Effects of vanadate on ouabain binding and inhibition of (Na+ + K+)-ATPase.

Effects of vanadate on ouabain binding and inhibition of sodium and potassium adenosine triphosphatase (Na+ + K+)-ATPase) were investigated under various ionic conditions. 1. Vanadate facilitated ouabain binding to (Na+ + K+)-ATPase in the presence of Mg2+ and this facilitation was partially reversed by catechol. 2. Vanadate antagonized the ability of high concentrations of NaCl to inhibit ouabain binding in the presence of magnesium. 3. Ouabain binding to the vanadate-enzyme complex, formed from magnesium and vanadate, was more sensitive to depression by potassium than that to the phosphoenzyme formed from magnesium and inorganic phosphate. 4. Preincubation of (Na+ + K+)-ATPase with vanadate in the presence of magnesium initially formed a potassium-insensitive complex as shown by a rapid initial rate of ouabain binding. However, within 5 min potassium overcame the vanadate potentiation of ouabain binding regardless of the order in which it was added to the reaction mixture. 5. Under conditions of enzyme turnover, vanadate failed to antagonize the inhibitory power of ouabain despite the presence of a high concentration of potassium. This suggests a possible relationship between the sensitivity of the sodium pump in various tissues to the cardiac glycosides and intracellular vanadate concentrations.

Propranolol in children: safety-toxicity.

Four hours after acute ingestion of 400 to 1,200 mg of propranolol by a healthy, 3-year-old boy, his plasma concentration of propranolol was 2,289 ng/ml. The only pharmacologic effect observed was a diminished heart rate response to crying and activity. In a second case, a 4-year-old boy on chronic propranolol therapy for renovascular hypertension had a hypoglycemic seizure when solid food was refused for three days because of an oral wound. The hypoglycemia was easily managed with intravenous glucose, and there were no sequelae. The first case alludes to the safety of propranolol in a healthy child even with very high plasma concentrations. The second case suggests the necessity of anticipating and avoiding hypoglycemia that can develop in children on chronic propranolol therapy when caloric intake is impaired.

Myocardial injury in infants with congenital heart disease: evaluation by creatine kinase MB isoenzyme analysis.

Total creatine kinase (CK) and the myocardial isoenzyme CK MB activity were prospectively determined in 282 children hospitalized for cardiac catheterization and evaluation for suspected congenital cardiac abnormalities and compared with a hospitalized control group of children without such abnormalities. The percent CK MB and CK MB activity were abnormally elevated in symptomatic children with a large left to right shunt due either to a large ventricular septal defect (n = 22; p less than 0.001) or to complete atrioventricular canal (n = 10; p less than 0.001). Serum CK MB activity and percent CK MB were significantly related to the size of the shunt and the age of presentation with clinical symptoms of congestive heart failure in infants with a ventricular septal defect. CK MB activity was abnormally elevated in infants with symptomatic coarctation of the aorta, either with or without a ventricular septal defect (n = 15; p less than 0.001), and in infants with symptomatic aortic stenosis (n = 4; p less than 0.02). In contrast, CK MB activity was normal in asymptomatic children with coarctation of the aorta (n = 14) or aortic stenosis (n = 8) despite comparable systolic pressure gradients. CK MB activity and percent CK MB were abnormally elevated in those children with the cyanotic congenital cardiac abnormalities of either transposition of the great arteries (n = 32; p less than 0.001) or right ventricular outflow tract obstruction (n = 31; p less than 0.001). These results suggest that children with congenital cardiac abnormalities may have significant myocardial cell injury and release of CK MB that may be detected by the determination of serum CK MB activity. Cell injury may be secondary to arterial desaturation or acute pressure-volume overload, or both, as manifested by clinical symptoms of heart failure and measured hemodynamic variables.

Left ventricular function in cyanotic congenital heart disease.

