Vascular responses after alpha adrenergic receptor blockade: I. Responses of capacitance and resistance vessels to norepinephrine in man

• Text
• PDF

Abstract

Experiments were done to test the hypothesis that alpha receptor blockers antagonize more effectively venous than arterial responses to norepinephrine in man.

Authors

Francois M. Abboud, Phillip G. Schmid, John W. Eckstein

Vascular responses after alpha adrenergic receptor blockade: II. Responses of venous and arterial segments to adrenergic stimulation in the forelimb of dog

• Text
• PDF

Abstract

The effects of nerve stimulation and of intraarterial injections of norepinephrine on arterial and venous resistances were studied in the perfused forelimb of dog before and after administration of the alpha adrenergic receptor blocker phenoxybenzamine.

Authors

Francois M. Abboud, John W. Eckstein

Estradiol metabolism in cirrhosis

• Text
• PDF

Abstract

Abnormal estrogen metabolism has been found in cirrhosis after administration of intravenous tracers of estradiol-3H to 6 patients and 23 healthy controls. The major abnormalities observed involved estrogen metabolites other than the 3 “classic” ones, i.e., estrone (E1), estradiol (E2), and estriol (E3). Urinary recovery of radioactivity was regularly elevated in the patients, to an average of 71% of the dose compared to 51% in normals. This is considered to reflect the component of intrahepatic cholestasis in cirrhosis. The per cent dose recovered as urinary glucosiduronates (42%) was normal in cirrhotics in contrast to impaired glucuronidation of cortisol metabolites in this disease. E1 and E2 were present in normal amounts, and E3 was slightly elevated to 21% of the extract compared to 14% in controls. There were strikingly decreased excretion of 2-hydroxyestrone (3% compared with normal 20%) and 2-methoxyestrone (2% compared with 5%) and increased excretion of 16α-hydroxyestrone (12% compared with normal 6%). Thus cirrhosis, too, is characterized by the reciprocal relationship between decreased 2-hydroxylation and increased 16α-hydroxylation previously described in hypothyroidism and male breast cancer. However, unlike these latter, the increase of 16α-hydroxy metabolites was less than the decrease of 2-hydroxy metabolites. The data indicate clearcut impairment of 2-hydroxylation, suggestive impairment of 16α-hydroxylation, and a definite depression of the reaction 16α-hydroxyestrone→estriol, the latter finding so far unique to cirrhosis. Demonstration of abnormal peripheral metabolism of estrogen in cirrhosis provides a new approach to the origin of the hyperestrogenic syndrome in this disease.

Authors

Barnett Zumoff, Jack Fishman, T. F. Gallagher, Leon Hellman

Estimation of thyroxine distribution in man

• Text
• PDF

Abstract

A group of 13 normal subjects were evaluated for their extrathyroidal thyroxine distribution. The method employed the measurement of the acute plasma disappearance of a thyroxine-131I tracer and its concomitant uptake into the liver and forearm. The analysis of these parameters allowed the theoretical construction of a four compartmental mathematical model system comprised of the plasma, extracellular fluid, hepatic, and extrahepatic thyroxine pools. The results of this analysis revealed that the exchange of thyroxine from the plasma into the hepatic and extrahepatic cellular fluid spaces appeared, in general, to be rapid, while the uptake into the extrahepatic tissues was relatively slow. The calculated distribution of thyroxine at equilibrium was estimated to be 14% in liver, 34% in extrahepatic tissues, and 26% each in the plasma and extracellular fluid pools in this group of normal subjects.

Authors

J. T. Nicoloff, J. Thomas Dowling

Metabolic clearance and production rates of human luteinizing hormone in pre- and postmenopausal women

