Left atrial booster function in valvular heart disease

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Abstract

This study was designed to assess atrial booster pump action in valvular heart disease and to dissect booster pump from reservoir-conduit functions. In five patients with aortic stenosis and six with mitral stenosis, sequential atrioventricular (A-V) pacing was instituted during the course of diagnostic cardiac catheterization. Continuous recording of valvular gradient allowed estimation of flow for each cardiac cycle by transposition of the Gorlin formula. Left ventricular ejection time and left ventricular stroke work in aortic stenosis or left ventricular mean systolic pressure in mitral stenosis were also determined. Control observations were recorded during sequential A-V pacing with well-timed atrial systole. Cardiac cycles were then produced with no atrial contraction but undisturbed atrial reservoir function by intermittently interrupting the atrial pacing stimulus during sequential A-V pacing. This intervention significantly reduced valvular gradient, flow, left ventricular ejection time, and left ventricular mean systolic pressure or stroke work. Cardiac cycles were then produced with atrial booster action eliminated by instituting synchronous A-V pacing. The resultant simultaneous contraction of the atrium and ventricle not only eliminated effective atrial systole but also placed atrial systole during the normal period of atrial reservoir function. This also significantly reduced all the hemodynamic measurements. However, comparison of the magnitude of change from these two different pacing interventions showed no greater impairment of hemodynamic state when both booster pump action and reservoir function were impaired than when booster pump action alone was impaired. The study confirms the potential benefit of well placed atrial booster pump action in valvular heart disease in man.

Authors

Fred P. Heidenreich, James A. Shaver, Mark E. Thompson, James J. Leonard

Evidence for suppression of parathyroid gland activity by hypermagnesemia

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Abstract

The effect of hypermagnesemia, produced by MgCl2 infusion, on the activity of parathyroid glands, as assessed by changes in levels of serum calcium (SCa) and in the fraction of filtered phosphate excreted (CP/CCr), was studied in 11 intact and 4 thyroparathyroidectomized (T-PTX) dogs. To exclude the effect of diurnal variation in CP/CCr on the results, studies were initiated in both morning and afternoon hours and each study with MgCl2 infusion was paired with a control experiment in the same dog not receiving MgCl2. During MgCl2 infusion, serum phosphorus rose progressively. Despite this rise, the levels of CP/CCr fell in all experiments and were significantly different from values observed at the same time of the day in the paired control experiments. The concentrations of total SCa fell by 1.0-2.4 mg/100 ml with a proportional decrease in the levels of the diffusible and ionized fractions. The pattern of the fall in CP/CCr during MgCl2 resembled that observed after CaCl2 infusion (seven dogs) and that which acutely followed thyroparathyroidectomy (seven dogs). When parathyroid extract was given to dogs receiving MgCl2 infusion both CP/CCr and SCa rose, and MgCl2 infusion did not affect CP/CCr and SCa in T-PTX dogs. These results indicate that hypermagnesemia suppresses the activity of the parathyroid glands, probably, by inhibiting production and (or) release of the hormone, without interfering with end-organ response. An increase in serum magnesium of 1.7-2.0 mg/100 ml was capable of producing the suppressive effect. Evaluation of the effect of simultaneous modest hypocalcemia and hypermagnesemia suggests that a decrease in the level of serum calcium is more potent than an increase in the concentration of serum magnesium in the regulation of parathyroid activity.

Authors

Shaul G. Massry, Jack W. Coburn, Charles R. Kleeman

The effect of altered sodium concentration in the distal nephron segments on renin release

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Abstract

Ethacrynic acid, a potent inhibitor of sodium reabsorption in the ascending limb of Henle's loop, produces a sharp rise in renal venous renin activity within 5 min after intravenous administration in anesthetized dogs. This response persists when volume depletion is prevented by returning urinary outflow to the femoral vein. Comparable studies with chlorothiazide, a diuretic with little or no effect on the medullary portion of the ascending limb of the loop of Henle, failed to produce a significant increase in renal venous renin activity.

