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Biomedical subjects

R A Kelly

Publications and source records attributed to R A Kelly.

122 records · Page 7Linked to original sources
PubMed1986

Endogenous digitalis-like factors in hypertension and chronic renal insufficiency.

Endogenous digitalis-like factors have been implicated in the adaptations that accompany renal insufficiency and in the pathogenesis of hypertension. We recently described several fractions of normal human plasma that inhibit NaK-ATPase and exhibit apparent digoxin-like immunoreactivity. To determine if hypertension and/or renal insufficiency affect plasma levels of these factors, we examined four patient groups: normotensive controls; hypertensive subjects with normal renal function; hypertensives with moderate renal insufficiency; and chronic dialysis patients. Plasma levels of digoxin-like immunoreactivity and NaK-ATPase inhibitory activity were significantly increased in hypertensive patients with mild renal failure (7.6 +/- 1.1 ouabain equivalents, mean +/- SEM, N = 21 vs 4.1 +/- 1.1 in normotensive controls, N = 20, P less than 0.05). NaK-ATPase inhibitory activity tended to be higher in patients with primary hypertension and normal renal function (5.5 +/- 0.7 ouabain equivalents, P less than 0.07); in dialysis patients, it was not different from controls. There was no correlation between NaK-ATPase inhibitory activity and blood pressure in any group. There was a significant rise in plasma NaK-ATPase inhibitory activity during dialysis (+ 1.8 +/- 0.7 ouabain equivalents, N = 22, P less than 0.03). As we have found that NaK-ATPase inhibitory activity in the plasma of normal humans can be separated into three distinct fractions, EI1, EI2, and EI3, we analyzed the plasma of 10 dialysis patients further. The increase in NaK-ATPase inhibitory activity could be attributed to fractions EI1 and EI3. These results suggest that plasma NaK-ATPase inhibitors increase with chronic renal insufficiency, but not hypertension alone. Although hemodialysis may acutely raise plasma levels, long-term dialysis returns them to the normal range.

Adult↗
PubMed1986

Excretion of artifactual endogenous digitalis-like factors.

Radioimmunoassays have been used to detect digoxin-like immunoreactive factors (DLF) in the plasma and urine of hypertensive patients and rats with deoxycorticosterone acetate (DOCA)-salt hypertension. Uninephrectomized rats (n = 9), given 15 mg DOCA . kg-1 . wk-1, were fed a standard rat chow supplemented with 2% NaCl (DOCA-HS); control animals (n = 15) were given vehicle injection and a specially formulated low-salt diet (0.05% NaCl). At 4 wk, DOCA-HS rats were hypertensive (121.4 +/- 10.1 vs. 88 +/- 4.4 Torr, mean +/- SEM, P less than 0.05) and excreted more DLF (2.7 +/- 1.1 vs. 0.2 +/- 0.1 ng digoxin equivalents . day-1, P less than 0.001) compared with control rats. DLF, partially purified from DOCA-HS urine by antidigoxin antibody immunoaffinity chromatography, was found to have a molecular weight less than 2,000, was resistant to acid hydrolysis or proteases, and had many properties of the cardiac glycosides, including inhibition of Na+-K+-ATPase activity, displacement of ouabain from human erythrocyte membranes, and inhibition of 86Rb influx into red blood cells. When DOCA-HS rats were switched to the low-sodium chow, DLF excretion dropped precipitously. No measurable DLF (less than 10 pg/ml) was detected in the plasma of rats eating either chow. However, greater than 95% of the urinary DLF could be attributed to a contaminant in the standard laboratory chow; rats fed the low-salt chow supplemented with 2% NaCl excreted much less DLF, and DLF was isolated from the standard chow.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism.

