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Biomedical subjects

M Samaja

Publications and source records attributed to M Samaja.

At least 37 records · Page 2Linked to original sources
PubMed1995

Myocardial metabolism and function in acutely ischemic and hypoxemic isolated rat hearts.

We tested the hypothesis that residual oxygen supply during acute low-flow ischaemia or hypoxemia is a major regulator of myocardial performance, metabolism and recovery. Rat hearts were exposed for 20 min to either ischemia (coronary flow reduced to 10% of baseline), hypoxemia (oxygen content reduced to 10% baseline) or a "mixed" condition (combined ischaemia and hypoxemia). The oxygen supply (coronary flow x oxygen content) was matched in all groups (n = 16 per group). Hypoxemic hearts had the highest performance (systolic and developed pressures, +/- dP/dtmax and oxygen uptake) and content of IMP and AMP. Ischaemic hearts had the highest content of ATP, phosphocreatine, adenine nucleotides and purines. As flow and/or oxygenation were restored, post-ischemic hearts showed better functional and metabolic recovery than post-hypoxemic ones. "Mixed" hearts were more similar to hypoxemic ones during oxygen shortage but to ischemic ones during recovery. We conclude that as oxygenation is critically limiting, coronary flow is relatively more important than oxygen supply in determining myocardial function, metabolism and recovery, most likely secondary to changes in the metabolism of diffusible substances.

Adenine Nucleotides↗
PubMed1995

[Thrombolysis & arrhythmias].

In this study, we assessed one particular aspect of the arrhythmogenic phenomena that occur during reperfusion secondary to thrombolysis, that is the therein involved metabolic mechanisms. The employed experimental model (isolated Langendorff-perfused rat heart) allowed us to distinguish which factor involved during ischemia, low coronary flow or low oxygen tension, is primarily involved during arrhythmogenesis. This was made possible by comparing two settings characterized by the same oxygen supply, but with different coronary flows and PO2 values, i.e., ischemia and hypoxemia. As expected, the contractile dysfunction was higher during reoxygenation at the end of hypoxemia than during reperfusion at the end of ischemia (p < 0.05). However, the incidence of arrhythmias was similar in both cases. Therefore, whereas the contractile dysfunction appears to be more sensitive to coronary flow, the incidence of arrhythmias appears to be more sensitive to the total oxygen supply to the heart. This implies that the mechanisms underlying the development of contractile dysfunction and arrhythmogenesis follow different paths.

Animals↗
PubMed1994

Effects of energy demand in ischemic and in hypoxemic isolated rat hearts.

Aim of this study was to assess the role of O2, lactate and energy demand in the regulation of myocardial work during severe dysoxia. For this purpose, we measured function and metabolism in isolated Langendorff-perfused rat hearts exposed to either ischemia or hypoxemia (matched for the O2 supply, 10% of baseline) with/out electrical stimulation. When hearts could adjust their HR, hypoxemia demanded more energy than ischemia (p < 0.05) despite same O2 supply. Venous PO2 was 12 +/- 2 or 139 +/- 20 mmHg (p < 0.0001), respectively, but VO2 was the same. After 10 min at HR = 300 min-1, myocardial performance increased in ischemic but not in hypoxemic hearts. PvO2 and VO2 were not affected by pacing. In contrast, both venous [lactate] and lactate production rate increased, but in ischemic hearts only. We conclude that ischemic hearts were downregulated while hypoxemic hearts were not. Likely, depressed washout of lactate during ischemia could offset the effects of O2 in severely dysoxic hearts. Anaerobic glycolysis provided the energy necessary to meet increased energy demand in ischemic hearts, but could not exploit this action in hypoxemic hearts probably because in these hearts it was already working near maximum.

Anaerobiosis↗
PubMed1994

Oxidative injury in reoxygenated and reperfused hearts.

In this study, we separated the effects of low oxygen supply and low coronary flow in isolated perfused rat hearts to focus on the genesis of free radicals-induced reperfusion injury. Hearts were exposed to either hypoxemia/reoxygenation or ischemia/reperfusion in various sequences, with hypoxemia and ischemia matched for duration (20 min), temperature (37 degrees C), and oxygen supply (10% of baseline). Hypoxemia/reoxygenation (n = 7) resulted in lower (developed pressure) x (heart rate) (p < 0.001) and higher end-diastolic pressure (p < 0.001) than ischemia/reperfusion (n = 9). The presence of 40 IU/ml superoxide dismutase and 104 IU/ml catalase nearly blunted the rise of the end-diastolic pressure (p = 0.02 vs. baseline), but could only partially prevent the depression of myocardial contractility (p < 0.001 vs. baseline, n = 7). Similar patterns were observed when hearts were made ischemic after hypoxemia, eliminating the intermediate reoxygenation step. We conclude that the major determinant of the reperfusion injury is associated with low oxygen supply rather than low coronary flow. Part of the injury is mediated by oxygen-derived free radicals, but a substantial portion of it is associated with energetic processes.

