonary artery banding, which initially elevated right ventricular systolic pressure by 10-15 mm Hg. Right ventricular mass increased by approximately 75%, three-quarters of which occurred during the first 2 wk after banding. Passive stiffness was assessed from resting length-tension relations of isometrically contracting isolated right ventricular papillary muscles. Stiffness constants, alpha and beta were determined from the relationship sigma = alpha (e beta epsilon - 1) where sigma = stress and epsilon = Lagrangian strain. Elastic stiffness (d sigma/d epsilon) was derived from: d sigma/d epsilon = beta sigma + beta alpha. Right ventricular hydroxyproline increased in proportion to muscle mass so that hydroxyproline concentration remained unchanged after banding. Both alpha, beta, and elastic stiffness-stress relations were similar to values in nonbanded controls. Thus, we did not observe an increase in passive stiffness or hydroxyproline concentration of pressure-stiffness or hydroxyproline concentration of pressure-induced hypertrophied myocardium in contrast to most previous studies.

Myocardial hydroxyproline and mechanical response to prolonged pressure loading followed by unloading in the cat.

To determine the myocardial response to prolonged pressure-loading and unloading, kittens weighing 0.8-1.2 kg underwent pulmonary artery banding, which initially elevated right ventricular (RV) systolic pressure by 10-15 mm Hg. 52 and 76 wk later; RV weight/body weight had increased by approximately 80%. Total RV hydroxyproline had increased significantly, whereas hydroxyproline concentration was unchanged from that of nonbanded animals of comparable age. In isometrically contracting RV papillary muscles, peak active force was significantly less at 76 wk (3.3 +/- 0.8 [SD] g/mm2 than at 52 wk (5.1 +/- 0.8 g/mm2) or in nonbanded animals (4.8 +/- 0.8 g/mm2). Velocity of muscle shortening at comparable loads was unchanged after 52 wk but was significantly less after 76 wk. In nonstimulated, slowly stretched muscles, passive stiffness constants, alpha and beta, derived from delta = alpha(e beta epsilon - 1), where delta is instantaneous stress and epsilon is Lagrangian strain, were unchanged by banding. The band was removed after 52 wk in additional animals that were studied 24 wk later. In those animals with normal RV pressures at death, hypertrophy had regressed and hydroxyproline concentration was comparable to that of nonbanded and banded animals; Active and passive mechanical function remained normal. In this model, changes in hydroxyproline parallel changes in muscle mass, and passive stiffness remains normal during development and regression of hypertrophy. Removal of the pressure load after prolonged hypertrophy prevents or retards the late development of myocardial dysfunction.

Cardiopulmonary hemodynamics during exercise in patients with pulmonary emphysema.

Abstract Five patients with pulmonary emphysema, 4 of whom had pulmonary hypertension at rest, were studied by right heart catheterization with determination of the pulmonary artery and “capillary” pressures and cardiac output at rest and during graded exercise. Two to three minutes of such exercise was sufficient to establish a “steady state” in these parameters, although a somewhat longer period of time may be required in those who have developed right ventricular failure. Pulmonary artery pressure and pulmonary vascular resistance after reaching a stable value do not fall as exericise progresses through nine minutes.

Relationship of cardiac muscle tension to Na+,K+-adenosine triphosphatase activity after chronic digitoxin administration in cats

Summary: To obtain a better understanding of the mechanism of action of the cardiac glycosides, we examined inotropic and biochemical effects of digitoxin in myocardium from cats chronically exposed to the drug. The mechanical function of papillary muscles was tested isometrically and left ventricular tissue was analyzed for Na+,K+-dependent adenosine triphosphatase ATPase activity. Muscles from control cat hearts developed tension at 2.5 ± 0.7 g/mm2; muscles from cats that received subcutaneous digitoxin—100 μg/kg on day 1, followed by 40 μg/kg/day for 4 days (group A), and 75 μg/kg on day 1, followed by 25 μg/kg/day for 9 days (group B)—developed significantly greater (p < 0.05) tension of 4.8 ± 0.3 and 3.6 ± 0.6 g/mm2, respectively. Further, in vitro maximal responsiveness to digitoxin was greater in the muscles from digitalized groups than in controls (p < 0.05): Muscles from control cats had a maximal response to in vitro addition of digitoxin of 3.5 ± 0.1 g/mm2; muscles from cats in group A reached 4.9 ± 0.3 g/mm2, and those from group B, 4.5 ± 0.7 g/mm2. Specific activity of microsomal Na+, K+ -ATPase from hearts of digitalized groups A and B was inhibited by 50–70% (p < 0.01). Developed tension, specific Na+,K+ -ATPase activity, and in vitro maximal responsiveness to digitoxin in a third group (C) of cats receiving the least daily digitoxin (75 μg/kg on day 1, followed by 15 μg/kg/day for 29 days) were not different from controls. Mean plasma digitoxin concentrations were 33, 16, and 3 ng/ml in groups A, B, and C, respectively. This report describes the simultaneous inhibition of Na+,K+ -ATPase activity and positive inotropic effect in hearts of animals chronically treated with a cardiac glycoside. It also shows that chronic in vivo administration of digitoxin has a greater effect on muscle tension than an acute in vitro addition of the drug.

The effect of diphenylhydantoin (Dilantin) on the positive inotropic action of ouabain.

Abstract Diphenylhydantoin (Dilantin), 5 mg/kg., given intravenously over five minutes during the infusion of ouabain, 45 μg/kg. per hr., transiently but significantly reduced the augmentation in right ventricular contractile force which had been produced by the glycoside in 10 anesthetized open chest dogs (group I). The magnitude of the reduction in contractile force and the duration of this effect were similar to those which occurred in 10 animals given Dilantin alone (group III). The administration of Dilantin during the infusion of isoproterenol (group IV, 6 animals) or after propranolol (group V, 5 animals) produced a decrease in contractile force, the magnitude of which was similar to that observed in the dogs given Dilantin alone. The duration of this effect of Dilantin in the dogs receiving isoproterenol also was similar to that observed in the groups I and III. Dilantin resulted in the deaths of 2 animals pretreated with propranolol and caused prolonged periods of contractile force alternans in another 2 animals in this group. The administration of Dilantin during the infusion of ouabain did not significantly increase the amount of glycoside required to produce arrhythmias or affect the maximal increase in contractile force produced by ouabain before the appearance of an arrhythmia. It is concluded that Dilantin does transiently reduce the positive inotropic action of ouabain. However, this effect of Dilantin is not directed specifically against the inotropic effect of the glycosides and apparently occurs as a result of the direct myocardial depressant properties of Dilantin.

The Labile Properties of the Pulmonary Vascular Bed in Patients with Pulmonary Emphysema.

Excerpt The factors which produce pulmonary hypertension in patients with pulmonary emphysema are poorly understood. The present study was undertaken in such patients to determine whether this vasc...