Left ventricular function was studied with quantitative biplane cineangiocardiography in 39 preoperative and 23 postoperative patients with cyanotic congenital heart disease. Diagnoses included pulmonary atresia or critical pulmonary stenosis with intact ventricular septum (group 1), tricuspid atresia (group 2) and pulmonary atresia with ventricular septal defect (group 3). Preoperative patients ranged in age from 1 day to 7 years and postoperative patients from 7 weeks to 23 years. Left ventricular end-diastolic volume was increased in preoperative patients in groups 1 and 2 (132 and 136 percent of normal, respectively) but was normal in patients in group 3. Left ventricular ejection fraction was decreased to a similar extent in preoperative groups 1 to 3: 0.54, 0.55 and 0.56, respectively. After a shunt procedure left ventricular end-diastolic volume increased to 228 and 266 percent of normal in groups 1 and 2, respectively, but remained within normal limits in group 3. Left ventricular ejection fraction was normal in postoperative group 1 patients, whose ages averaged 1.8 years, but remained decreased in group 2 and 3 patients, whose ages averaged 8.1 and 5.6 years, respectively. Duration of cyanosis and degree of left ventricular dilatation appear to be important variables in regard to pump function in patients with cyanotic congenital heart disease.

Assessment of ventricular size and function in congenitally corrected transposition of the great arteries.

Twenty-four quantitative cineangiographic studies were performed in 19 patients with congenitally corrected transposition of the great arteries to assess right and left ventricular size and function. Ages ranged from 7 days to 44 years and associated lesions included ventricular septal defect (13 of 19), pulmonary stenosis (9 of 19), and systemic (tricuspid) valvular insufficiency (7 of 19). Systemic (anatomically right) ventricular end-diastolic volume was within normal limits in most patients and averaged 119% of predicted normal. Pulmonary (anatomically left) ventricular end-diastolic volume also was normal in most patients, averaged 112% of predicted, and was not different from systemic (right) ventricular end-diastolic volume. Systemic ventricular ejection fraction (RVEF) averaged 0.61 +/- 0.02 and was not different from pulmonary ventricular ejection fraction (LVEF) (0.65 +/- 0.02), but important differences were apparent when age was considered. With exclusion of 2 patients with hypoplastic systemic ventricles and 2 studies performed less than 6 months after open heart surgery, all 12 patients aged less than 10 years had a normal RVEF, whereas 2 of 5 patients aged greater than 17 years had a definitely low RVEF and 1 of 5 had a value at the lower limit of normal. In children, systemic and pulmonary ventricular pump function is usually normal in congenitally corrected transposition of the great arteries and any deviation from normal should suggest ventricular hypoplasia or an increase in afterload. After childhood, systemic ventricular dysfunction is more common and may reflect the inability of the anatomic right ventricle to function as the systemic pumping chamber over a normal lifetime in most patients with congenitally corrected transposition of the great arteries.

Management of children with hypertension from reflux or obstructive nephropathy.

During a ten-year period, 35 children presenting with vesicoureteral reflux, ureteropelvic junction obstruction, or a "small kidney" were found to be hypertensive. Of these, 15 subsequently underwent surgical procedures for relief of hypertension. Seven were "cured," six were "improved," and two were "unchanged." The severity of hypertension could not be correlated with the degree of reflux nor with the degree of obstructive uropathy. However, all children with reflux in our study who were hypertensive had some degree of calicectasis noted preoperatively on intravenous pyelogram. Also it was noted that hypertension may occur several years after successful anti-reflux surgery. Children with vesicoureteral reflux, ureteropelvic junction obstruction, or a small kidney need to have blood pressure determinations at regular intervals, even if all previous readings had been in the normotensive range and whether or not they were followed up medically or post surgically. We suggest that blood pressure determinations be made every three months for the first year after diagnosis of reflux or ureteropelvic junction obstruction, and at least once a year thereafter.

Characterization of polymorphonuclear leukocyte aggregation in vitro induced by heat-inactivated group B streptococcus.

We studied the aggregatory characteristics of human polymorphonuclear leukocytes (PMNs) in response to heat-inactivated group B streptococcus. PMNs suspended in physiologic salt solution do not aggregate to heat-inactivated group B streptococcus (GBS) unless the GBS is previously opsonized in autologous plasma. The aggregating activity of both opsonized GBS and activated plasma are reduced if the plasma is decomplemented before incubation with GBS. Pretreatment of PMNs with pronase inhibited opsonized GBS-induced aggregation, suggesting aggregation via cell membrane receptors for opsonic fragments of C3. Pronase pretreatment had no significant effect on aggregation induced by activated plasma or arachidonic acid. Unlike PMNs in physiologic salt solution, PMNs suspended in plasma aggregate when stimulated by unopsonized GBS. GBS aggregates PMNs via complement cascade activation, opsonization, and interaction with cell membrane receptors to stimulate cellular mechanisms resulting in PMN aggregation.

