Studies of the inotropic mechanisms of cardiac glycosides in cultured heart cells.
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Biomedical subjects
Publications and source records attributed to D Kim.
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Many Blalock-Taussig shunts (subclavian to pulmonary artery anastomoses) have been created and a significant number are still being done. Two cases of aneurysmal degeneration of a Blalock-Taussig shunt and their management are described. Development of this rare complication may be related to large shunt flow and long duration. Large, symptomatic or enlarging aneurysms should be repaired and smaller ones studied by serial computed axial tomography. A simple and safe approach to correct this lesion is division and oversewing of the proximal subclavian artery through an anterior approach, assuming adequate pulmonary blood flow is already present or can be established concomitantly.
Growth of cultured cells in low potassium medium has been shown to result in an increase in the number of Na,K-ATPase sites. This phenomenon and its physiological and pharmacological consequences were examined in spontaneously beating monolayers of cultured chick heart cells. Growth of cells in 1 mM extracellular potassium, 2 microM ouabain, or 1 microM veratridine for 48 hours caused 60%, 40%, or 20% increases, respectively, in the total number of specific ouabain binding sites measurable in intact cells. Acute exposure of control cells grown in 4 mM to 1 mM extracellular potassium caused elevation of steady state [Na+]i by 37%, while 1 microM veratridine exposure increased [Na+]i by 12%. After 48 hours of growth in 1 mM extracellular potassium, intracellular sodium concentrations declined to near-control levels. In cells grown in low extracellular potassium and then equilibrated with 4 mM potassium for 30 minutes, the positive inotropic effects of 1 mM extracellular potassium and 0.3 microM isoproterenol, expressed as a percent of contractile response to 3.6 mM calcium, were 40 +/- 6% and 37 +/- 5% (means +/- SEM), respectively, in low potassium-grown cells, compared with 63 +/- 8% and 35 +/- 4% in control cells. Growth of cells in low potassium shifted the concentration-effect curve for ouabain to the right. The rapid component of calcium uptake in zero extracellular sodium was significantly lower in low potassium-grown cells than in control cells after equilibration in 1 mM extracellular potassium for 30 minutes. These findings demonstrate that prolonged exposure of cultured heart cells to 1 mM extracellular potassium or ouabain causes induction of additional functional sarcolemmal sodium pump sites. The increased levels of intracellular sodium caused by these interventions appear to be an important determinant of sodium pump site density. The reduced contractile response of cells grown in 1 mM extracellular potassium and ouabain (but not isoproterenol) supports the view that elevated intracellular sodium due to Na,K-ATPase inhibition mediates the positive inotropic response to low extracellular potassium and ouabain, probably via augmented transsarcolemmal sodium-calcium exchange. In addition, our results support a mechanism of inotropic action of digitalis glycosides based on inhibition of the sodium pump rather than altered calcium binding properties of sarcolemmal sites due to cardiac glycoside binding to Na,K-ATPase.
Sensitivity of cardiac muscle to digitalis glycosides depends on the thyroid state. The mechanism of this interaction was investigated at the cellular level using spontaneously beating monolayers of cultured chick embryo ventricular cells. Cells were grown for 48 h in serum-free medium containing concentrations of triiodothyronine (T3) from zero to 10(-7) M, and the total number of sodium pump sites, sodium content, and contractile amplitude in the presence and absence of various concentrations of ouabain were determined. T3 caused a concentration-dependent increase in the number of specific ouabain binding sites; the maximal increase to 160% of control was observed in response to 10(-8) M T3. T3 lowered steady-state cellular sodium content in a concentration-dependent manner, also. Ouabain (1 microM) exposure elevated cellular sodium content in all cells, but the increase was greatest in cells grown in T3-free medium and least in cells grown in 10(-8) M T3. The positive inotropic and toxic effects of ouabain in cells grown in 10(-8) M T3 were diminished at any given ouabain concentration, and thus, the dose-response curve was shifted to the right. These results indicate that T3 causes induction of additional sodium pump sites that are functional. The increased tolerance of hyperthyroid cells and reduced tolerance of hypothyroid cells to cardiac glycosides can be explained by these changes in the number of sodium pump sites and cellular sodium content, and consequently, calcium influx via sodium-calcium exchange.
