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Biomedical subjects

S Carlone

Publications and source records attributed to S Carlone.

At least 19 recordsLinked to original sources
PubMed2001

HIV type 1 Tat protein is a survival factor for Kaposi's sarcoma and endothelial cells.

The HIV-1 Tat protein has been directly implicated in the pathogenesis of AIDS-related Kaposi's sarcoma (KS); however, its effects on KS spindle-shaped and endothelial cell apoptosis are largely unexplored. Since susceptibility to apoptosis is relevant for tumor development and response to therapy, we investigated the effects of Tat on KS and endothelial cell survival from apoptosis. The effect of Tat was evaluated in three KS cell lines (KS-imm, KS-C1, and KS-L3) exposed to the chemotherapy agent vincristine, currently used for the treatment of this tumor, and in human umbilical vein-derived endothelial cells (HUVECs) induced to undergo apoptosis by serum withdrawal. Apoptosis was assessed by enzymatic assays, microscopic examination of chromatin and cytoskeleton, evaluation of plasma membrane integrity and subdiploid DNA content, TUNEL assays, and measurement of caspase-3 activity. Tat, in a dose-dependent manner, protected the three KS cell lines and HUVECs from apoptosis induced by vincristine or serum starvation, respectively. This effect appeared to be independent of modulation of Fas, Bcl-2, or Bax expression. In contrast, Tat upregulated Bcl-X(L) expression and induced a relevant decrease in caspase-3 activity in vincristine-treated KS cells. Taken together, these results suggest that the HIV-1 Tat protein may factor KS development and progression by sustaining endothelial and transformed cell survival.

Apoptosis↗
PubMed2000

N-Acetylcysteine counteracts erythrocyte alterations occurring in chronic obstructive pulmonary disease.

A key role has been proposed for reactive oxygen species (ROS) in chronic obstructive pulmonary disease (COPD). Aim of the present work was to evaluate possible implications of ROS in the integrity and function of the cell type mainly involved in oxygen uptake and delivery to the peripheral tissues: the erythrocyte. Red blood cells (RBCs) were thus collected from blood samples from COPD patients. Furthermore, blood samples from the same patients treated with the antioxidizing drug of widespread use in such disease i.e., N-acetylcysteine (NAC), were also considered. Morphometric and analytical cytology studies were then conducted. We report herein that: (i) alterations of RBC ultrastructure were detectable in RBCs from COPD patients, that (ii) relevant changes of spectrin cytoskeleton and glycophorin expression were also found and that (iii) NAC treatment was capable of significantly counteracting these changes. These results are consistent with a reappraisal of the role of RBCs in this disease.

Acetylcysteine↗
PubMed2000

Kaposi's sarcoma cells of different etiologic origins respond to HIV-Tat through the Flk-1/KDR (VEGFR-2): relevance in AIDS-KS pathology.

Kaposi's sarcoma (KS) is an hyperplastic lesion whose main histological features are typical spindle shaped cells with a mixed endothelial-mesenchymal-macrophage phenotype, an intense vascularization and an inflammatory infiltrate. The etiology of KS appears to be linked to activation of a latent HHV8 infection. Sporadic and iatrogenic KS are slow progressing lesions that can undergo spontaneous regression. In contrast, KS, which is frequently associated with HIV infection, is found in a highly aggressive form in AIDS patients. The HIV-1 Tat has been shown to activate the VEGF receptor KDR in endothelial and KS spindle cells, suggesting this HIV protein could contribute to KS pathogenesis. We used primary 'reactive' KS cell culture from sporadic and epidemic KS, and an immortal KS-line (KS-Imm) isolated in our laboratory from a iatrogenic KS lesion, to verify if Tat-induced cell signaling is able to mediate cellular responses. We demonstrate that KS cells migrated in response to Tat and that VEGF is able to compete with the Tat chemotactic activity towards these cells. A function-blocking anti-KDR antibody was able to abrogate both VEGF and Tat-induced KS chemotactic response, indicating a direct involvement of this receptor. Our data show that HIV-Tat can also activate KS cells derived from sporadic or iatrogenic lesions, suggesting that in AIDS patients Tat could cooperate with VEGF in activation of KDS on KS precursor spindle and endothelial cells, and contribute to the aggressiveness of AIDS-KS lesions.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Ventilatory and metabolic adaptations to walking and cycling in patients with COPD.