Prednisolone plus albuterol versus albuterol alone in mild to moderate bronchiolitis.

To evaluate combination therapy of mild to moderate bronchiolitis with bronchiodilators and corticosteroids, we treated 51 young children with first-time wheezing and symptoms of respiratory tract infection with albuterol plus either prednisolone or placebo for 5 days. Disease severity was scored on days 0, 2, 3, and 6. On day 2, prednisolone resulted in significantly lower scores (2.7 +/- 1.4 vs. 4.0 +/- 1.5 in all patients evaluated, p < 0.05) than placebo, whereas there was no detectable difference on day 6, suggesting that addition of prednisolone to albuterol transiently accelerates recovery from bronchiolitis. The clinical significance of this effect needs to be evaluated in further studies.

Clonidine poisoning. A complex problem.

Clonidine hydrochloride poisoning in children has become more frequent with increasing availability of this drug. We report four cases of accidental clonidine poisoning that demonstrate the various signs and symptoms of clonidine poisoning. The most frequent and significant toxic effects are depression of consciousness, bradycardia, hypotension, and respiratory depression. Ventilatory support must be available if apnea occurs. Bradycardia can be treated with atropine sulfate, epinephrine chloride, dopamine hydrochloride, or tolazoline hydrochloride. Hypotension is treated with intravenous fluids and dopamine, reserving tolazoline for refractory cases. Hypothermia is common but is of minor clinical significance. Paradoxical hypertension should be treated with tolazoline. Clonidine may not be detected in body fluids by routine toxicology-screening procedures, so poisoning should be suspected on clinical grounds.

Dose-response relation of diazoxide in children with hypertension.

Diazoxide was administered to sixteen pediatric patients (ages 10 months to 13 years) with secondary forms of hypertension. Admission BP was 178+/-8/130+/-5 mm Hg (mean +/- SEM). Diazoxide was administered rapidly intravenously in doses ranging from 2 to 7.5 mg/kg. A significant (P less than 0.001), linear log dose-response relation was obtained which showed that a 3 mg/kg dose of diazoxide lowered diastolic BP by an average of 30 mm Hg. In five patients reduction of idastolic BP by a single injection of diazoxide was no different than when the same total dose was given as two or three small injections repeated at fifteen to twenty minute intervals. It is concluded that 1) many hypertensive children respons significantly to doses of diazoxide smaller than the usually recommended 5 mg/kg; 2) diazoxide has a significant dose-response relation in hypertensive pediatric patients; and 3) the desired blood pressure response in hypertensive children can be titrated using repeated small injections of diazoxide.

Relationship between the in-situ activity of ornithine decarboxylase and contractile function of the rabbit papillary muscle.

The relationship between isometric contraction and myocardial ornithine decarboxylase (ODC; EC.4.1.1.17) activity was studied in right ventricular papillary muscles isolated from rabbits. ODC specific activity and polyamine content were significantly increased in papillary muscles contracting isometrically 90 times per minute at the apex of the length-tension relationship for 4 to 5 hours when compared with paired non-contracting muscles or isometrically contracting muscles stimulated at 30 times per min. The increase in ODC activity appeared to be due to new protein synthesis since cycloheximide blocked the increase in ODC activity without affecting isometric function. Thus, the present results suggest that increased contractile demands of the heart may stimulate the synthesis of myocardial ODC, increase ODC activity and polyamine content.

Efficacy of sulfhydryl compounds as inhibitors of iron-dependent doxorubicin-enhanced lipid peroxidation.

The ability of sulfhydryl compounds to inhibit doxorubicin enhanced lipid peroxidation in the presence of added iron was evaluated. Optimal conditions for doxorubicin-enhanced lipid peroxidation were 25 microM doxorubicin, 2 mM ADP and 250 microM ferric chloride at pH 8.0. Lipid peroxidation was inhibited by EDTA (500 microM), SKF 525 A (100 microM) and vitamin E (0.1 unit/ml). Cysteamine (1 mM) stimulated basal lipid peroxidation but produced net inhibition of lipid peroxidation with doxorubicin. Cysteamine (10 mM) was more efficacious at inhibiting lipid peroxidation. N-acetylcysteine at 1 and 10 mM was a potent stimulator of lipid peroxidation and was ineffective at inhibiting lipid peroxidation in the presence of doxorubicin either at optimal or suboptimal concentrations of iron. In contrast, glutathione (1 mM) was a potent inhibitor of lipid peroxidation. The data suggests that N-acetylcysteine protects against doxorubicin by prior conversion to glutathione.

