Biomedical subjects

Marcos Intaglietta

Publications and source records attributed to Marcos Intaglietta.

At least 19 recordsLinked to original sources

PubMed2007

Deferoxamine lowers tissue damage after 80% exchange transfusion with polymerized hemoglobin.

Hemoglobin (Hb) solutions have been proposed as potential substitutes for erythrocytes to maintain oxygen-carrying capacity in situations in which blood is not available. This study investigated systemic and microvascular hemodynamics as well as tissue oxygenation and viability after an 80% exchange transfusion with an oxygen-carrying blood substitute based on polymerized bovine hemoglobin (PBH). Studies were carried in unanesthetized hamsters prepared with a window-chamber model for microcirculation evaluation. Heme iron-mediated injury to the tissue was analyzed by using deferoxamine (an iron chelator), which reduces free iron toxicity. Exchange transfusion led to a significant decrease in hematocrit (Hct) and an increase in plasma Hb, in addition to a significant decrease of arteriolar and venular diameters, flow velocity, and, therefore, microvascular blood flow. Capillary perfusion was severely compromised after exchange, but tissue pO2 increased above baseline, and oxygen extraction was reduced. Apoptotic and necrotic cells increased significantly after the exchange; however, this effect was only partially due to the toxicity of free iron. Iron therapy decreased the microvascular and oxygenation changes but did not fully reverse the adverse effects. Assessment of tissue viability after exchange suggests that chelation treatment in cases of large exchange transfusions with acellular Hb could be potentially beneficial.

Animals↗

PubMed2006

Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria.

The role of nitric oxide (NO) in the genesis of cerebral malaria is controversial. Most investigators propose that the unfortunate consequence of the high concentrations of NO produced to kill the parasite is the development of cerebral malaria. Here we have tested this high NO bioavailability hypothesis in the setting of experimental cerebral malaria (ECM), but find instead that low NO bioavailability contributes to the genesis of ECM. Specifically, mice deficient in vascular NO synthase showed parasitemia and mortality similar to that observed in control mice. Exogenous NO did not affect parasitemia but provided marked protection against ECM; in fact, mice treated with exogenous NO were clinically indistinguishable from uninfected mice at a stage when control infected mice were moribund. Administration of exogenous NO restored NO-mediated signaling in the brain, decreased proinflammatory biomarkers in the blood, and markedly reduced vascular leak and petechial hemorrhage into the brain. Low NO bioavailability in the vasculature during ECM was caused in part by an increase in NO-scavenging free hemoglobin in the blood, by hypoargininemia, and by low blood and erythrocyte nitrite concentrations. Exogenous NO inactivated NO-scavenging free hemoglobin in the plasma and restored nitrite to concentrations observed in uninfected mice. We therefore conclude that low rather than high NO bioavailability contributes to the genesis of ECM.

Alkenes↗

PubMed2006

Hemorrhagic shock resuscitation with carbon monoxide saturated blood.

The response to exchange transfusion with red blood cells (RBCs) saturated with carbon monoxide (CO) in amelioration of microvascular function and providing tissue protection in hemorrhagic shock resuscitation was investigated in the hamster chamber window model. Shock was induced by the withdrawal of 50% of blood volume (BV). Blood volume was restored 1 h after hemorrhage with a single volume infusion (resuscitation) of 25% BV with fresh RBCs (saturated or unsaturated with CO) suspended in human serum albumin (HSA). Hemorrhage, shock and resuscitation were monitored continuously in terms of mean arterial pressure (MAP), microvascular blood flow, capillary perfusion and systemic gas parameters. Eight hours after resuscitation, Annexin V and propidium iodide (PI) were injected into the window chamber to study tissue viability, and labeled cells were observed by using intravital epifluorescence microscopy. TUNEL staining was performed on the tissue to confirm in vivo results. Systemic and microvascular restoration were not different with or without CO up to 90 min after resuscitation. CO concentration decreased over 90 min, increasing oxygen carrying capacity and gradually reoxygenating the tissue. CO saturated blood partially mitigated cell injury at 8 h after resuscitation. The precise cellular mechanisms involved require further elucidation. CO is a novel experimental strategy to improve tissue viability and requires the appropriated preclinical studies to confirm its efficacy.