To test the hypothesis that in chronic obstructive pulmonary disease (COPD) patients the ventilatory and metabolic requirements during cycling and walking exercise are different, paralleling the level of breathlessness, we studied nine patients with moderate to severe, stable COPD. Each subject underwent two exercise protocols: a 1-min incremental cycle ergometer exercise (C) and a "shuttle" walking test (W). Oxygen uptake (VO(2)), CO(2) output (VCO(2)), minute ventilation (VE), and heart rate (HR) were measured with a portable telemetric system. Venous blood lactates were monitored. Measurements of arterial blood gases and pH were obtained in seven patients. Physiological dead space-tidal volume ratio (VD/VT) was computed. At peak exercise, W vs. C VO(2), VE, and HR values were similar, whereas VCO(2) (848 +/- 69 vs. 1,225 +/- 45 ml/min; P < 0. 001) and lactate (1.5 +/- 0.2 vs. 4.1 +/- 0.2 meq/l; P < 0.001) were lower, DeltaVE/DeltaVCO(2) (35.7 +/- 1.7 vs. 25.9 +/- 1.3; P < 0. 001) and DeltaHR/DeltaVO(2) values (51 +/- 3 vs. 40 +/- 4; P < 0.05) were significantly higher. Analyses of arterial blood gases at peak exercise revealed higher VD/VT and lower arterial partial pressure of oxygen values for W compared with C. In COPD, reduced walking capacity is associated with an excessively high ventilatory demand. Decreased pulmonary gas exchange efficiency and arterial hypoxemia are likely to be responsible for the observed findings.

Adaptation, Physiological↗
PubMed1999

Somatostatin controls Kaposi's sarcoma tumor growth through inhibition of angiogenesis.

Somatostatin and its analogs are active in the inhibition of SST receptor-positive endocrine neoplasms, but their activity and mechanism in nonendocrine tumors is not clear. Somatostatin potently inhibited growth of a Kaposi's sarcoma xenograft in nude mice, yet in vitro the tumor cells did not express any known somatostatin receptors and were not growth inhibited by somatostatin. Histological examination revealed limited vascularization in the somatostatin-treated tumors as compared with the controls. Somatostatin was a potent inhibitor of angiogenesis in an in vivo assay. In vitro, somatostatin inhibited endothelial cell growth and invasion. Migration of monocytes, important mediators of the angiogenic cascade, was also inhibited by somatostatin. Both cells types expressed somatostatin receptor mRNAs. These data demonstrate that somatostatin is a potent antitumor angiogenesis compound directly affecting both endothelial and monocytic cells. The debated function of somatostatin in tumor treatment and the design of therapeutic protocols should be reexamined considering these data.

Animals↗
PubMed1999

Pulmonary gas exchange and exercise capacity in patients with systemic lupus erythematosus.

OBJECTIVE: Exercise tolerance is often reduced in patients with systemic lupus erythematosus (SLE). Mechanisms have been proposed but the underlying causes have not yet been elucidated. The study of pulmonary gas exchange during exercise may be helpful in revealing circulatory, ventilatory, and metabolic abnormalities. We hypothesized that in SLE, exercise aerobic capacity would be reduced due to chronic inactivity and poor muscle energetics. METHODS: Thirteen women with SLE and low disease activity were studied; 5 age matched subjects served as controls. Clinical examination, chest radiography, electrocardiogram, and pulmonary function test were all normal. Subjects underwent 1 min incremental cycle ergometer exercise to exhaustion. Oxygen uptake (VO2), CO2 output (VCO2), minute ventilation (VE), heart rate (HR), and arterial O2 saturation were monitored. Anaerobic threshold (AT), VO2/HR, deltaVO2/deltaWatt, respiratory rate (RR), Ti/Ttot, VE/VCO2, and breathing reserve (BR) were computed. RESULTS: At rest, patients exhibited high VE, respiratory alkalosis, and a wide alveolar-arterial O2 gradient [(A - a)O2] during 50% O2 breathing. Other indexes of respiratory function were within the normal range. In the 6 patients with SLE where pulmonary artery systolic pressure at Doppler echocardiography was measurable, mean level was in the upper limits of normal. During exercise, maximal aerobic capacity was reduced in all patients (VO2 peak, 1098+/-74 vs. 2150+/-160 ml/min, p<0.01; AT, 36 +/-3 vs. 48+/-3% predicted VO2 max, p<0.05). Ventilation adjusted for the metabolic demand (VE/VCO2 at AT) was increased (31+/-1 vs. 24+/-1; p<0.05). A normal breathing pattern was observed during all tests. No patient stopped exercising because of ventilatory limitation (i.e., they had normal breathing reserve). CONCLUSION: Reduced muscle aerobic capacity is common in SLE and is most likely because of peripheral muscle deconditioning. Increased ventilatory demand, secondary to diffuse interstitial lung disease, is not a significant contributor to the reduction in exercise tolerance.