Comparative influence of ouabain, norepinephrine and heart rate on myocardial oxygen consumption and inotropic state in dogs.

The purpose of this study was to compare the myocardial oxygen cost of augmented inotropic state produced by ouabain, norepinephrine, or increased heart rate. This problem was examined in dogs using an isovolumically contracting left ventricular preparation. Inotropic state was measured as the maximum observed contractile element velocity at the lowest common level of wall stress (MAX V). Peak left ventricular wall stress was maintained constant in each dog so that it would not influence changes in myocardial oxygen consumption (MVO2). Ouabain (4 X 10(-2) mumoles/Kg.) and norepinephrine (2 X 10(-3) mumoles/Kg./minute) always augmented inotropic state (MAX V) and increased MVO2. The positive slopes of the regression of MVO2 on MAX V for ouabain (45.4 +/- 12.5 microliter/beat/100 Gm./muscle length/sec; mean +/- SEM) and norepinephrine (34.5 +/- 5.6 microliter/beat/100 Gm./muscle length/sec; mean +/- SEM) were not significantly different, indicating that for an equal augmentation of inotropic state, ouabain increases myocardial oxygen demands to the same extent as does norepinephrine. When the results with ouabain or norepinephrine were compared to results obtained by altering heart rate, it was found that increasing inotropic state by these pharmacologic agents is more costly in terms of myocardial energy demands than when inotropic state is enhanced by increasing heart rate.

Functional significance of reduced cardiac sympathetic innervation in the newborn dog.

The functional significance of anatomically reduced cardiac sympathetic innervation in the newborn is not known. This problem was investigated by examining ventricular contractile responses to repeated maximal left stellate ganglion stimulation in adrenalectomized and sham-adrenalectomized newborn (4-12 days of age) and adult dogs. At the end of five periods (5 min/period) of stimulation, sham-adrenalectomized puppies were still able to augment left ventricular force 13.0 +/- 3.8% (mean +/- SE; P less than 0.05) above control values. However, adrenalectomized puppies did not maintain their ability to enhance left ventricular force after the first period of stimulation. Similar results were obtained with measurements of the first time derivative of left ventricular force (dF/dt), right ventricular force, right ventricular dF/dt, and peak left ventricular pressure. Adult dogs were able to augment these measurements of cardiac function significantly throughout five stimulation periods whether or not their adrenal glands were intact. After five stimulation periods, adrenalectomized newborn dogs responded to isoproterenol, indicating that their cardiac beta-adrenergic receptors remained functional. We conclude that the known sparse ventricular sympathetic innervation in the newborn dog is associated with inability to maintain significant cardiac functional responses after repeated sympathetic stimulation and that adrenal integrity is required in the newborn to maintain appropriate ventricular responses to sympathetic stimulation.

Short-term hemodynamic effects of hydralazine in infants with complete atrioventricular canal defects.

We evaluated the acute hemodynamic responses to hydralazine during cardiac catheterization in eight infants (ages 1.0 to 5.5 months) with congestive heart failure due to complete atrioventricular canal defect. Hydralazine administered intravenously (0.5 to 1.0 mg/kg body weight) increased heart rate and systemic blood flow and decreased mean right atrial pressure, systemic and pulmonic arterial pressures, systemic arteriolar resistance, and the ratio of pulmonary to systemic blood flow (p less than .05). The percentage of pulmonary flow contributed by shunted blood (percent left-to-right shunt; measured by indicator dilution) was decreased by hydralazine in six (mean = 85% before to 64% after hydralazine; p less than .01), but remained unchanged (79%) in two infants. The two infants with no change in percent left-to-right shunt had higher pulmonary arteriolar resistances (Rp) before hydralazine (mean = 12.8 vs 3.2 U/m2) and had greater declines in Rp (mean change = -5.1 vs + 0.3 U/m2) in response to hydralazine. Thus, if Rp does not fall, hydralazine reduces the percentage of left-to-right shunt over the short term and therefore might be useful for managing congestive heart failure in these infants. However, because the response varies, an evaluation of the short-term hemodynamic effects of hydralazine may be warranted in an attempt to select those infants who might respond favorably to long-term hydralazine therapy.