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Biomedical subjects

M Intaglietta

Publications and source records attributed to M Intaglietta.

At least 55 records · Page 3Linked to original sources
PubMed1996

Microvascular and tissue oxygen distribution.

Understanding of oxygen delivery by the microcirculation has been dominated by the unitary component analysis of Krogh and Erlangen focussed on oxygen transport mediated by single capillaries, oxygenation of tissue as a whole being extrapolated from findings on oxygen exchange in these vessels. This analysis is under revision since capillaries are not sole sources of oxygen. It is increasingly apparent that arterioles are a significant equivalent source, while venules may serve as sinks for capillary and arteriolar oxygen. As a consequence detailed descriptions of the architecture of the microcirculation based on the tissue cylinder conceptualization does not yield new information given the non-exclusive role of capillaries as purveyors of oxygen to tissue. In the present study we investigate how tissue is oxygenated directly from the arteriolar supply on the basis of current results with newly developed optical techniques for the measurement of local intra- and extravascular pO2 by phosphorescence decay. This methodology shows that tissue regions between arterioles and venules have essentially uniform tissue pO2. The only experimentally detectable gradients in pO2 are those present in the immediate vicinity of arterioles. Findings on vascular longitudinal gradients are used to devise a model that links convective and diffusive processes, showing how blood viscosity, blood oxygen-carrying capacity and the slope of the oxygen dissociation curve are linked in determining intravascular and tissue pO2. The integrated approach provides a numerical basis for interpreting consequences of alterations in transport properties of blood applicable to the field of blood substitutes.

Humans↗
PubMed1995

Capillary reperfusion after L-arginine, L-NMMA, and L-NNA treatment in cheek pouch microvasculature.

The effects of arginine (L-arg), promoter of nitric oxide (NO) production and NO synthesis inhibitors, NG-monomethyl-L-arginine (L-NMMA) and N omega-nitro-L-arginine (L-NNA), on arteriolar responses and capillary perfusion after 30 min ischemia were studied in the cheek pouch preparation under pentobarbital anesthesia and intravenous drug infusion. Capillary density, venular leukocyte sticking, and vessel diameters were investigated by fluorescence microscopy. Damage due to photoactivation of intravascular dyes was investigated by injecting fluorescent dextran 150,000 MW prior to and after ischemia reperfusion. No difference was found indicating that effects were independent from exposure time to photoactivated dyes. Capillary perfusion reduction was always present after reperfusion in untreated, L-NMMA-treated, and L-NNA-treated animals, with increased venular leukocytes adhesion. Arteriolar vasomotion was induced by L-NMMA treatment. Capillary perfusion recovered in L-arg-treated hamsters, where capillary blood flow velocity was lower than in L-NMMA group and the number of adhering leukocytes was lower than in untreated controls, L-NMMA, and L-NNA groups. It is concluded that L-arg determines perfusion with increased blood flow heterogeneity while inhibition of NO preserves capillary perfusion causing appearance of vasomotion in the arterial network.

Animals↗
PubMed1995

Analysis of arterial flowmotion in spinal cord injured and elderly subjects in an area at risk for the development of pressure sores.

Flowmotion (blood flow changes due to vasomotion) in the skin over a risk area for pressure sores, the sacrum, and a non-risk area, the gluteus muscle, was evaluated by laser Doppler fluxmetry during resting conditions and post-occlusive reactive hyperaemia (PRH) response. Measurements were made in healthy younger subjects and in two risk groups for pressure sores-spinal cord injured (SCI) and the elderly. The SCI were divided into two subgroups, one with and one without distinct flowmotion seen on the original recordings over the sacrum. The Prony spectral line estimation (PSLE) method was used to determine the power spectrum of the flowmotion activity. During the PRH, flowmotion frequencies were found in two separated bands, 5.4-6.6 cpm (cycles min-1) and 7.8-9.0 cpm. In the subgroup without distinct flowmotion, the PSLE method found flowmotion frequencies similar to the other groups. During the PRH, the flowmotion power pattern over the sacrum was similar within all groups, but the power was extremely low in one subgroup of SCI subjects. To conclude, flowmotion (vasomotion) was present in the two skin areas and increased during the PRH response, reaching a maximum within 50 s. This study shows that the flowmotion frequencies might be locally driven, whereas the power might be centrally mediated. Disturbances in microcirculatory flowmotion can be a part of the mechanisms leading to skin ischaemia and pressure sores. A new method has been developed for analysing differences in flowmotion behaviour such that statistical comparisons can be made.

Adult↗
PubMed1995

Systemic and subcutaneous microvascular oxygen tension in conscious Syrian golden hamsters.