Adult↗
PubMed1998

Effect of reduced body weight on muscle aerobic capacity in patients with COPD.

BACKGROUND: Reduced muscle aerobic capacity in COPD patients has been demonstrated in several laboratories by phosphorus magnetic resonance spectroscopy and by analysis of oxygen uptake (VO2) kinetics. COPD patients are usually elderly, hypoxemic, poorly active with muscle atrophy, and often malnourished. Under these conditions there is usually reduction of O2 delivery to the tissues (bulk O2 flow), redistribution of fiber type within the muscle, capillary rarefaction, and decreased mitochondrial function, alterations all capable of reducing muscle aerobic capacity. In COPD, the effect of reduced body mass on muscle aerobic capacity has not been investigated (to our knowledge). METHODS: We studied 24 patients with stable COPD with moderate-to-severe airway obstruction (68+/-5 [SD] years; FEV1, 39+/-12% predicted; PaO2, 66+/-8 mm Hg; PaCO2, 41+/-3 mm Hg) with poor to normal nutritional status, as indicated by a low-normal percent of ideal body weight (IBW). Each subject first underwent 1-min maximal incremental cycle ergometer exercise for determination of VO2 peak and lactate threshold (LT). Subsequently, they performed a 10-min moderate (80% of LT-VO2) constant load exercise for determination of oxygen deficit (O2DEF) and mean response time VO2 (MRT). VO2, CO2 output (VCO2), and minute ventilation were measured breath by breath. RESULTS: Patients displayed low VO2 peak (1,094+/-47 [SE] mL/min), LT-VO2 (35+/-3% predicted O2 max), and higher MRT-VO2 (67+/-4 s). Univariate regression analysis showed that percent of IBW correlated with indexes of maximal and submaximal aerobic capacity: vs VO2 peak, R=0.53 (p<0.01); vs MRT R=-0.77 (p<0.001). Using stepwise regression analysis, MRT correlated (R2=-0.70) with percent of IBW (p<0.01) and with PaO2 (p<0.05). CONCLUSIONS: Reduced body mass has an independent negative effect on muscle aerobic capacity in COPD patients: this effect may explain the variability in exercise tolerance among patients with comparable ventilatory limitation.

Aged↗
PubMed1997

Suppression of invasive behavior of melanoma cells by stable expression of anti-sense perlecan cDNA.

BACKGROUND: Heparan sulfate proteoglycans are one of the major components of extracellular matrix and are secreted at different levels by several normal and tumoral cells. Perlecan, the basement membrane proteoglycan, has structural domains involved in cell/matrix interactions and growth factor storage. Metastatic melanoma cells show an increase in perlecan expression as compared to low metastatic ones. We examined whether reduction of perlecan expression could down-modulate the malignant phenotype in melanoma clones. MATERIALS AND METHODS: We transfected B16-F10 murine malignant melanoma cells with a perlecan antisense cDNA construct and tested the in vitro behavior of the selected clones. RESULTS: The expression of antisense mRNA corresponded to a reduction of perlecan synthesis. The clones with reduced perlecan synthesis showed a down-regulation of proliferation and invasion. CONCLUSIONS: These results further indicate the importance of perlecan as a regulator of growth factor activity affecting the biological properties of metastatic cells, and suggest the potential use of antisense perlecan DNA in anti-melanoma gene therapy approaches.

DNA, Antisense↗
PubMed1997

The beta-core fragment of human chorionic gonadotrophin inhibits growth of Kaposi's sarcoma-derived cells and a new immortalized Kaposi's sarcoma cell line.

OBJECTIVE: Kaposi's sarcoma (KS), a condition often associated with HIV infection, is more common in men than in women; pregnancy and sex hormones could be involved. Urinary human chorionic gonadotrophin (hCG) has been reported to inhibit the growth of KS cell lines, with great variability among preparations. Urinary hCG often contains free forms of the hCG subunits and a fragment of the free beta-subunit, the beta-core, which may have biological activity. We compared the effect of the beta-core fragment, the beta-subunit, recombinant and urinary hCG on KS immortal and spindle cells. DESIGN AND METHODS: A new immortal KS cell line was phenotypically and karyotypically characterized. The effects on growth of this cell line and of primary KS spindle cells by hCG and its purified derivatives were tested. Induction of apoptosis was demonstrated using acridine orange/ethidium bromide staining. RESULTS: The beta-core fragment harboured the most potent growth inhibitory activity on a molar basis. After 72 h of treatment with the beta-core, 60-70% of KS cells show apoptotic nuclei. No effects were observed on endothelial cells. CONCLUSIONS: The beta-core fragment of hCG proved to be the most effective part of the hCG molecule, inducing growth inhibition and apoptosis of KS cells. Thus, the beta-core could be the most appropriate hCG derivative for the therapy of KS.