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To define further the mechanism of positive inotropic action of cardiac glycosides, the temporal relationships among ouabain binding, sodium pump inhibition and positive inotropy were examined using cultured chick embryo ventricular cells. In K+-free medium, specific [3H]ouabain binding to intact cells followed pseudo first-order kinetics with saturation of binding sites occurring at 1 microM ouabain. The KD values calculated from the association and dissociation rate constants were 1.4 and 4.9 X 10(-7) M, respectively, in K+-free and 4 mM K+ medium. The Scatchard plot of binding in K+-free medium was linear, consistent with the presence of a single class of binding sites (KD = 1.3 X 10(-7) M). In 4 mM K+, 0.1 microM ouabain occupied 10% of the total binding sites and failed to produce an inotropic effect, inhibit 42K+ uptake or alter [Na+]i. Exposure of cells to 1 microM ouabain caused a significant increase in contractile state after 30 sec, reaching a plateau after 7 min with 50 +/- 6% augmentation of the amplitude of cell motion; the 42K+ uptake rate was concurrently inhibited by 36% accompanied by a 35% increase in [Na+]i and occupation of 38% of total ouabain binding sites. The initial rate of 42K+ uptake in cells loaded with Na+ by incubation in K+-free medium was 4 times greater than that observed without Na+ loading. These results indicate that more than 10% of sodium pump sites must be inhibited to produce an appreciable change in the rate of monovalent cation transport, [Na+]i or contractile state, due to the reserve capacity of uninhibited sodium pumps.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute myocardial ischemia reduces tolerance of the heart to arrhythmogenic actions of digitalis glycosides. Because both ischemia and the glycoside produce profound changes in activity of the autonomic nervous system and because sympathetic discharge or catecholamines enhance toxic actions of the cardiac glycosides, the possibility that alterations in digitalis sensitivity of ischemic heart involve changes in sympathetic nerve activity was examined using alpha-chloralose-anesthetized cats. Left anterior descending coronary artery (LAD) was completely occluded by ligation and, 40 min later, a slow i.v. infusion of digoxin was started at a rate of 1 microgram/kg/min. LAD ligation alone did not produce arrhythmias in that condition, but shortened the time to onset of digoxin-induced arrhythmias and thereby reduced the amount of digoxin required to produce the toxic manifestation. Concomitantly, digoxin concentration in plasma and nonischemic areas of the heart were lower in LAD-ligated cats at the onset of arrhythmias than those in sham-operated cats. Myocardial digoxin content in the ischemic area of the LAD-occluded heart was lower than that in nonischemic areas of the same heart. At the onset of digoxin-induced arrhythmias, Na,K-adenosine triphosphatase activity of ischemic myocardium was significantly higher than that in the nonischemic area, reflecting a lower digoxin occupancy of the glycoside binding sites on the sodium pump. Spinal cord (C1) transection or propranolol treatment prolonged the time to arrhythmias in both control and LAD-ligated cats, but failed to abolish the effect of LAD ligation to augment digoxin toxicity. Bilateral vagotomy also did not alter the enhancement of digoxin toxicity caused by ligation of LAD.(ABSTRACT TRUNCATED AT 250 WORDS)
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We present a case of successful transcatheter embolization of a leaking pseudoaneurysm of an autogenous saphenous vein aortocoronary graft that developed 9 years following bypass surgery.
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Two patients with pseudomyxoma peritonei (PP) had repeated intraperitoneal washing with 5% dextrose in water. Both responded to this therapy with decrease in abdominal girth. The second patient is alive, without abdominal distention, more than 112 weeks since beginning peritoneal washing therapy (PWT) for ovarian PP. Biochemical assays of urine before and after PWT show that acid mucopolysaccharide is excreted in the urine, probably after being absorbed through the peritoneal surface. The long-term effects of this procedure on renal function are not known, but PWT appears to be reasonable and safe ambulatory therapy for PP.
Intact rats exposed for 30 days to various levels of simulated altitude from 12,000 (3,658 m) to 20,000 ft (6,096 m) showed a sharp increase in circulating red blood cells in reticulocytes, and in spleen-to-body weight ratios above 15,000 ft (4.572 m). Nucleated erythrocytes in splenic section increased significantly at 18,000 ft (5,486 m), but not at 12,000 ft. Acute splenectomy 1 day before killing sharply reduced the reticulocyte counts at 18,000 and 20,000 ft, but the red cell counts were not reduced at any altitude by the operation. Indeed, at 18,000 ft the splenectomy significantly increased the degree of polycythemia. With altitude exposure the spleen but not the liver or the bone marrow showed an increased 59Fe uptake that was related to the degree of hypoxia. These results suggest that the rat spleen of the present strain carries the full load of the erythropoietic effort in response to a hypoxic stimulus, and that it may exert an inhibitory influence on any extraerythropoietic effort by the bone marrow. In intact rats returned from 18,000 ft to sea level, the reticulocytosis is reversed much more slowly than it is in splenectomized rats, suggesting the presence of a persistent stimulus initiated by hypoxia or a committed pool of reticulocyte precursors.
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