Arteriolar and venular oxygen tension distribution was studied in the subcutaneous connective tissue of the chamber window preparation in conscious Syrian golden hamsters as a function of the systemic PO2, PCO2, pH, arterial pressure and hematocrit, microvascular red blood cell (RBC) velocity, vessel diameter, and blood flow in the same microvessels. PO2 was measured with the phosphorescence decay technique using Pd-meso-tetra(4-carboxyphenyl)porphyrin (30 mg/kg body wt iv). Systemic arterial and venous PO2s were 71.6 +/- 13.1 and 28.4 +/- 5.1 mmHg, while oxygen tension was 45.1 +/- 13.3 mmHg in arterioles and 30.1 +/- 10.7 mmHg in venules. The relatively low arteriolar PO2 and the small arteriolar-venular PO2 gradient indicate that some blood oxygen exits directly to the tissue or is shunted before reaching the capillaries. RBC velocity was the strongest correlate of microvascular PO2 (arterial correlation coefficient = 0.503 and venous correlation coefficient = 0.560, P < 0.001). Microvascular PO2 was also correlated with blood flow, vessel diameter, blood pH, and PCO2 but not with systemic PO2. Arterial oxygen tension was only significantly related to PCO2, pH, and hematocrit. These findings suggest that oxygen delivery to the tissue improves with increasing blood flow velocity and that microvascular PO2 is a locally regulated parameter in the absence of major systemic perturbations.

Animals↗
PubMed1995

Oxidative-stress response in vascular endothelial cells exposed to acellular hemoglobin solutions.

We investigated the effect of different hemoglobins on the activation of endothelial heme oxygenase (HO), an inducible "stress" protein, which is responsible for heme catabolism, and we determined whether the propensity of hemoglobins to autoxidize correlates with endothelial heme uptake and cell injury. Porcine aortic endothelial cells were incubated for 6 h in the presence of 60 microM unmodified hemoglobin A0 (HbA0), hemoglobin cross-linked between the alpha-chains with bis-(3,5-dibromosalicyl)fumarate (alpha alpha Hb), or cyanomet-alpha alpha-hemoglobin (CNmet alpha alpha Hb). Endothelial HO activity augmented 4.1-fold in the presence of alpha alpha Hb, 2.7-fold with HbA0, and 1.8-fold with CNmet alpha alpha Hb over the control value. Deferoxamine, but not catalase or dimethylthiourea, partially attenuated the HO induction produced by alpha alpha Hb. The rates of methemoglobin formation exhibited a linear relationship over the time of incubation (r = 0.94), and the apparent rate constant was 1.8-fold higher for alpha alpha Hb (0.023 h-1) than for HbA0 (0.013 h-1). Endothelial heme content and lactate dehydrogenase (LDH) release, an index of cell injury, were also higher in alpha alpha Hb compared with HbA0 and CNmet alpha alpha Hb groups (P < 0.05). Deferoxamine but not catalase markedly reduced the release of LDH induced by alpha alpha Hb, whereas dimethylthiourea provided only a partial cytoprotection. These studies suggest that 1) the higher rate of oxidation of alpha alpha Hb contributes to the augmented endothelial HO activity, and 2) both heme release and iron-mediated oxygen radical formation are major contributors to endothelial oxidative stress and cytotoxicity generated by the cross-linked hemoglobin.

Animals↗
PubMed1995

Cellular basis of inflammation, edema and the activity of Daflon 500 mg.

Inflammation activates leukocytes causing the release of agents that disrupt the endothelial barrier to such an extent that retention of plasma protein is impaired. This phenomenon can be observed using microvascular methods in which ischemia-reperfusion-induced inflammation-like condition are analyzed in terms of the increased adherence of leukocytes to the venular endothelium. Pretreatment with Daflon 500 mg, a purified, micronized, flavonoid fraction consisting of 90% diosmin and 10% hesperidin, prior to the induction of 4 h of tourniquet ischemia significantly lowers the number of adherent leukocytes. This observation is linked to the protective effect of flavonoids in the treatment of edema, as decreased activation is also associated with a decreased platelet and complement system activation, leading to a lowered release of histamine and decreased leukocyte-dependent endothelial damage. It is proposed that attenuation of leukocyte adherence during ischemia-reperfusion is evidence of the protective endothelial effect of Daflon 500 mg and its ability to control edema in clinical situation.

Animals↗
PubMed1994

Noninvasive measurement of microvascular and interstitial oxygen profiles in a human tumor in SCID mice.