Animals↗

PubMed2006

Dissociation of local nitric oxide concentration and vasoconstriction in the presence of cell-free hemoglobin oxygen carriers.

Cell-free hemoglobin's (CFH) high affinity for nitric oxide (NO) could limit CFH's use as an oxygen-carrying blood replacement fluid because it scavenges NO, causing vasoconstriction and hypertension. However, the extent to which perivascular NO levels change following intravascular administration of hemoglobin (Hb) with different molecular dimensions correlates with vasoconstrictive responses in the microcirculation is unknown. The study objective was to determine vasoconstrictive effects following bolus infusions of (1) alphaalpha cross-linked Hb; (2) polymerized bovine Hb; or (3) polyethylene glycol-decorated Hb (PEG-Hb), by measurements of in vivo microvessel diameter, blood flow, perivascular NO concentration, and systemic hemodynamic parameters. All CFHs caused reductions in perivascular NO levels, not correlated to microvascular responses. PEG-Hb (largest molecular volume) maintained blood flow, while the others caused vasoconstriction and reduced perfusion. All solutions increased mean arterial pressure due to vasoconstriction and blood volume expansion, except for PEG-Hb, which increased blood pressure due to blood volume expansion and maintenance of cardiac output. In conclusion, perivascular NO reduction is similar for all Hb solutions because NO binding affinities are similar; however, effects on vascular resistance are related to the type of molecular modification, molecular volume, and oxygen affinity.

Animals↗

PubMed2006

Arteriolar vasoconstrictive response: comparing the effects of arginine vasopressin and norepinephrine.

INTRODUCTION: This study was designed to examine differences in the arteriolar vasoconstrictive response between arginine vasopressin (AVP) and norepinephrine (NE) on the microcirculatory level in the hamster window chamber model in unanesthetized, normotonic hamsters using intravital microscopy. It is known from patients with advanced vasodilatory shock that AVP exerts strong additional vasoconstriction when incremental dosage increases of NE have no further effect on mean arterial blood pressure (MAP). METHODS: In a prospective controlled experimental study, eleven awake, male golden Syrian hamsters were instrumented with a viewing window inserted into the dorsal skinfold. NE (2 microg/kg/minute) and AVP (0.0001 IU/kg/minute, equivalent to 4 IU/h in a 70 kg patient) were continuously infused to achieve a similar increase in MAP. According to their position within the arteriolar network, arterioles were grouped into five types: A0 (branch off small artery) to A4 (branch off A3 arteriole). RESULTS: Reduction of arteriolar diameter (NE, -31 +/- 12% versus AVP, -49 +/- 7%; p = 0.002), cross sectional area (NE, -49 +/- 17% versus AVP, -73 +/- 7%; p = 0.002), and arteriolar blood flow (NE, -62 +/- 13% versus AVP, -80 +/- 6%; p = 0.004) in A0 arterioles was significantly more pronounced in AVP animals. There was no difference in red blood cell velocities in A0 arterioles between groups. The reduction of diameter, cross sectional area, red blood cell velocity, and arteriolar blood flow in A1 to A4 arterioles was comparable in AVP and NE animals. CONCLUSION: Within the microvascular network, AVP exerted significantly stronger vasoconstriction on large A0 arterioles than NE under physiological conditions. This observation may partly explain why AVP is such a potent vasopressor hormone and can increase systemic vascular resistance even in advanced vasodilatory shock unresponsive to increases in standard catecholamine therapy.

Animals↗

PubMed2006

Blood viscosity maintains microvascular conditions during normovolemic anemia independent of blood oxygen-carrying capacity.