Antineoplastic Agents↗
PubMed1996

Isolation of spindle-shaped cell populations from primary cultures of Kaposi's sarcoma of different stage.

Cell lines derived both from sporadic and epidemic KS biopsies show similar characteristics: a mixture of mesenchymal and vascular markers as well as production of factors which recruit endothelial cells in vitro and induce neoangiogenesis in vivo. Most established KS spindle cell strains are derived from patch or plaque stage KS lesions, which are easily collected during routine biopsies. Here we have characterized KS-derived spindle cell lines obtained from the four different stages typical of KS progression: angiomatous macula, patch, plaque and nodular KS to show if the similar features of our KS cell lines are linked to a particular stage of progression or to an in vitro selection/differentiation during KS cell culture. These four KS cell lines have shown the same pattern of characterization as the previous established KS cell lines, apart from an early selection of the spindle cell population we have also observed an easy inducible phenotypic differentiation through a myofibroblastic spindle cell type simply plating cells on gelatin-coated flasks. These data confirm the hypothesis of spindle cell selection in culture and the possible differentiation of these mesenchymal cells.

Adult↗
PubMed1995

The alpha 3 beta 1 integrin is involved in melanoma cell migration and invasion.

The VLA3 (alpha 3 beta 1) integrin receptor recognizes several ligands; however, the function of this integrin is still debated. Expression of VLA3 appears to be increased in malignant melanoma and correlates with the degree of dermal invasiveness. Here we have studied the role the alpha 3 integrin subunit in malignant melanoma cell migration and invasion into extracellular matrices. The 2/14 clone of the Me665/2 human melanoma cell line, which expresses high levels of VLA integrins, was highly migratory and invasive, while the low integrin expressing 2/56 clone showed limited migration and was not invasive. Antibodies to the beta 1 subunit inhibited adhesion, migration, and invasion of two different malignant melanoma cell lines, the 2/14 clone and A2058 cells, indicating a crucial role for VLA integrins in these phenomena. While anti-alpha 6 antibodies inhibited adhesion to laminin and anti-alpha 5 antibodies inhibited adhesion to fibronectin, antibodies to the alpha 3 subunit did not inhibit adhesion of these cells to laminin, fibronectin, or collagen i.v. In contrast, the P1B5 anti-alpha 3 antibodies were good inhibitors of the migration of these cells toward laminin, fibronectin, and collagen IV and also blocked invasion of these cells through a reconstituted basement membrane matrix (Matrigel). Another anti-alpha 3 antibody, F4, did not effect migration, while both the P1B5 and F4 antibodies induced cellular aggregation on Matrigel. Our data suggest a specific role for alpha 3 beta 1 in the migration and invasion of melanoma cells.

Antibodies, Monoclonal↗
PubMed1995

Oxygen effect on O2 deficit and VO2 kinetics during exercise in obstructive pulmonary disease.

We evaluated the effect of supplemental O2 on energy metabolism of hypoxemic humans by measuring O2 uptake (VO2) kinetics and other cardiorespiratory parameters in nine male chronic obstructive pulmonary disease (COPD) patients and seven age-matched control subjects (on air and on 30% O2) at rest and during moderate cycle ergometer exercise. Heart rate, ventilation, VO2, CO2 output, respiratory exchange ratio, O2 cost of work, and work efficiency were measured with a computerized metabolic cart; O2 deficit and VO2 time courses were calculated. In COPD patients, 30% O2 breathing resulted in 1) reduction of O2 deficit (from 488 +/- 34 ml in air to 398 +/- 27 ml in O2; P < 0.05) and phase 2 VO2 time constant (from 116 +/- 13 s in air to 74 +/- 12 s in O2; P < 0.05); 2) a smaller steady-state increment in CO2 output than in room air (315 +/- 17 ml/min in O2 vs. 358 +/- 27 ml/min in air; P < 0.02), which resulted in a lower exercise respiratory exchange ratio (0.75 +/- 0.02 in O2 vs. 0.80 +/- 0.02 in air; P < 0.02); and 3) reduced steady-state ventilation (22.6 +/- 1.0 l/min in O2 vs. 25.4 +/- 1.1 l/min in air; P < 0.05). In conclusion, 30% O2 breathing accelerated exercise VO2 kinetics in mildly hypoxemic COPD patients. The observed VO2 kinetics improvement with O2 supplementation is consistent with an enhancement of aerobic metabolism in skeletal muscles during moderate exercise.