Authors

C. Robert Cooke, Torrey C. Brown, Barry J. Zacherle, W. Gordon Walker

Hormone synthesis and secretion by rat parathyroid glands in tissue culture

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Abstract

Rat parathyroid glands maintained in organ culture secrete biologically active parathyroid hormone (PTH) and synthesize and secrete labeled proteins from 3H- or 14C-labeled amino acids added to the medium. The amounts of biological activity and labeled protein in the medium are both inversely proportional to the calcium concentration. Some of the labeled low molecular weight protein was identified as PTH which had been synthesized and secreted in culture by preliminary isolation on Sephadex G-100 columns and further purification using an antibody to bovine PTH which cross-reacted with rat PTH. The cross-reacting antibody inhibited the biological effects of rat PTH and caused hypocalcemia in intact rats. The antibody bound some of the labeled low molecular weight protein of the medium at neutral pH so that it migrated as a large molecular weight complex on Sephadex. Biologically active, labeled PTH was recovered by dissociation of this complex in acid and rechromatography.

Authors

William Y. W. Au, Alan P. Poland, Paula H. Stern, Lawrence G. Raisz

The role of pH, P_CO2, and bicarbonate in regulating rat diaphragm citrate content

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Abstract

Intact rat diaphragms were exposed in vitro to varying CO2 tensions and bicarbonate concentrations, and the steady-state citrate content of diaphragm muscle was measured to investigate the relationship between metabolism and extracellular pH, PCO2, and (HCO3-). In addition, rat hemidiaphragms were incubated with 1,5-citrate-14C under different acid-base conditions, and 14CO2 production was determined as a measure of citrate oxidation.

Authors

Sheldon Adler

Effects of hematocrit on renal hemodynamics and sodium excretion in hydropenic and volume-expanded dogs

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Abstract

The effects of hematocrit on renal hemodynamics and sodium excretion were studied in anesthetized dogs during both hydropenia and volume expansion. The hematocrit was decreased by isovolemic exchange with the animal's own previously harvested plasma and increased by isovolemic exchange with fresh, washed red blood cells. Renal perfusion pressure was maintained constant throughout the experiments by the adjustment of a suprarenal aortic clamp. During hydropenia, a decrease in hematocrit was associated with an increase in sodium and potassium excretion and solutefree water reabsorption. These changes were accompained by an increase in renal plasma flow and renal blood flow and a decrease in renal vascular resistance. Glomerular filtration rate was unchanged and filtration fraction was significantly decreased as hematocrit was lowered. Increasing hematocrit during hydropenia had the opposite effects on electrolyte excretion, solute-free water reabsorption, and renal hemodynamics. In another group of animals, hematocrit was lowered during volume expansion with either saline or plasma, then returned to the control level by isovolemic exchange with washed red blood cells. This increase in hematocrit during volume expansion had a similar effect on electrolyte excretion, solute-free water reabsorption, and renal hemodynamics as during hydropenia. These results therefore suggest that acute changes in hematocrit may significantly affect sodium excretion and renal hemodynamics during both hydropenia and volume expansion. The changes in solute-free water reabsorption and potassium excretion suggest that the alterations in hematocrit may affect primarily the reabsorption of sodium in the proximal tubule. The concommitant effects of hematocrit on renal vascular resistance and filtration fraction may mediate this change in sodium reabsorption by altering hydrostatic and oncotic pressures in the peritubular circulation.

Authors

Robert W. Schrier, Laurence E. Earley

Release of phospholipid fatty acid from human erythrocytes

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Abstract

To study the catabolism of erythrocyte phospholipids, human erythrocytes were labeled with radioactive fatty acid (FA). Labeling was performed by the two separate routes which together are thought to be responsible for the majority of phosphatide renewal in the red cell: (a) passive equilibration of erythrocytes with preformed acid-labeled red cell phosphatidylcholine (PC) and (b) active, “acylase”-dependent, incorporation of free fatty acid in the presence of ATP coenzyme A and magnesium. (As measured here “acylase” = the over-all effect of fatty acid thioesterification and the action of acyl-CoA: acylglycerophosphoryl acyltransferase.) The labeled cells were then reincubated in serum and the loss of radioactivity from cells into serum was examined.