Responses to exchange transfusion with red blood cells (RBCs) containing methemoglobin (MetRBC) were studied in an acute isovolemic hemodiluted hamster window chamber model to determine whether oxygen content participates in the regulation of systemic and microvascular conditions during extreme hemodilution. Two isovolemic hemodilution steps were performed with 6% dextran 70 kDa (Dex70) until systemic hematocrit (Hct) was reduced to 18% (Level 2). A third-step hemodilution reduced the functional Hct to 75% of baseline by using either a plasma expander (Dex70) or blood adjusted to 18% Hct with all MetRBCs. In vivo functional capillary density (FCD), microvascular perfusion, and oxygen distribution in microvascular networks were measured by noninvasive methods. Methylene blue was administered intravenously to reduce methemoglobin (rRBC), which increased oxygen content with no change in Hct or viscosity from MetRBC. Final blood viscosities after the entire protocol were 2.1 cP for Dex70 and 2.8 cP for MetRBC (baseline, 4.2 cP). MetRBC had a greater mean arterial pressure (MAP) than did Dex70. FCD was substantially higher for MetRBC [82 (SD 6) of baseline] versus Dex70 [38 (SD 10) of baseline], and reduction of methemoglobin to oxyhemoglobin did not change FCD [84% (SD 5) of baseline]. P(O2) levels measured with palladium-meso-tetra(4-carboxyphenyl)porphyrin phosphorescence were significantly changed for Dex70 and MetRBC compared with Level 2 (Hct 18%). Reduction of methemoglobin to oxyhemoglobin partially restored P(O2) to Level 2. Wall shear rate and wall shear stress decreased in arterioles and venules for Dex70 and did not change for MetRBC or rRBC. Increased MAP and shear stress-mediated factors could be the possible mechanisms that improved perfusion flow and FCD after exchange for MetRBC. Thus the fall in systemic and microvascular conditions during extreme hemodilution with low-viscosity plasma expanders seems to be, in part, from the decrease in blood viscosity independent of the reduction in oxygen content.

Anemia↗

PubMed2006

Increased cardiac output and microvascular blood flow during mild hemoconcentration in hamster window model.

The effect of small hematocrit (Hct) increases on cardiac index (cardiac output/body wt) and oxygen release to the microcirculation was investigated in the awake hamster window chamber model by means of exchange transfusions of homologous packed red blood cells. Increasing Hct between 8 and 13% from baseline increased cardiac index by 5-31% from baseline (P < 0.05) and significantly lowered systemic blood pressure (P < 0.05). The relationship between Hct and cardiac index is described by a second-order polynomial (R2 = 0.84; P < 0.05) showing that Hct increases up to 20% from baseline increase cardiac index, whereas increases over 20% from baseline decrease cardiac index. Combining this data with measurements of blood pressure allowed to determine total peripheral vascular resistance, which was a minimum at 8-13% Hct increase and was described by a second-order polynomial (R2 = 0.83; P < 0.05). Oxygen measurements in arterioles, venules, and the tissue at 8-13% Hct increase were identical to control; thus, as a consequence of increased flow and oxygen-carrying capacity, oxygen delivery and extraction increased, but the change was not statistically significant. Previous results with the same model showed that the observed effects are related to shear stress-mediated release of nitric oxide, an effect that should be also present in the heart microcirculation, leading to increased blood flow, myocardial oxygen consumption, and contractility. We conclude that a minimum viscosity level is necessary for generating the shear stress required for maintaining normal cardiovascular function.

Animals↗

PubMed2006

Microvascular effects following treatment with polyethylene glycol-albumin in lipopolysaccharide-induced endotoxemia.