Aged↗
PubMed1995

Nutritional state and exercise tolerance in patients with COPD.

We hypothesized that in patients with COPD, poor nutritional status adversely influences exercise tolerance by limiting aerobic capacity of exercising muscles. In 28 patients with stable COPD, we correlated nutritional status with gas exchange indexes obtained during maximal incremental cycle ergometer exercise and with respiratory function parameters. On the basis of percent of ideal body weight (%IBW), patients were divided into three groups (GP): GP1 (n = 8, %IBW < 90); GP2 (n = 13, %IBW > or = 90 < 110); and GP3 (n = 7, %IBW > or = 110). When compared with normally nourished individuals (GPs 2 and 3), malnourished GP1 patients showed greater reduction in maximal workload and in peak O2 uptake (VO2 peak), with earlier onset of metabolic acidosis (anaerobic threshold [AT]); in addition, indexes reflecting O2 cost of ventilation were higher in GP1. Nutritional status could be correlated with exercise tolerance (VO2 peak, r = 0.82, p < 0.0001), with onset of metabolic acidosis (AT, r = 0.69, p < 0.0001) and with dead space/tidal volume ratio (VD/VT, r = -0.59, p < 0.001). Body weight was inversely correlated with indexes that are likely to reflect the increase in O2 cost of ventilation. We conclude that in patients with stable COPD, (1) malnutrition significantly affects muscle aerobic capacity and exercise tolerance, and (2) high wasted ventilation and O2 cost of ventilation may be responsible for the weight loss.

Aged↗
PubMed1994

Cardiopulmonary exercise testing in the evaluation of patients with ventilatory vs circulatory causes of reduced exercise tolerance.

INTRODUCTION: Cardiopulmonary exercise testing (CPX) is considered a useful procedure in the evaluation of circulatory, ventilatory, or mixed origin of reduced exercise tolerance. Our study was designed to compare CPX and a standard clinical-instrumental approach in the evaluation of patients with cardiopulmonary disorders. METHODS: Fifty-seven patients (31 male, 26 female; mean [+/- SE] age, 60 +/- 2 years) were studied. Each patient was evaluated by two different observers: one used standard clinical criteria, the other used gas exchange indexes, monitored during a maximal incremental CPX, performed on a cycle ergometer. Cardiac output (CO), at rest and at submaximal work level, was also obtained. RESULTS: In 46 patients (80.7 percent), a concordant evaluation was reached by the two observers (24 were found to have a predominant ventilatory disorder, 22 to have a circulatory disorder); among these, in subjects considered to have circulatory impairment, the maximal CO/maximal workload ratio was significantly lower than in the ventilatory group; in those with ventilatory impairment, the reduced exercise tolerance correlated with the resting spirometric values. In the remaining 11 patients (19.3 percent), CPX better defined the underlying pathophysiology of exercise limitation: in 10 of them, clinically classified as having a mixed or predominantly ventilatory disorder, a greater importance of the circulatory component was detected; 4 had evidence of pulmonary vascular impairment (high VE/VCO2 at anaerobic threshold). CONCLUSIONS: Our study confirmed the sensitivity of CPX in the evaluation of a reduced exercise tolerance in dyspneic patients with cardiopulmonary conditions; when compared with a clinical-laboratory approach, in some patients it allowed the detection of an underestimated circulatory component causing exercise limitation.

Aged↗
PubMed1992

Induction of invasive and experimental metastasis potential in BALB/c 3T3 cells by benzo(a)pyrene transformation.