Analysis of Variance↗
PubMed1994

Regulation of bioenergetics in O2-limited isolated rat hearts.

Assessing the role of O2 supply in the regulation of cardiac function in O2-limited hearts is crucial to understanding myocardial ischemic preconditioning and adaptation to hypoxia. We exposed isolated Langendorff-perfused rat hearts to either ischemia (low coronary flow) or hypoxemia (low PO2 in the perfusing medium) with matched O2 supply (10% of baseline). Myocardial contractile work and ATP turnover were greater in hypoxemic than in ischemic hearts (P < 0.05; n = 12). Thus, the energy demand was higher during hypoxemia than during ischemia, suggesting that ischemic hearts are more downregulated than hypoxemic hearts. Venous PO2 was 12 +/- 2 and 120 +/- 15 Torr (P < 0.0001) for ischemic and hypoxemic hearts, respectively, but O2 uptake was the same. Lactate release was higher during hypoxemia than during ischemia (9.7 +/- 0.9 vs. 1.4 +/- 0.2 mumol/min, respectively; P < 0.0001). Electrical stimulation (300 min-1; to increase energy demand) increased performance in ischemic (P < 0.005) but not in hypoxemic hearts without changes in venous PO2 or O2 uptake. However, venous lactate concentration and lactate release increased in ischemic (P < 0.002) but not in hypoxemic hearts, suggesting that anaerobic glycolysis provides the energy necessary to meet the increased energy demand in ischemic hearts only. We conclude that high intracellular lactate or H+ concentration during ischemia plays a major role as a downregulating factor. Downregulation disappears in hypoxemic hearts secondary to enhanced washout of lactate or H+.

Animals↗
PubMed1994

Enhanced oxidation of bis(3,5-dibromosalicyl) fumarate alpha-alpha cross linked hemoglobin by free radicals generated by xanthine/xanthine oxidase.

The xanthine/xanthine oxidase reaction produces reproducible amounts of oxygen-derived free radicals that oxidize human oxyhemoglobin (Hb). We monitored the kinetics of the oxidation of stripped Hb (sHb), purified HbA0 and alpha-alpha cross-linked Hb (HbXL99 alpha) at [Hb] in the 5 to 150 microM (heme) range. For increasing [Hb], the oxidation halftime (t1/2) increased for all Hbs, but t1/2 was always less for HbXL99 alpha than for HbA0 and sHb. Such feature was attributed to the lower affinity for O2 of HbXL99 alpha and may represent a serious problem for use of this Hb as blood substitute.

Aspirin↗
PubMed1993

Human red blood cell aging at 5,050-m altitude: a role during adaptation to hypoxia.

To test the hypothesis that the human red blood cell aging process participates actively in the adaptation to hypoxia, we studied some physical and biochemical hematologic variables in 10 volunteers at sea level (SL) and after 1 (1WK) or 5 wk (5WK) of exposure to 5,050-m altitude. The 2,3-diphosphoglycerate-to-hemoglobin ratio (2,3-DPG/Hb) was 0.88 +/- 0.03 (mol/mol) at SL and increased to 1.08 +/- 0.03 (P = 0.002) and 1.28 +/- 0.05 (P < 0.0001) at 1WK and 5WK, respectively. The average red blood cell density (D50), which is inversely proportional to the fraction of young red blood cells and is therefore an index of the red blood cell aging process, was 1.1053 +/- 0.0007 g/ml at SL and decreased to 1.1046 +/- 0.0008 g/ml (NS) and 1.1018 +/- 0.0008 g/ml (P < 0.001) at 1WK and 5WK, respectively. D50 was correlated with 2,3-DPG/Hb at SL (P = 0.004), only weakly at 5WK (P = 0.1), but not at all at 1WK. The arterial O2 saturation was correlated with the change of 2,3-DPG/Hb in 1WK (P = 0.02) and that of D50 in 5WK (P = 0.04). It is concluded that short-term (1WK) increase of 2,3-DPG/Hb is not associated with the erythropoietic response but is presumably due to respiratory alkalosis. By contrast, after prolonged hypoxia (5WK), erythropoiesis may provide an efficient way for increasing blood 2,3-DPG through an augmented proportion of young red blood cells.