OBJECTIVE: To determine whether resuscitation with polyethylene glycol conjugated bovine serum albumin (2.5% weight/volume) infused at 16 mL/kg/hr (PEG-BSA-16) or at 24 mL/kg/hr (PEG-BSA-24) for 1 hr improves microcirculatory conditions in endotoxemia compared with dextran 70 (6% weight/volume) infused at 24 mL/kg/hr (Dex). DESIGN: Prospective study. SETTING: University research laboratory. SUBJECTS: Male Golden Syrian hamsters. INTERVENTIONS: Hamsters implemented with a skinfold window chamber were given an intravenous injection of lipopolysaccharide and resuscitated within 10 mins with Dex, PEG-BSA-16, or PEG-BSA-24. MEASUREMENTS AND MAIN RESULTS: Hamsters were observed during 24 hrs after lipopolysaccharide injection. Systemic variables measured included mean arterial pressure, heart rate, and systemic arterial blood gas. Microvascular function was characterized by measuring vessel diameter; red blood cell velocity; functional capillary density (FCD); P(O2) in arterioles, venules, and tissue; and perivascular nitric oxide concentration 6 hrs after lipopolysaccharide injection. At 6 hrs, animals with no treatment had the lowest FCD (6.7 +/- 5.7% of baseline). PEG-BSA provided significantly improved microvascular conditions as shown by restoration of FCD. Recovery of FCD was related to improved microvascular flow and perivascular and tissue P(O2), normalization of shear rate, and decreased perivascular nitric oxide concentration. These effects were related to improved fluid retention using PEG-BSA-24 as evidenced by the significantly lower hematocrit at 24 hrs after resuscitation. Nitric oxide at 6 hrs after induction of sepsis achieved perivascular millimolar concentrations, which were reduced to normal values by PEG-BSA-24 treatment. At 6 hrs there were significant differences in FCD, tissue P(O2), and perivascular nitric oxide concentration following PEG-BSA treatment by comparison with Dex treatment, although there were no differences in systemic variables between Dex and PEG-BSA groups. CONCLUSIONS: PEG-BSA produces improved microcirculatory conditions in the treatment of endotoxemia when compared with dextran 70.

Animals↗

PubMed2006

The vascular wall as a regulator of tissue oxygenation.

PURPOSE OF REVIEW: The development of the phosphorescence quenching oxygen measurement technique has allowed for a simultaneous measurement of intra and perivascular partial pressure oxygen along arteriolar vessels in vivo. Mapping the microvascular distribution and oxygen gradients across the vascular walls using this high-resolution technique reveals the existence of large radial gradients between the vasculature and the tissue, with concomitant longitudinal oxygen loss. Mass balance analysis along vessel segments indicates that the vascular wall has a high rate of oxygen consumption. This review presents the current status of in-vivo studies on the partitioning of oxygen between blood, the vascular wall and the surrounding tissue, thereby positioning an oxygen sink between blood and tissue regulating oxygen release. RECENT FINDINGS: Induced vasoactivity (vasoconstriction and vasodilation) has been shown to modulate oxygen consumption of the vascular wall and directly affect the portion of oxygen available to the tissue. Inhibition of the endothelial layer of the vessel wall resulted in a decrease in the oxygen gradient across the vessel. SUMMARY: The vascular wall is a sink for oxygen. The modulation of vessel wall oxygen consumption can substantially impact the amount of oxygen released to the tissue.

Arteries↗

PubMed2006

Rapid restoration of microcirculatory blood flow with hyperviscous and hyperoncotic solutions lowers the transfusion trigger in resuscitation from hemorrhagic shock.

Resuscitation from hemorrhagic shock relies on fluid retransfusion. However, the optimal properties of the fluid have not been established. The aim of the present study was to test the influence of the concentration of hydroxyethyl starch (HES) solution on plasma viscosity and colloid osmotic pressure (COP), systemic and microcirculatory recovery, and oxygen delivery and consumption after resuscitation, which were assessed in the hamster chamber window preparation by intravital microscopy. Awake hamsters were subjected to 50% hemorrhage and were resuscitated with 25% of the estimated blood volume with 5%, 10%, or 20% HES solution. The increase in concentration led to an increase in COP (from 20 to 70 and 194 mmHg) and viscosity (from 1.7 to 3.8 and 14.4 cP). Cardiac index and microcirculatory and metabolic recovery were improved with HES 10% and 20% when compared with 5% HES. Oxygen delivery and consumption in the dorsal skinfold chamber was more than doubled with HES 10% and 20% when compared with HES 5%. This was attributed to the beneficial effect of restored or increased plasma COP and plasma viscosity as obtained with HES 10% and 20%, leading to improved microcirculatory blood flow values early in the resuscitation period. The increase in COP led to an increase in blood volume as shown by a reduction in hematocrit. Mean arterial pressure was significantly improved in animals receiving 10% and 20% solutions. In conclusion, the present results show that the increase in the concentration of HES, leading to hyperoncotic and hyperviscous solutions, is beneficial for resuscitation from hemorrhagic shock because normalization of COP and viscosity led to a rapid recovery of microcirculatory parameters.