• Text
• PDF

Abstract

Metabolic clearance rates and production rates of human luteinizing hormone (HLH) were determined in pre- and postmenopausal women by the constant infusion technique. Highly purified HLH-131I was infused into the fasting subjects at a constant rate. Serial plasma samples were obtained and the radioactive hormone was precipitated by a double antibody technique. Plasma HLH-131I levels reached equilibrium by 4 hr after the infusion started. Metabolic clearance rates were: 24.4 ± 1.8 (mean ± SE) ml/min in five normal premenopausal women; 23.3 ± 1.1 ml/min in five normal women taking norethinodrel and mestranol; and 25.6 ± 4.1 ml/min in four postmenopausal women. Endogenous plasma HLH levels measured in the same subjects by radioimmunoassay immediately before infusion were 32.0 ± 9.6 mU/ml in the normal women, 16.8 ± 3.2 mU/ml in the women on oral contraceptives, and 99.2 ± 23.2 mU/ml in the postmenopausal women. The corresponding HLH production rates were: 734 ± 170 mU/min in the normal women: 387 ± 86 mU/min in the women on norethinodrel and mestranol; and 2400 ± 410 mU/min in the postmenopausal women. The metabolic clearance rate did not change after ovariectomy in one women, but the production rate rose from 583 to 1420 mU/min. Based on previously reported bioassay values for pituitary content and urinary excretion of HLH, the estimated turnover of HLH in the pituitary is about once per day and less than 5% of the total HLH produced appears in the urine in a biologically active form.

Authors

Peter O. Kohler, Griff T. Ross, William D. Odell

Characterization of the responses of circulating glucagon-like immunoreactivity to intraduodenal and intravenous administration of glucose

• Text
• PDF

Abstract

The effects of ingested and infused glucose upon circulating glucagon-like immunoreactivity (GLI) were compared in 14 triply catheterized conscious dogs. Within 60 min after the intraduodenal administration of 2 g/kg of glucose, the mean level of glucagon-like immunoreactivity in the vena caval plasma more than doubled, whereas after intravenous infusion of the same dose over a 90 min period no change in the mean vena caval level was observed; during glucose infusion mean glucagon-like immunoreactivity in the pancreatic venous effluent declined, suggesting that hyperglycemia suppresses rather than stimulates pancreatic glucagon secretion.

Authors

Roger H. Unger, Akira Ohneda, Isabel Valverde, A. M. Eisentraut, John Exton

Reduced nicotinamide adenine dinucleotide and the reduction of oxidized glutathione in human erythrocytes

• Text
• PDF

Abstract

The ability of reduced nicotinamide adenine dinucleotide (NADH), generated through the activity of lactic acid dehydrogenase, to support the reduction of endogenous oxidized glutathione in intact human erythrocytes and in hemolysates was investigated. Rapid initial oxidation of endogenous reduced glutathione was effected with methyl phenylazoformate. Freshly obtained normal erythrocytes and erythrocytes deficient in glucose-6-phosphate dehydrogenase activity were unable to regenerate reduced glutathione upon incubation with lactate. Only normal erythrocytes were capable of reducing oxidized glutathione after preincubation with glucose, inosine, or a medium which promoted the synthesis of increased amounts of intracellular NAD. This regeneration of reduced glutathione could be explained by the generation of reduced nicotinamide adenine dinucleotide phosphate through the metabolism of accumulated phosphorylated intermediates of glycolysis. Hemolysates prepared from both normal erythrocytes and from erythrocytes deficient in glucose-6-phosphate dehydrogenase activity were able to reduce oxidized glutathione in the presence of added lactate and NAD. The results obtained indicated either an inability of the intact erythrocyte to utilize the NAD at the concentrations attained or an altered behavior of the system for the regeneration of reduced glutathione after lysis of the cell.

Authors

Egmond E. Rieber, Nechama S. Kosower, Ernst R. Jaffé

The phospholipid requirement of tissue factor in blood coagulation

• Text
• PDF

Abstract

Using a coagulation assay specific for tissue factor, we found that removal of 95% of the tissue factor-phospholipid resulted in a loss of 98% of its biological activity. The activity could be restored, with yields in excess of 100% by combining the extracted tissue factor with either mixed brain phospholipids or highly purified phospholipids. Phosphatidylethanolamine was the most active, followed by phosphatidylcholine. Phosphatidylserine, phosphatidylinositol, and sphingomyelin had little or no activity. In addition, a requirement for unsaturation and the presence of two fatty acids was demonstrated. The activity of phosphatidylcholine was also dependent on the presence of the base. Furthermore, it was shown that activity was not a function of binding of phospholipids to tissue factor, as both active and inactive lipids were equally bound.