Authors

Stephen B. Shohet

The effect of hydrocortisone on immunoglobulin metabolism

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Abstract

The serum concentration of all subclasses of IgG (γ2A, γ2B, and γ1) as well as IgA and IgM were reduced in normal and low pathogen mice receiving hydrocortisone acetate. Turnover studies using 131I-labeled γ2A subclass of IgG demonstrated that high dose corticosteroids cause a significantly shortened survival (increased catabolic rate) which contributes to the observed hypogammaglobulinemia. This increase in fractional catabolism is not due to excess loss in the urine or stool but reflects an increase in endogenous catabolism.

Authors

Arthur L. Levy, Thomas A. Waldmann

Effect of insulin and acute diabetes on plasma FFA and ketone bodies in the fasting rat

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Abstract

The metabolism of FFA and ketone bodies was studied in fasted rats by infusing at a constant rate tracer amounts of FFA-3H, β-hydroxybutyrate-14C or acetoacetate-14C for periods up to 2 hr. Blood that was removed for analyses was replaced by continuous transfusion. The rates of turnover of FFA, β-hydroxybutyrate, and acetoacetate in rats fasted for 2 days were, respectively, 3.2, 5.6, and 2.5 μmoles/100 g body weight per min.

Authors

Frederick A. Bieberdorf, Sidney S. Chernick, Robert O. Scow

Serum and urinary proteins, lysozyme (muramidase), and renal dysfunction in mono- and myelomonocytic leukemia

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Abstract

Serum levels, urinary excretion, and clearances of several proteins of different molecular weights were studied in 18 patients with mono- and myelomonocytic leukemia. Nine patients had normal renal function (group A) and nine had impaired renal function with azotemia (group B). The majority of patients in both groups had increased concentration of immunoglobulins, particularly IgG, IgA, and IgM; IgD level was normal. Serum transferrin and α2-macroglobulin were frequently reduced while the level of ceruloplasmin was often increased, especially in patients with azotemia. The activity of lysozyme in the serum was high in all patients, but was considerably higher in group B.

Authors

W. Pruzanski, M. E. Platts

Detection of thrombopoietic activity in plasma by stimulation of suppressed thrombopoiesis

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Abstract

Rabbits in which thrombocytosis had been produced by five daily transfusions of platelet concentrates had suppressed endogenous thrombopoiesis, as reflected by decreased incorporation of selenomethionine-75Se (75SeM) into the circulating platelet mass. Rabbits in which endogenous thrombopoiesis had been suppressed by transfusion-induced thrombocytosis were used to detect thrombopoietic activity in rabbit plasma. Thrombopoietic activity was demonstrated in the plasma of both normal and thrombocytopenic donor rabbits. A dose response relationship was observed between the incorporation of 75SeM into platelets and the dose of plasma administered. Infusion of 20-150 ml of plasma from thrombocytopenic donors increased the incorporation of 75SeM into platelets from 52 to 107% above control values. A dose response effect also was seen after infusion of normal plasma, but normal plasma produced less effect than comparable doses of plasma from thrombocytopenic donors.