Animals↗

PubMed2006

Early resuscitation with polymerized bovine hemoglobin reverses acidosis, but not peripheral tissue oxygenation, in a severe hamster shock model.

Awake hamsters equipped with the dorsal window chamber preparation were subjected to hemorrhage of 50% of the estimated blood volume. Initial resuscitation (25% of estimated blood volume) with polymerized bovine hemoglobin (PBH) or 10% hydroxyethyl starch (HES) occurred in concert with an equivolumetric bleeding to simulate the early, prehospital setting (exchange transfusion). Resuscitation (25% of estimated blood volume) without bleeding was performed with PBH, HES, or autologous red blood cells (HES-RBCs). Peripheral microcirculation, tissue oxygenation, and systemic hemodynamic and blood gas parameters were assessed. After exchange transfusion, base deficit was -8.6 +/- 3.7 mmol/L (PBH) and -5.1 +/- 5.3 mmol/L (HES) (not significant). Functional capillary density was 17% +/- 6% of baseline (PBH) and 31% +/- 11% (HES) (P < 0.05) and arteriolar diameter 73% +/- 3% of baseline (PBH) and 90% + 5% (HES) (P < 0.01). At the end, hemoglobin levels were 3.7 +/- 0.3 g/dL with HES, 8.2 +/- 0.6 g/dL with PBH, and 10.4 +/- 0.8 g/dL with HES-RBCs (P < 0.01 HES vs. PBH and HES-RBCs, P < 0.05 PBH vs. HES-RBCs). Base excess was restored to baseline with PBH and HES-RBCs, but not with HES (P < 0.05). Functional capillary density was 46% +/- 5% of baseline (PBH), 62% + 20% (HES-RBCs), and 36% +/- 19% (HES) (P < 0.01 HES-RBCs vs. HES). Peripheral oxygen delivery and consumption was highest with HES-RBCs, followed by PBH (P < 0.05 HES-RBCs vs. PBH, P < 0.01 HES-RBCs and PBH vs. HES). In conclusion, the PBH led to a correction of base deficit comparable to blood transfusion. However, oxygenation of the peripheral tissue was inferior with PBH. This was attributed to its negative impact on the peripheral microcirculation caused by arteriolar vasoconstriction.

Acidosis↗

PubMed2006

Microvascular perspective of oxygen-carrying and -noncarrying blood substitutes.

The development of an alternative to natural blood has evolved from the initial goal of replicating blood properties to the current objective of formulating a fluid that can be used to replace blood while preserving microvascular function and delivering oxygen. The properties of this fluid are counterintuitive and different from blood because it has high viscosity, oxygen affinity, and a low oxygen carrier concentration when compared with blood. The optimal oxygen carrier devised presently is poly-ethylene-conjugated human hemoglobin, a material demonstrated to be vasoinactive and void of the toxicities present in previous hemoglobin formulations. A feature of this material is that it is effective in small quantities, and therefore amplifies the equivalent supply of blood derived from blood donations.

Animals↗

PubMed2006

Blood pressure and hematocrit in diabetes and the role of endothelial responses in the variability of blood viscosity.

OBJECTIVE: To investigate the relationship between mean arterial blood pressure and hematocrit in a population of treated diabetic patients and a control population of healthy individuals. RESEARCH DESIGN AND METHODS: Data on hematocrit and blood pressure were obtained from 129 diabetic subjects (87 women and 42 men) and 103 healthy subjects (76 women and 27 men) enrolled in a cross-sectional study. Alcohol consumption, ischemic heart disease, stroke, neoplasia, renal, hepatic, and chronic inflammatory disease were exclusion criteria. RESULTS: The hematocrit of diabetic patients ranged from 0.35 to 0.52, and blood pressure had a bimodal distribution described by a second-order polynomial (P < 0.001), whereby elevated pressures correlated with low and high hematocrit, while the minimum average pressure was at hematocrit 0.43. Hematocrit of normal control subjects (range 0.28-0.55) was uncorrelated to blood pressure (averaged 99.7 +/- 9.7 mmHg). High blood pressure, low hematocrit diabetic subjects up to the minimum average hematocrit of 0.43 had a negative correlation (P < 0.0001) between these variables. CONCLUSIONS: Our findings are compatible with the hypothesis that diabetic patients present normal responses to hematocrit variation and therefore blood viscosity and shear stress in mediating the release of vasodilators and lack the ability to autoregulate blood pressure relative to differences in hematocrit by comparison to nondiabetic subjects. These findings also suggest that the treatment of diabetes should target maintaining an optimal hematocrit in order to lower cardiovascular risk.