Authors

Yale Nemerson

Regional distribution of pulmonary ventilation and perfusion in elderly subjects

• Text
• PDF

Abstract

Using radioactive xenon, we measured the regional distribution of pulmonary ventilation and blood flow in six normal men, whose ages ranged between 65 and 75 yr. The measurements were made in the standing position. The static volume-pressure relation of the lungs was also measured in five of the subjects. The results indicate that by comparison with normal young men: (a) Blood flow to the upper lung zones was increased, although it still remained predominant in the lower zones. (b) Ventilation distribution during a vital capacity inspiration was similar to that seen in young subjects. (c) In five of the six elderly subjects, however, the distribution of ventilation in the resting tidal volume range was not preferential to the lower zones as it was in young men. This was probably caused by airway closure in the lower lung zones. The elderly subjects thus exhibit during normal tidal volume breathing a ventilation distribution pattern similar to that observed in young subjects when breathing at low lung volumes, i.e., near residual volume. This difference is probably due to the combined effect of the loss in elastic recoil of the lungs observed in the elderly subjects and of a decreased resistance to collapse of the aged airways. These findings suggest that in the elderly subjects there is a significant regional ventilation-perfusion impairment during quiet breathing, which may explain in part the reported increase in alveolar-arterial oxygen difference with advancing age.

Authors

J. Holland, J. Milic-Emili, P. T. Macklem, D. V. Bates

Metabolic clearance rates and interconversions of estrone and 17β-estradiol in normal males and females

• Text
• PDF

Abstract

The continuous infusion of 3H-6,7-estrone and 3H-6,7-estradiol has been used to study the metabolic clearance rate (MCR), the interconversions, and the red cell uptake of these steroids in normal males and females. The whole blood MCR of estrone is 1,990 ± 120 liters per day/m2 (SE) in males and 1,910 ± 100 liters per day/m2 in females. The whole blood MCR of estradiol is 1,600 ± 80 liters per day/m2 in males and 1,360 ± 40 liters per day/m2 in females. The values in females do not vary significantly when studied in the follicular or luteal phase of the cycle. At least 35% of the total estrone metabolism in both sexes is extrasplanchnic and at least 25% of the total estradiol metabolism in males, and 15% in females is extrasplanchnic. The [ρ]BB2,1 [transfer constant of estradiol to estrone, which is equivalent to the fraction of the precursor (estradiol) converted to the product (estrone) when both the infusion of the precursor and the measurement of the product are in peripheral blood] is 15%; and the [ρ]BB1,2 [transfer constant of estrone to estradiol, which is equivalent to the fraction of the precursor (estrone) converted to product (estradiol) when both the infusion of the precusor and the measurement of the product are in peripheral blood] is 5% in both males and females. Our findings concerning the radioactivity in whole blood, as measured by our procedure, were the following: 15-20% of estrone in both sexes and 15% of estradiol in males is associated with red cells. Only 2% of the whole blood radioactivity of estradiol in females is associated with red cells. Changes in the distribution of radioactivity between plasma and red cells will influence the MCR as calculated from plasma, but not as calculated from whole blood.

Authors

Christopher Longcope, Donald S. Layne, James F. Tait

Studies on steroid fever: I. Production of leukocyte pyrogen in vitro by etiocholanolone

• Text
• PDF

Abstract

When a serum-buffer solution of etiocholanolone is incubated with human blood leukocytes in vitro, a pyrogen is released. Like endogenous pyrogen of leukocyte origin, this pyrogen produces prompt monophasic fevers in rabbits, does not induce fever tolerance when given daily, and is inactivated by trypsin. In many respects, the characteristics of the in vitro reaction resemble experimental steroid-induced fever. For example, release of pyrogen varies directly with the concentration of steroid. 4-8 hr of contact between steroid and leukocyte is required for activation of the cell. Rabbit leukocytes are not activated by etiocholanolone. Finally, androsterone, the 5α-isomer of etiocholanolone, does not induce pyrogen release in vitro. These studies suggest that experimental steroid fever in man may be mediated by an endogenous pyrogen released from leukocytes.