Authors

David P. Shreiner, Jack Levin

Hydrocortisone choleresis in the dog

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Abstract

Hydrocortisone sodium succinate (Solu-Cortef; Upjohn Co., Kalamazoo, Mich.) has been found to induce choleresis in unanesthetized fasting dogs fitted with Thomas duodenal cannulae for direct quantitative collection of bile. In all experiments, bile flow increased (average, 68%) 15-20 min after beginning hydrocortisone by infusion in association with an equivalent increment in the output of sodium, potassium, chloride, and bicarbonate. In five animals, the choleretic response occurred independently of, and apparently additive to, the effect of simultaneously administered sodium taurocholate. The fluid added to the bile resembled an ultrafiltrate of plasma. Erythritol clearance increased in proportion to flow, suggesting an effect at the hepatocellular rather than ductal level and probably independent, therefore, of endogenous secretin release. Hydrocortisone and its metabolites were excreted in amounts too small to induce choleresis osmotically. Simultaneous administration of sulfobromophthalein sodium blocked the choleretic response without preventing hydrocortisone excretion. The data suggest that a previously ill-defined mechanism of canalicular bile formation, not mediated by bile salt excretion, may be operative in choleretic response to a variety of agents.

Authors

Veronika Macarol, Thomas Q. Morris, Katharine J. Baker, Stanley E. Bradley

On the role of antidiuretic hormone in the inhibition of acute water diuresis in adrenal insufficiency and the effects of gluco- and mineralocorticoids in reversing the inhibition

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Abstract

In order to determine whether or not antidiuretic hormone (ADH) is essential to the inhibition of an acute water diuresis in adrenal insufficiency, the response to oral water loads was tested in rats with hereditary hypothalamic diabetes insipidus (DI) which lack ADH. It was found that 60 min after water loads of 3 or 5% of body weight urine flow was significantly lower and urine osmolality significantly higher in adrenalectomized DI rats than in the same DI rats before removal of their adrenal glands.

Authors

Howard H. Green, Avery R. Harrington, Heinz Valtin

Dihydrotestosterone in prostatic hypertrophy: I. The formation and content of dihydrotestosterone in the hypertrophic prostate of man

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Abstract

To explore the relation between androgens and prostatic hypertrophy in man, the concentrations of testosterone, dihydrotestosterone, and androstenedione and the rate of conversion of testosterone to dihydrotestosterone have been measured in normal and hypertrophic prostate tissue. First, a double isotope derivative technique was adapted for the measurement of tissue androgen content in 15 normal and 10 hypertrophic prostates. Although there was no significant difference in the content of androstenedione and testosterone between the two types of tissue, the content of dihydrotestosterone was significantly greater in the hypertrophic tissue (0.60 ±0.10 μg/100 g) than in the normal glands (0.13 ±0.05 μg/100 g). Second, a regional study was performed in three normal prostates and four glands with early hypertrophy, and it was demonstrated that the dihydrotestosterone content was two and three fold greater in the periurethral area where prostatic hypertrophy usually commences than in the outer regions of the gland. Finally, the rate of conversion of testosterone to dihydrotestosterone has been measured under standardized conditions in tissue slices from 4 normal and 20 hypertrophic prostates. There was no significant difference in the rate of dihydrotestosterone formation between the two types of gland (6.0 ±0.8 and 7.8 ±0.5 μμmoles/15 mg of tissue per hr). While the mechanism by which dihydrotestosterone accumulation occurs remains unexplained, it is possible that the local accumulation of dihydrotestosterone may be involved in the pathogenesis of prostatic hypertrophy in man.

Authors

Pentti K. Siiteri, Jean D. Wilson

Dihydrotestosterone in prostatic hypertrophy: II. The formation and content of dihydrotestosterone in the hypertrophic canine prostate and the effect of dihydrotestosterone on prostate growth in the dog

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Abstract

Three types of studies have been performed in immature, mature, and hypertrophic prostate glands of the dog. First, the concentrations of testosterone and dihydrotestosterone have been measured in the three types of gland. Dihydrotestosterone was the predominant hormone recovered in all prostates studied and was present in approximately five times higher concentration in the hypertrophic as compared to the other types of dog prostate. Second, pharmacological doses of dihydrotestosterone were administered to castrated dogs for 9 months and resulted in a distinct acceleration of prostatic growth as compared to testosterone treatment. Third, the rates of formation and degradation of dihydrotestosterone were measured in normal and hypertrophic tissue and were found to be essentially the same. These observations suggest that dihydrotestosterone accumulation may be causally linked to the development of canine prostatic hypertrophy. However, the mechanism by which dihydrotestosterone accumulates in the prostate remains to be determined.