Adult↗

PubMed2005

Oxygen release from arterioles with normal flow and no-flow conditions.

The rate of oxygen release from arterioles ( approximately 55 microm diameter) was measured in the hamster window chamber model during flow and no-flow conditions. Flow was stopped by microvascular transcutaneous occlusion using a glass pipette held by a manipulator. The reduction of the intra-arteriolar oxygen tension (Po2) was measured by the phosphorescence quenching of preinfused Pd-porphyrin, 100 microm downstream from the occlusion. Oxygen release from arterioles was found to be 53% greater during flow than no-flow conditions (2.6 vs. 1.7 x 10(-5) ml O2.cm(-2).s(-1), P < 0.05). Acute hemodilution with dextran 70 was used to reduce vessel oxygen content, significantly increase wall shear stress (14%, P < 0.05), reduce Hct to 28.4% (SD 1.0) [vs. 48.8% (SD 1.8) at baseline], lower oxygen supply by the arterioles (10%, P < 0.05), and increase oxygen release from the arterioles (39%, P < 0.05). Hemodilution also increased microcirculation oxygen extraction (33% greater than nonhemodilution, P < 0.05) and oxygen consumption by the vessel wall, as shown by an increase in vessel wall oxygen gradient [difference in Po2 between the blood and the tissue side of the arteriolar wall, nonhemodiluted 16.2 Torr (SD 1.0) vs. hemodiluted 18.3 Torr (SD 1.4), P < 0.05]. Oxygen released by the arterioles during flow vs. nonflow was increased significantly after hemodilution (3.6 vs. 1.8 x 10(-5) ml O2.cm(-2).s(-1), P < 0.05). The oxygen cost induced by wall shear stress, suggested by our findings, may be >15% of the total oxygen delivery to tissues by arterioles during flow in this preparation.

Animals↗

PubMed2005

Nitric oxide regulation of microvascular oxygen exchange during hypoxia and hyperoxia.

The objective of this work was to test the hypothesis that the limitation of nitric oxide (NO) availability accentuates microvascular reactivity to oxygen. The awake hamster chamber window model was rendered hypoxic and hyperoxic by ventilation with 10 and 100% oxygen. Systemic and microvascular parameters were determined in the two conditions and compared with normoxia in a group receiving the NO scavenger nitronyl nitroxide and a control group receiving only the vehicle (saline). Mean arterial blood pressure did not change with different gas mixtures during infusion of the vehicle, but it increased significantly in the NO-depleted group. NO scavenging increased the reactivity of microvessels to the changed oxygen supply, causing the arteriolar wall to significantly increase oxygen consumption. Tissue Po2 was correspondingly significantly reduced during NO scavenger infusion. The present findings support the hypothesis that microvascular oxygen consumption is proportional to oxygen-induced vasoconstriction. The effect of oxygen on vascular tone is modulated by NO. As a consequence, NO acts as a regulator of the vessel wall oxygen consumption. The vessel wall consumes oxygen in proportion to the local Po2, and an impairment of NO availability renders the circulation more sensitive to changes in the oxygen supply.

Animals↗

PubMed2005

Cell- rather than antibody-mediated immunity leads to the development of profound thrombocytopenia during experimental Plasmodium berghei malaria.