Authors

Phyllis Bodel, Morris Dillard

The influence of the parathyroid glands on the hypercalcemia of experimental magnesium depletion in the rat

• Text
• PDF

Abstract

Magnesium-deficient rats develop significant hypercalcemia, hypophosphatemia, and hyperphosphaturia. These changes suggest a state of hyperparathyroidism. This study examines the regulation of parathyroid gland activity in magnesium-deficient rats. Magnesium deficiency was induced in intact and chronically parathyroidectomized animals by feeding them a diet free of this cation. Control animals were pair fed and treated identically except for the inclusion of magnesium in their gavage solution.

Authors

H. J. Gitelman, S. Kukolj, L. G. Welt

Usefulness of chromic oxide as an internal standard for balance studies in formula-fed patients and for assessment of colonic function

• Text
• PDF

Abstract

In 35 patients maintained solely on liquid formula diets, chromic oxide has been evaluated as an internal standard for balance studies that require stool collections. In 28 patients the excretion of chromic oxide was ideal: steady states were attained in which mean daily output was 90% (or more) of mean daily intake. In these patients corrections for fecal flow could validly be applied.

Authors

Jean Davignon, W. J. Simmonds, E. H. Ahrens Jr.

Role of the venous system in baroreceptor-mediated reflexes in man

• Text
• PDF

Abstract

Although baroreceptor stimulation produced by marked alterations in arterial pressure has been shown to produce reflex changes in venous tone in animals, the effects on venous tone in man of altering arterial pressure within the physiologic range have not been clear. In six subjects, venous tone did not change when mean arterial pressure was raised by 25-40 mm Hg, although heart rate fell reflexly by 40%. Venous tone remained constant in 10 subjects when arterial pressure was lowered. This contrasted to the sustained rise in forearm vascular resistance and the persistent tachycardia that occurred. However, 12 subjects continued to respond to these interventions by transient venoconstriction. To eliminate possible emotional influences on venous tone due to the experimental intervention, venous responses were studied before and during general anesthesia in five of these subjects. In contrast to the response before anesthesia, an equivalent fall in arterial pressure during anesthesia no longer evoked a venoconstrictor response. Venous reactivity and the baroreceptor reflex arc remained intact during anesthesia, since venous tone always rose after a deep inspiration, and tachycardia always accompanied the fall in arterial pressure. It is concluded that changes in arterial pressure in the physiologic range in man do not induce measurable reflex alterations in venous tone, and that the increases sometimes seen with decreases in arterial pressure appear to be due to extraneous psychic factors.

Authors

Stephen E. Epstein, G. David Beiser, Morris Stampfer, Eugene Braunwald

The role of adipose cell size and adipose tissue insulin sensitivity in the carbohydrate intolerance of human obesity

• Text
• PDF

Abstract

Glucose metabolism and insulin sensitivity of isolated human adipose tissue was studied as a function of adipose cell size and number. Glucose metabolism by these tissues was closely related to the number of cells in the fragment, irrespective of cell size. Adipose cells of obese individuals metabolized glucose to carbon dioxide and triglyceride at rates similar to adipose cells of nonobese subjects. In contrast, insulin responsiveness of adipose tissue was dependent upon adipose cell size. The larger its adipose cells the less insulin sensitive was the tissue. Thus, adipose tissue of obese subjects, with enlarged cells, showed a diminished response to insulin. After weight loss and reduction in adipose cell size, insulin sensitivity of the adipose tissue of obese patients was restored to normal. When adipose tissue of obese individuals showed impaired responsiveness to insulin, their plasma insulin levels, after oral glucose, were elevated. Weight loss and reduction in adipose cell size restored plasma insulin concentration to normal, concomitant with the return of normal tissue insulin sensitivity.

Authors

Lester B. Salans, Jerome L. Knittle, Jules Hirsch

Cholesterol synthesis in the squirrel monkey: relative rates of synthesis in various tissues and mechanisms of control

• Text
• PDF

Abstract

Cholesterol synthesis has been extensively investigated in various tissues of lower mammals; however, there is little specific information concerning cholesterologenesis in the primate. Furthermore, experiments in whole animals suggest that important differences may exist in the features of cholesterologenesis in the dog and rat versus the monkey and man. Using the new world squirrel monkey, therefore, we performed the present studies to determine the rates of cholesterologenesis in various tissues per unit weight, to define the relative rates of whole organ synthesis, and to evaluate the operation of control mechanisms in these tissues.