A clone of BALB/c 3T3 cells (A-31), which is highly resistant to spontaneous in vitro transformation, was treated with the carcinogen benzo(a)pyrene [B(a)P]. This agent was capable of inducing in vitro transformation in the presence of S9 activating system and 6 weeks after treatment large foci were detected. Transformation frequency in solvent control groups was very low. Three foci from a single plate of two different experiments were pooled and the cells tested for their in vitro invasive properties and in vivo tumorigenic and metastatic potential. B(a)P-transformed 3T3 cells grew in soft agar and were highly tumorigenic when injected s.c. in nude mice (75% incidence within 7 weeks). Untreated cells were poorly tumorigenic (0/4 mice had tumors within 7 weeks), though they also gave rise to neoplasms after a longer latency. Spontaneous metastasis incidence was low for both controls and treated cells; however, almost all animals (15/16) injected i.v. with B(a)P-transformed cells had pulmonary nodules in the experimental metastasis assay. A few nodules in some of the animals in the control group were detected (4/16). B(a)P-transformed cells were able to invade a thin coating of matrigel in the chemoinvasion assay and also grew in matrigel showing an invasive, branching morphology. Untreated cells did not grow or invade. Our data suggest that a single treatment with a chemical carcinogen can increase tumorigenicity as well as confer invasive and experimental metastasis potential in BALB/c 3T3 cells. This work provides evidence for a role of chemical carcinogens in tumor progression.

3T3 Cells↗
PubMed1991

Regulation of atrial natriuretic peptide release in normal humans.

Atrial volume, pressure, and heart rate are considered the most important modulators of atrial natriuretic peptide (ANP) release, although their relative role is unknown. Continuous positive-pressure breathing in normal humans may cause atrial pressure and atrial volume to go in opposite directions (increase and decrease, respectively). We utilized this maneuver to differentially manipulate atrial volume and atrial pressure and evaluate the effect on ANP release. Effective filling pressure (atrial pressure minus pericardial pressure) was also monitored, because this variable has been proposed as another modulator of ANP secretion. We measured right atrial (RA) pressure, RA area, esophageal pressure (reflection of pericardial pressure), and RA and peripheral venous ANP in seven healthy adult males at rest and during continuous positive-pressure breathing (19 mmHg for 15 min). Continuous positive-pressure breathing decreased RA area (mean +/- SE, *P less than 0.05) 13.6 +/- 1.1 to 10.5 +/- 0.8* cm2, increased RA pressure 4 +/- 1 to 16 +/- 1* mmHg, increased esophageal pressure 2 +/- 1 to 12 +/- 1* mmHg, and increased effective filling pressure 2 +/- 0 to 4 +/- 1* mmHg. RA ANP increased from 67 +/- 17 to 91 +/- 18* pmol/l and peripheral venous ANP from 43 +/- 4 to 58 +/- 6* pmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Pharmacologic elevation of blood inorganic phosphate in hypoxemic patients with COPD.

We have shown that in patients with COPD, myocardial efficiency during exercise is enhanced following acute elevations of plasma phosphate (Pi). A decrease in Hb-O2 affinity (increase in P50) was not responsible for the improvement. We postulated that the physiologic benefit was due to the acute reversal of a subclinical myocardial Pi depletion. To further test this hypothesis in a chronic state, we studied nine stable hypoxemic (PaO2 = 64 +/- 2 mm Hg [+/- SEM]) patients with COPD over five weeks: two weeks at normal plasma Pi; and three weeks at elevated plasma Pi, induced by etidronate disodium (Didronel; 750 mg orally daily). Administration of etidronate disodium increased (p less than 0.05) plasma level of Pi (4.4 +/- 0.2 to 5.8 +/- 0.1 mg/dl), RBC level of Pi (3.1 +/- 0.2 to 4.1 +/- 0.2 mg/dl), RBC level of 2,3-DPG (16.2 +/- 1.1 to 21.3 g+/- 1.3 mumol/g of Hb) and P50 (23.7 +/- 0.5 to 26.0 +/- 0.8 mm Hg). At the end of the treatment, the widening of the C(a-v)O2 with exercise (7.1 +/- 0.8 to 8.9 +/- 0.6 ml/dl) was less pronounced than under control conditions (6.9 +/- 0.4 to 10.1 +/- 0.6 ml/dl; p less than 0.02); concomitantly, the crossover point (COP; the PaO2 below which a rightward-shifted Hb-O2 curve causes the C(a-v)O2 to become narrower rather than wider) increased (37 +/- 2 to 49 +/- 1 mm Hg). Indicators of myocardial work efficiency were not affected by etidronate disodium at rest or during exercise. We postulate that during exercise the potential beneficial effect of the rightward shift of the Hb-O2 curve upon cardiac function was negated by the fall of PaO2 to or below the COP level, a situation which would limit increases in tissue O2 extraction.

2,3-Diphosphoglycerate↗