Metabolic acidosis is associated with enhanced renal ammonia-genesis which is regulated, in part, by glucocorticoids. The interaction between glucocorticoids and chronic metabolic acidosis on nitrogen utilization and muscle protein metabolism is unknown. In rats pair-fed by gavage, we found that chronic acidosis stunted growth and caused a 43% increase in urinary nitrogen and an 87% increase in urinary corticosterone. Net protein degradation in incubated epitrochlearis muscles from chronically acidotic rats was stimulated at all concentrations of insulin from 0 to 10(4) microU/ml. This effect of acidosis persisted despite supplementation of the media with amino acids with or without insulin, indomethacin, and inhibitors of lysosomal thiol cathepsins. Acidosis did not change protein synthesis; hence, the increase in net protein degradation was caused by stimulation of proteolysis. Acidosis did not increase glutamine production in muscle. The protein catabolic effect of acidosis required glucocorticoids; protein degradation was stimulated in muscle of acidotic, adrenalectomized rats only if they were treated with dexamethasone. Moreover, when nonacidotic animals were given 3 micrograms/100 g of body weight dexamethasone twice a day, muscle protein degradation was increased if the muscles were simply incubated in acidified media. We conclude that chronic metabolic acidosis depresses nitrogen utilization and increases glucocorticoid production. The combination of increased glucocorticoids and acidosis stimulates muscle proteolysis but does not affect protein synthesis. These changes in muscle protein metabolism may play a role in the defense against acidosis by providing amino acid nitrogen to support the glutamine production necessary for renal ammoniagenesis.

Acidosis↗
PubMed1985

Characterization of digitalis-like factors in human plasma. Interactions with NaK-ATPase and cross-reactivity with cardiac glycoside-specific antibodies.

Much of the evidence for a physiologically important endogenous inhibitor of the sodium pump has been either contradictory or indirect. We have identified three discrete fractions in desalted deproteinized plasma from normal humans that resemble the digitalis glycosides in that they: are of low molecular weight; are resistant to acid and enzymatic proteolysis; inhibit NaK-ATPase activity; inhibit Na+ pump activity in human erythrocytes; displace [3H]ouabain bound to the enzyme; and cross-react with high-affinity polyclonal and monoclonal digoxin-specific antibodies but not with anti-ouabain or anti-digitoxin antibodies. An additional fraction cross-reacted with digoxin-specific antibodies but had no detectable activity against NaK-ATPase. The three inhibitory fractions differed from cardiac glycosides in that their concentration-effect curves in a NaK-ATPase inhibition and [3H]ouabain radioreceptor assays were steeper than unlabeled ouabain. This suggests that these inhibitors are not simple competitive ligands for binding to NaK-ATPase. In the presence of sodium, no fraction required ATP for binding to NaK-ATPase, and in the presence of potassium, only one fraction had the reduced affinity for the enzyme that is characteristic of cardiac glycosides. Unlike digitalis, all three NaK-ATPase inhibitory fractions stimulated the activity of skeletal muscle sarcoplasmic reticulum Ca-ATPase. The presence of at least three fractions in human plasma that inhibit NaK-ATPase and cross-react to a variable degree with different digoxin-specific antibody populations could explain much of the conflicting evidence for the existence of endogenous digitalis-like compounds in plasma.

Adenosine Triphosphate↗
PubMed1984

Factors affecting potassium balance during frusemide administration.

We investigated the effects of Na+ intake, the renin-angiotensin-aldosterone system and anti-diuretic hormone (ADH) on K+ balance during 3 days of frusemide administration to six normal subjects. Subjects received 40 mg of frusemide for 3 days during three different protocols: Na+ intake 270 mmol/day (high salt); Na+ intake 20 mmol/day to stimulate the renin-angiotensin-aldosterone system (low salt); Na+ intake 270 mmol/day plus captopril (25 mg/6 h) to prevent activation of the renin-angiotensin-aldosterone system. In a fourth protocol, a water load was given during high salt intake to prevent ADH release and then frusemide was given. During high salt intake, frusemide increased K+ excretion (UKV) over 3 h, but the loss was counterbalanced by subsequent renal K+ retention so that daily K+ balance was neutral. During low salt intake, the magnitude of the acute kaliuresis following the first dose of frusemide and the slope of the linear relationship between UKV and the log of frusemide excretion were increased compared with that found during the high salt intake. In addition, low salt intake abolished the compensatory renal retention of K+ after frusemide and cumulative K+ balance over 3 days of diuretic administration was uniformly negative (-86 +/- 7 mmol/3 days; P less than 0.001). Captopril abolished the rise in plasma aldosterone concentration induced by frusemide. The acute kaliuresis after frusemide was unchanged compared with that observed during high salt intake. The compensatory reduction in UKV occurring after the diuretic was slightly potentiated. In fact, captopril given without the diuretic induced a small positive K+ balance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Systemic response to thermal injury in rats. Accelerated protein degradation and altered glucose utilization in muscle.