Authors

John M. Dietschy, Jean D. Wilson

Biosynthetic origin of serum cholesterol in the squirrel monkey: evidence for a contribution by the intestinal wall

• Text
• PDF

Abstract

The possibility that the intestinal wall serves as a biosynthetic site for serum cholesterol has been examined in two types of studies in the squirrel monkey. First, animals were fed cholesterol in order to inhibit cholesterol synthesis in the liver, and the intestinal lymph ducts were cannulated. After the administration of acetate-2-14C it was possible to demonstrate that cholesterol synthesized by the intestinal wall enters intestinal lymph and thereby in the intact animal enters the circulating pool. Second, an attempt to quantitate the significance of this intestinal contribution has been made in animals fed cholesterol-3-3H and injected with cholesterol-4-14C for long periods. By an application of the technique of analysis utilizing the isotopic steady state we estimated as a minimal value that in the squirrel monkey 1.5-2.0 mg of cholesterol synthesized in the intestinal wall reaches the circulation each day.

Authors

Jean D. Wilson

Respiratory adjustment to chronic metabolic alkalosis in man

• Text
• PDF

Abstract

This study examined the ventilatory adjustment to chronic metabolic alkalosis induced under controlled conditions in normal human volunteers. Metabolic alkalosis induced by buffers (sodium bicarbonate, trishydroxymethylamine methane) or ethacrynic acid was associated with alveolar hypoventilation, as evidenced by a rise in arterial Pco2, a fall in arterial Po2, a reduced resting tidal volume, and a diminished ventilatory response to CO2 inhalation. Alveolar hypoventilation did not occur when metabolic alkalosis was induced in the same subjects by thiazide diuretics or aldosterone despite comparable elevations of the arterial blood pH and bicarbonate concentration.

Authors

Roberta M. Goldring, Paul J. Cannon, Henry O. Heinemann, Alfred P. Fishman

Micropuncture study of nephron function in the rhesus monkey

• Text
• PDF

Abstract

The function of the proximal and distal tubule was studied in the rhesus monkey during antidiuresis and during the diuresis after furosemide administration (during which extracellular fluid volume was maintained).

Authors

Cleaves M. Bennett, Barry M. Brenner, Robert W. Berliner

The effect of steady-state increases in systemic arterial pressure on the duration of left ventricular ejection time

• Text
• PDF

Abstract

The effect of steady-state increases in systemic arterial pressure on the duration of left ventricular ejection time was studied in 11 normal male subjects. Methoxamine, a pressor amine of predominantly vasoconstrictor activity but lacking significant inotropic effect, was administered intravenously resulting in an average increase in mean arterial pressure of 27 mm Hg. Heart rate was held constant by high right atrial pacing, and there was no significant change in cardiac output. During methoxamine infusion, when stroke volume, heart rate, and inotropic state were held constant, left ventricular ejection time increased as mean arterial pressure increased. There was a highly significant correlation between the increase in mean systolic blood pressure and the prolongation of left ventricular ejection time (r = 0.870). In one subject, an increase in mean systolic pressure of 75 mm Hg prolonged left ventricular ejection time 55 msec, producing paradoxical splitting of the second heart sound. The prolongation of left ventricular ejection time during infusion was not blocked by the prior intravenous administration of atropine sulfate or propranolol hydrochloride, thus ruling out both vagal inhibition of the left ventricle and reflex withdrawal of sympathetic tone as its cause. In three subjects, left ventricular end diastolic pressure was measured and found to be significantly increased. This finding suggests that the normal left ventricle maintains a constant stroke volume in the presence of an increased pressure load by the Frank Starling mechanism. This study concludes that arterial pressure must be included as a prime determinant of left ventricular ejection time along with stroke volume, heart rate, and inotropic state in intact man.

Authors

James A. Shaver, Frank W. Kroetz, James J. Leonard, H. W. Paley