Authors

Robert E. Gloyna, Pentti K. Siiteri, Jean D. Wilson

Radioimmunoassay of human plasma retinol-binding protein

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Abstract

A radioimmunoassay for human plasma retinol-binding protein (RBP) has been developed utilizing a double antibody precipitation technique. RBP was purified 1500- to 2000-fold by procedures described previously. A specific anti-human RBP antiserum was prepared in rabbits by three once-weekly injections of purified RBP emulsified with Freund's adjuvant. RBP was iodinated with 131I and the RBP-131I was purified by gel filtration on Sephadex G-100 after complex formation with human plasma prealbumin. The RBP-131I was completely (> 95%) immunoprecipitable in the presence of an excess of specific antiserum, it was not (< 5%) immunoprecipitable in the absence of specific antiserum, and it could be completely displaced from antibody by excess unlabeled RBP. The standard curve obtained in the immunoassay with normal plasma was identical to that with pure RBP. Duplicate samples differed from their mean by 5 ±5% (±SD). There was a quantitative recovery of pure RBP added in varying amounts to normal plasma. The immunoassay accurately measured RBP in amounts of 10-100 ng per assay tube. There was no significant difference in the immunoreactivity of apo-RBP as compared to holo-RBP. The mean plasma values (±SEM) for a group of 76 normal subjects were 47.2 ±1.6 μg/ml for males and 41.6 ±1.6 μg/ml for females. Plasma RBP levels were markedly depressed (15 ±2.3 μg/ml) in 14 patients with acute viral hepatitis. There was a highly significant correlation between the plasma levels of RBP and of vitamin A in both normal subjects and patients with hepatitis. In all subjects plasma RBP was generally saturated with retinol. The data suggest that under normal circumstances RBP circulates almost exclusively as the holoprotein.

Authors

Frank Rees Smith, Amiram Raz, DeWitt S. Goodman

Homocystinuria due to cystathionine synthase deficiency: the effect of pyridoxine

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Abstract

We investigated the effect of pyridoxine administration in three patients with homocystinuria due to cystathionine synthase deficiency. The drug decreased the plasma concentration and urinary excretion of methionine and homocystine and the urinary excretion of homolanthionine and the homocysteine-cysteine mixed disulfide. Urinary cystine rose somewhat. Oral methionine tolerance tests before and during the patients' response to pyridoxine indicated that during response they remained deficient in their capacity to convert the sulfur of methionine to inorganic sulfate, although this capacity increased somewhat. During pyridoxine response only, the methionine loads caused increased homocystinuria. There was no indication that pyridoxine stimulated an alternate pathway of metabolism. The values for specific activity of cystathionine synthase in liver biopsy specimens from two patients in pyridoxine response were 3 and 4% of the mean control value. When these patients were not receiving pyridoxine, comparable values were 2 and 1%, respectively. The hepatic enzyme activity of the mutant patients was similar to normal enzyme activity with respect to trypsin activation, heat inactivation, and stabilization by pyridoxal phosphate. Approximate estimates were made of the relation between total body capacity to metabolize methionine and hepatic cystathionine synthase activity. These estimates suggested that because of the large normal reserve capacity of cystathionine synthase, a few per cent residual activity is sufficient to metabolize the normal dietary load of methionine. Thus, small increases in residual capacity may be of major physiological importance. However, many liver biopsies would be required to establish unequivocally that such changes were due to the administration of a particular therapeutic agent rather than to biological variation. All the data in the present study are consistent with the interpretation that pyridoxine does act by causing an increase in residual cystathionine synthase activity.

Authors

S. Harvey Mudd, William A. Edwards, Peter M. Loeb, Michael S. Brown, Leonard Laster