Negative nitrogen balance and increased oxygen consumption after thermal injury in humans and experimental animals is related to the extent of the burn. To determine whether defective muscle metabolism is restricted to the region of injury, we studied protein and glucose metabolism in forelimb muscles of rats 48 h after a scalding injury of their hindquarters. This injury increased muscle protein degradation (PD) from 140 +/- 5 to 225 +/- 5 nmol tyrosine/g per h, but did not alter protein synthesis. Muscle lactate release was increased greater than 70%, even though plasma catecholamines and muscle cyclic AMP were not increased. Insulin dose-response studies revealed that the burn decreased the responsiveness of muscle glycogen synthesis to insulin but did not alter its sensitivity to insulin. Rates of net glycolysis and glucose oxidation were increased and substrate cycling of fructose-6-phosphate was decreased at all levels of insulin. The burn-induced increase in protein and glucose catabolism was not mediated by adrenal hormones, since they persisted despite adrenalectomy. Muscle PGE2 production was not increased by the burn and inhibition of prostaglandin synthesis by indomethacin did not inhibit proteolysis. The increase in PD required lysosomal proteolysis, since inhibition of cathepsin B with EP475 reduced PD. Insulin reduced PD 20% and the effects of EP475 and insulin were additive, reducing PD 41%. An inhibitor of muscle PD, alpha-ketoisocaproate, reduced burn-induced proteolysis 28% and lactate release 56%. The rate of PD in muscle of burned and unburned rats was correlated with the percentage of glucose uptake that was directed into lactate production (r = +0.82, P less than 0.01). Thus, a major thermal injury causes hypercatabolism of protein and glucose in muscle that is distant from the injury, and these responses may be linked to a single metabolic defect.

Adrenalectomy↗
PubMed1983

Response of the kidney to furosemide. II. Effect of captopril on sodium balance.

We investigated the role of the renin-angiotensin-aldosterone (RAA) system during furosemide (F) administration. The effects of adding captopril (C) (25 mg . 6 hr-1) to F (40 mg daily for 3 days) were studied in six normal subjects equilibrated to a daily sodium (Na) intake of 270 mmoles. Without C, F produced a marked natriuresis but Na+ excretion fell sharply between drug doses. This resulted in neutral Na balance (+22 +/- 58 mmoles . 3 days-1; mean +/- SE). Plasma angiotensin (AII) and aldosterone (Aldo) rose, but mean blood pressure (MBP) was unaltered. C abolished the F-induced increases in AII and Aldo but did not modify the pattern of Na+ excretion. Na+ balance remained neutral (+42 +/- 54 mmoles . 3 days-1). With C alone, Na+ balance was positive (+110 +/- 30 mmoles . 3 days-1; P less than 0.02). In protocols C alone and F + C, MBP fell by a comparable amount. F alone and F + C increased plasma norepinephrine and prostaglandin E2 metabolite; these did not change with C alone. In conclusion, activation of the RAA system by F is not essential for the compensatory increase in Na+ reabsorption that maintains Na+ balance after F.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗
PubMed1983

Response of the kidney to furosemide. I. Effects of salt intake and renal compensation.