2,3-Diphosphoglycerate↗
PubMed1992

Functional and metabolic effects of propionyl-L-carnitine in the isolated perfused hypertrophied rat heart.

Aim of this study was to assess the effect of propionyl-L-carnitine (PLC), a naturally occurring derivative of L-carnitine, in cardiac hypertrophy induced by pressure overload in rats. The abdominal aorta was banded and the rats received one daily administration of PLC (50 mg/kg) or saline for four days. The hearts were excised 24 h after the last administration and were perfused retrogradely with oxygenated Krebs-Henseleit buffer containing 1.2 mM palmitate bound to 3% (w/v) albumin, 2.5 microM PLC and 25 microM L-carnitine. A saline-filled balloon was inserted into the left ventricle and the heart contractility was measured at three volumes of the balloon, corresponding to zero diastolic pressure and to increased volumes (110 and 220 microliters) over the zero volume. At the end of the perfusion, the hearts were freeze-clamped, weighed and analyzed for adenine nucleotide and phosphocreatine (PCr) content by HPLC methods. No differences in the myocardial performance were found at zero diastolic pressure. In contrast, at high intraventricular volume, the maximal rate of ventricular relaxation was increased in PLC-treated with respect to saline-treated controls (p < 0.05). In addition, the increase of the end-diastolic pressure at increasing balloon volume was more marked in controls than in the PLC-treated hearts (p < 0.02). These data correlate well with the measured higher level of total adenine nucleotides (p < 0.05) and ATP (p < 0.02) in the PLC-treated hearts, while PCr was the same in both groups. Parallel experiments performed in the absence of palmitate in the perfusing media failed to show any effect of PLC.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Early recognition of a discordant xenogeneic organ by human circulating lymphocytes.

Cell-mediated immune mechanisms underlying discordant xenograft rejection are poorly characterized. In our study, using a human to rat xenogeneic ex vivo model, we show that a fraction of human lymphocytes, when perfused through the coronary system of a rat heart, rapidly and specifically adheres to the vascular endothelium and infiltrates the myocardium. Lymphocyte phenotypic analysis before and after perfusion, as well as the use of purified cell subpopulations, demonstrate preferential adhesion of CD3- CD16+ NK cells. NK cell adhesion occurs via xenoreactive antibody-dependent and -independent pathways, because the selective removal of human IgG from the perfusion buffer markedly reduces but does not completely abrogate NK cell sequestration. However, T lymphocytes are retained in the xenoorgan via an antibody-independent pathway, as assessed by the lack of influence of IgG removal. Leukocyte integrins appear to play a crucial role in mediating adhesion of both lymphocyte subsets, because the pretreatment of lymphocytes with anti-CD11a, anti-CD11b, and anti-CD18 antibodies markedly reduces their retention into the xenogeneic organ. Retained human lymphocytes mediate rapid and direct damage of the xenoorgan, as demonstrated by histologic and functional alterations of the endothelium, impaired vascular resistance and in vitro lysis of rat endothelial cells by human NK cells. Taken together, these findings suggest a role for cell-mediated mechanisms in the rapid recognition and rejection of vascularized xenografts.

Animals↗
PubMed1992

Thyroid hormones and active calcium transport of inside-out red cell membrane vesicles.

Thyroid hormones may influence the active transport of Ca2+ across the cell membrane. To test the physiologic relevance of this mechanism, we used inside-out human red cell membrane vesicles as a model of the cell membrane Ca2+ pump. We monitored by spectrophotometric methods the kinetics of the uptake of Ca2+ in the presence of 10(-5)-10(-10) M thyroid hormones or their analogues. Vesicles freed of calmodulin and protein inhibitor(s) of the Ca2+ pump were also obtained. The results are as follows: (1) Thyroxine inhibits the active Ca2+ uptake; (2) this effect antagonizes that of soluble calmodulin; and (3) triiodothyronine and other analogues of the thyroid hormones are less active than thyroxine. We conclude that the thyroid hormones may influence cell Ca2+ homeostasis by direct action on the Ca2+ pump.

Adult↗
PubMed1992

[The effects due to reduced coronary inflow and hypoxemia during myocardial ischemia].