Experimental malarial thrombocytopenia can reach life-threatening levels and is believed to be due to Abs targeting platelets for destruction by the reticuloendothelial system. However, we report that Abs account for at most 15% of platelet destruction as Plasmodium berghei-infected B cell-deficient mice exhibited profound thrombocytopenia (83%) as did C57BL/6 controls (98%). Further, no significant increase in Abs bound to intact platelets was observed during infection. P. berghei infection can enhance the activity of anti-platelet Abs as indicated by a significantly (p < 0.005) increased thrombocytopenia on day 4 of infection in mice that were administered a low dose anti-CD41 mAb compared with rat IgG1-injected controls. RAG1-/- and CD4- plus CD8-deficient mice were markedly protected from thrombocytopenia (p < 0.005) and malarial pathogenesis. CD8- or TCRgammadelta-deficient mice were not protected from thrombocytopenia and CD4-deficient mice were modestly protected. RAG1-/- mice exhibited significantly (p < 0.05) lower levels of plasma TNF, IFN-gamma, and IL-12 during infection. IFNgamma-/- and IL-12-/- mice exhibited increased survival but similar thrombocytopenia to C57BL/6 controls. Collectively, these data indicate that thrombocytopenia is necessary but not sufficient for malarial pathogenesis and Abs are not the major contributors to malarial thrombocytopenia. Rather, we propose that both CD4+ and CD8+ T cell populations play key roles in malarial thrombocytopenia; a complex bidirectional interaction between cell-mediated immunity and platelets exists during experimental severe malaria that regulates both responses.

Animals↗

PubMed2005

Role of endothelial nitric oxide in microvascular oxygen delivery and consumption.

Nitric oxide (NO) is an important signaling molecule modulating diverse processes such as vasodilation, neurotransmission, long-term potentiation, and immune responses. The endothelium contributes a significant fraction of NO from endothelial NO synthase (eNOS). The objective of this work was to analyze the role of eNOS in the modulation of oxygen supply to the tissues and in adaptation to maintain oxygenation uncompromised. Oxygen delivery and consumption were measured in the microcirculation of homozygous mutant endothelial nitric oxide synthase-deficient (eNOS(-/-)) and wild-type mice. Animals were implanted with a dorsal window chamber, allowing us to assess the intact microvascular system. Hemodynamics and oxygen tension were assessed in the microcirculation of conscious animals. The eNOS(-/-) mice had significantly higher blood pressure and lower heart rate (146 +/- 8 mm Hg, 401 +/- 17 bpm) than wild type (127 +/- 6 mm Hg, 428 +/- 20 bpm). Microvascular hemodynamic parameters were not significantly different between groups. The eNOS(-/-) animals delivered less oxygen to the microcirculation and released more oxygen to the tissue; both differences were statistically significant compared to wild type. The arteriolar vessel wall oxygen gradient, a measure of vascular smooth muscle cells and endothelial cell wall oxygen consumption, was significantly lower for eNOS(-/-) than for wild type, suggesting that the inhibition of eNOS is an antianoxia (oxygen sparing) mechanism. Finally, the findings of the study support the argument that NO availability limits oxygen consumption by the tissue.

Animals↗

PubMed2005

Effect of erythrocyte aggregation at normal human levels on functional capillary density in rat spinotrapezius muscle.

Previous studies have shown that functional capillary density (FCD) is substantially reduced by erythrocyte aggregation. However, only supranormal levels of aggregability were studied. To investigate the effect of erythrocyte aggregability at the level seen in healthy humans, the FCD of selected capillary fields in rat spinotrapezius muscle was determined with high-speed video microscopy under normal (nonaggregating) conditions and after induction of erythrocyte aggregation with Dextran 500 (200 mg/kg). To examine shear rate dependence, the effect was studied both at normal and reduced arterial pressures (50 and 25 mmHg), the latter achieved by short periods of hemorrhage. In a separate study, volume flow was determined in arterioles (52.1 +/- 3.7 microm) under the same conditions. Before Dextran 500 infusion, FCD fell to 91% and 76% of control values, respectively, when arterial pressure was reduced to 50 and 25 mmHg. After Dextran 500 infusion, FCD was 96% at normal arterial pressure and fell to 79% and 37% of normal control values at 50 and 25 mmHg. All FCD values were significantly lower after dextran infusion. FCD reduction after lowering arterial pressure or dextran infusion appeared to be due to plasma skimming rather than capillary plugging. Reduction of FCD by dextran at reduced pressure was compensated by increased red blood cell flux in capillaries with red blood cell flow. We conclude that the level of aggregability seen in healthy humans is an important determinant of FCD only at reduced arterial pressure.

Animals↗