We investigated the effects of varying salt intake on five factors that could affect sodium balance during furosemide (F) administration: the quantity of F reaching the renal tubules; the magnitude of the acute natriuresis; Na+ excretion in the period after the acute diuresis; diuretic tolerance; and changes in plasma aldosterone. Six normal subjects were given F (40 mg day-1) for 3 days after equilibration to Na+ intakes of 20 mmol day-1 (low salt, LS) and 270 mmol day-1 (high salt, HS). Salt intake did not modify F excretion. Salt restriction reduced the short-term natriuretic response to F, led to diuretic tolerance, and potentiated the F-induced rise in plasma aldosterone. There was a progressive diminution in the quantity of Na+ excreted per unit of F excreted during LS. In spite of this, cumulative Na+ balance was negative only during LS because of a compensatory increase in Na+ reabsorption in the period between diuretic doses. During HS, this compensation exactly matched the short-term loss of Na+ produced by F, leading to neutral Na+ balance. During LS, the acute natriuresis exceeded the daily Na+ intake, so that, despite the renal compensation, Na+ balance was negative. In conclusion, salt restriction impairs the short-term natriuretic response to F and leads to diuretic tolerance. However, homeostatic mechanisms activated by the diuretic can maintain Na+ balance even in subjects without a disease causing Na+ retention, unless dietary salt is restricted.

Adult↗
PubMed1981

Cutaneous necrosis caused by systemically administered heparin.

Two cases of cutaneous necrosis occurred that were caused by intravenous administration of porcine heparin for deep venous thrombophlebitis. The lesions grossly resembled those of warfarin sodium-induced skin necrosis. However, histologically, no fibrin thrombi were noted in capillaries and vessels, a characteristic finding in warfarin necrosis. There was no evidence of vasculitis in the lesions. Both patients subsequently received warfarin without complications.

Adult↗
PubMed1976

Laboratory investigation and infection control of cholera in Kingston, Ont.

Vibrio cholerae, biotype El Tor, was isolated in a hospital laboratory in Kingston, Ont. in 1974. Confirmation and complete identification by the Ontario regional and provincial public health laboratories was obtained within 3 days. Institution of well established infection-control and public health measures prevented spread of the infection within the hospital and the community.

Adult↗
PubMedDate not supplied

Cardiac endothelium and tissue growth.

In recent years, a number of peptide and nonpeptide signalling autacoids have been implicated in the regulation of cardiac myocyte growth as well as vasculogenesis and angiogenesis, and in the function of cardiac muscle following development. In this review, we first examine the evidence for a role for specific cytokines during cardiac ontogeny, including fibroblast factors, TGFbeta, neuregulins, and gp/30-mediated signalling pathways. Evidence is also reviewed for a role for local, intracardiac generation of endothelins and angiotensins in the regulation of cardiac muscle function and adaptation to physiologic stress. The role of cardiac myocytes in regulating angiogenesis in the developed heart is then reviewed briefly. Finally, the effects of the endogenous generation of nitric oxides by the inflammatory cytokine-inducible isoform of nitric oxide synthase (iNOS or NOS2) within the heart are also reviewed.

Angiotensins↗
PubMedDate not supplied

Cardiac glycosides in the next millennium.

Despite the documented efficacy of cardiac glycosides in improving symptoms in patients with heart failure caused by systolic ventricular dysfunction, considerable debate continues as to whether the use of this class of drugs should continue into the next millennium. In this review, the authors briefly examine the basic pharmacology of these drugs relevant to the treatment of heart failure, emphasizing their role in reducing sympathetic nervous system activity in patients with advanced heart failure. Next, withdrawal trials and the Digoxin Investigation Group dataset are reviewed in some detail. Despite these important additional data on the safety and efficacy of digitalis use in heart failure that became available in the 1990s, considerable controversy remains. Perhaps most importantly, if the mechanism by which these drugs improve symptoms in patients with heart failure is principally mediated by sympatholytic activity, do they remain relevant as beta-adrenergic antagonists become standard therapy for this disease?

Cardiac Glycosides↗
PubMedDate not supplied

Treatment of supraventricular tachyarrhythmias with intravenous calcium channel blockers: are subtle differences worth the cost?

Verapamil and diltiazem are effective in terminating paroxysmal supraventricular tachycardias and slowing ventricular response during atrial fibrillation or flutter. Results from clinical trials for each individual drug demonstrate comparative efficacy rates, and both drugs share the same contraindications and relative precautions. Well-designed comparative clinical trials are needed to establish if either drug has any clinical advantages in a particular patient population.

Calcium Channel Blockers↗