The events associated to myocardial ischemia result from 2 overlapping phenomena due to reduced blood flow (ischemia) and reduced O2 supply (hypoxemia). To distinguish these effects, 2 groups of isolated rat hearts were perfused through the aorta (Langendorff's method) with Krebs-Henseleit buffer, and were exposed for 20 min to hypoxemia or ischemia, matched in terms of the O2 supply (10% of baseline), with continuous monitoring of cardiac contractility, O2 uptake and lactate production. The developed pressure and the O2 uptake were similar in hypoxemic and ischemic hearts; heart rate, end-diastolic pressure and lactate production rate were higher in hypoxemia than in ischemia; the recovery from hypoxemia was less than that from ischemia, despite the same O2 supplies; treatment with superoxide dismutase and catalase, scavengers of the O2 derived free radicals, during hypoxemia, allowed hypoxemic hearts to recover as ischemic hearts. Therefore, the main determinant of the reperfusion injury is to be attributed to the low O2 supply rather than to the low coronary flow; part of the injury is due to free radicals; a substantial portion is mediated by the energy demand during the stress which was higher in hypoxemia than in ischemia.

Animals↗
PubMed1992

Hemodynamic and metabolic activities of propionyl-L-carnitine in rats with pressure-overload cardiac hypertrophy.

Evidence has been put forth that a number of human and experimental cardiomyopathies are associated with a lower myocardial carnitine content. This study was performed to test the hypothesis that the correction of carnitine derivative, propionyl-L-carnitine (PLC), may improve cardiac function. Repeated administration of PLC was compared to saline with respect to cardiac function in rats with pressure-overload cardiac hypertrophy and low myocardial carnitine levels. Cardiac hypertrophy was induced by abdominal aorta constriction in rats. Separate groups of rats were used for (a) determination of myocardial carnitine content, (b) evaluation of in vivo hemodynamics, and (c) evaluation of performance and metabolic state of Langendorff perfused hearts. Results showed the following: (i) The myocardial carnitine content was inversely correlated to cardiac hypertrophy (r = 0.68, p less than 0.05) and PLC treatment (50 mg/kg i.a. for 4 days) restored it to normal values (ii) The PLC effect on cardiac function was significantly and directly related to cardiac hypertrophy [correlations between heart weight and percent changes in cardiovascular parameters: cardiac output (CO), p less than 0.001; cardiac work (CW), p less than 0.01, stroke volume (SV) and stroke work (SW), p less than 0.02]. In animals with heart weight greater than 1,400 mg, the effect of PLC on CO, CW, SV, SW, and total peripheral resistance (TPR) was significantly different from that of saline (CO, CW, SV, and SW, p less than 0.005 each; TPR, p less than 0.05). The effect was observed 24 h after the first PLC administration and significantly diminished following a 4 day suspension of the treatment. (iii) Perfused hearts from PLC-treated rats displayed a significantly lower left ventricular end-diastolic pressure (p less than 0.01) and greater relaxation rate (p less than 0.05) than those from control rats. Moreover, in PLC-treated hearts, the content of creatine phosphate, ATP, and total adenine nucleotides (ATP+ADP+AMP; TAN) was significantly increased (CP, p less than 0.05; ATP and TAN, p less than 0.01 vs. control). These data show that PLC exerts a stimulatory activity on hearts with hypertrophy and low carnitine content, implying that carnitine deficiency may contribute to the depression of cardiac function in this model.

Adenine Nucleotides↗
PubMed1991

The relationship between the blood oxygen transport and the human red cell aging process.

We have studied the relationship between the in vivo aging process of the human red cell (RBC) and its main function, the transport of O2 from the lungs to the tissues. This study included several approaches. First, we observed that the affinity for O2 in young RBCs was lower than in old RBCs (p less than 0.0005) due to different intracellular concentration of 2,3-diphosphoglycerate, main effector of hemoglobin. Second, we explored whether there are some subgroups of the healthy human population with altered RBC age distribution: females in the age range 25-35 exhibited significantly younger RBCs (p less than 0.0005) and lower RBC-O2 affinity (p less than 0.01) than other groups. Correspondingly, the RBC-O2 affinity in female blood was significantly lower (p less than 0.002) than in male blood. Third, we correlated by two independent methods the lowered RBC-O2 affinity to a more efficient O2 delivery to the tissues by two independent methods: 1) calculating the size of the cardiac output increase required to sustain the tissue oxygenation after an increase of the RBC affinity for O2; and 2) monitoring the enhanced cardiac function in isolated rat hearts perfused with RBCs at low O2 affinity. Finally, comparing some hematologic findings relevant for the O2 transport in two healthy populations with different RBC age distributions, such as age-matched females and males, it appeared that the low RBC-O2 affinity in females is an adaptive response to their lower [Hb].(ABSTRACT TRUNCATED AT 250 WORDS)

2,3-Diphosphoglycerate↗