Simultaneous measurements of intravascular and interstitial oxygen partial pressure (PO2) in any tissue have not previously been reported, despite the importance of oxygen in health and in disease. This is due to the limitations of current techniques, both invasive and noninvasive. We have optically measured microscopic profiles of PO2 with high spatial resolution in subcutaneous tissue and transplanted tumors in mice by combining an oxygen-dependent phosphorescence quenching method and a transparent tissue preparation. The strengths of our approach include the ability to follow PO2 in the same location for several weeks and to relate these measurements to local blood flow and vascular architecture. Our results show that (i) PO2 values in blood vessels in well-vascularized regions of a human colon adenocarcinoma xenograft are comparable to those in surrounding arterioles and venules, (ii) carbogen (95% O2/5% CO2) breathing increases microvascular PO2 in tumors, and (iii) in unanesthetized and anesthetized mice PO2 drops to hypoxic values at < 200 microns from isolated vessels but drops by < 5 mmHg (1 mmHg = 133 Pa) in highly vascularized tumor regions. Our method should permit noninvasive evaluations of oxygen-modifying agents and offer further mechanistic information about tumor pathophysiology in tissue preparations where the surface of the tissue can be observed.

Adenocarcinoma↗
PubMed1994

Effect of hemodilution and resuscitation on tumor interstitial fluid pressure, blood flow, and oxygenation.

Hemodilution due to hemorrhage may increase tumor blood flow (TBF) by lowering blood viscosity and decrease tumor interstitial fluid pressure (TIFP) by moving fluid from the interstitium to the vascular compartment and by lowering microvascular pressure (MVP), mainly due to the decrease in systemic pressure. To test this hypothesis, we measured mean arterial blood pressure (MABP), TIFP, hematocrit, relative TBF (RBC flux), and intratumor pO2 during hemorrhage and volume restitution in severe combined immunodeficient mice, bearing LS174T human colon adenocarcinoma xenografts. MABP and TIFP significantly decreased after 0.2 ml of blood (approximately 12% of blood volume) was withdrawn. MABP decreased from 87.5 +/- 3.9 mmHg (mean +/- standard error) to 59.8 +/- 4.8 mmHg (n = 5, P = 0.01) within 2.5 min after the withdrawal of blood and then returned to control value within 10 min. TIFP gradually decreased from 18.7 +/- 2.3 mmHg to 11.3 +/- 0.9 mmHg after 1 hr (n = 8, P = 0.01), while RBC flux increased by a factor of 1.99 +/- 0.38 (n = 5, P = 0.02). The systemic hematocrit decreased from 51.2 to 45.9% (n = 7, P = 0.02). Tumor oxygenation did not significantly improve (median pO2 for control, 28 mmHg, and median pO2 after blood withdrawal, 32 mmHg; P = 0.14). When 0.2 ml blood was withdrawn and replaced (within 2.5 min) with the same volume of normal saline, MABP significantly decreased from 86.4 +/- 2.4 mmHg to 65.6 +/- 4.6 mmHg (n = 11) at 1 hr post-treatment (P = 0.001). TIFP decreased, but not significantly, from 24.2 +/- 2.9 mmHg to 20.4 +/- 2.4 mmHg (P = 0.35). Blood withdrawals in excess of 0.3 ml significantly decreased MABP and TIFP without recovery during 1 hr of observation. Volume restitution with hyperoncotic/hyperosmotic 6.0% Dextran 70 and 7.5% saline had effects attributable to a direct transmission of systemic pressure to the tumor microcirculation and to a lowering of tumor venous resistance. These effects appear to be common to saline blood restitution and volume top-load with Dextran 70. In conclusion, mild hemorrhage (withdrawal of approximately 12% of blood volume) can significantly lower TIFP without a reduction in TBF and pO2.

Adenocarcinoma↗
PubMed1994

Effects of L-NMMA and indomethacin on arteriolar vasomotion in skeletal muscle microcirculation of conscious and anesthetized hamsters.

The purpose of this study was to determine the influence of NG-monomethyl-L-arginine (L-NMMA) and indomethacin (INDO), respectively inhibitors of nitric oxide synthase and cyclooxygenase, on spontaneous arteriolar activity (vasomotion) in the skeletal muscle of awake and anesthetized hamsters. Unanesthetized hamsters, implemented with the skin fold chamber window, displayed vasomotion, whose frequency and amplitude were quantified by power spectrum analysis. Intravenous administration of L-NMMA significantly increased vasomotion frequency and did not change the amplitude at the lower dose, but in order 3 arterioles amplitude decreased significantly. With higher doses L-NMMA caused constriction of order 1-2 vessels, frequency decreased and amplitude increased, and the arteriolar vasodilator response to acetylcholine decreased significantly. During anesthesia topically applied L-NMMA significantly decreased diameter and caused the appearance of vasomotion in order 1-2 arterioles. INDO did not affect vasomotion in unanesthetized hamsters and did not initiate vasomotion during anesthesia leading to the conclusion that prostaglandins do not regulate vasomotion. Vasomotion is not directly related to nitric oxide (NO) in conscious animals while NO blockage stimulates vasomotion in smaller arterioles of anesthetized hamsters without vasomotion; however, the simultaneous inhibition of cyclooxygenase and NO had no effect on arteriolar diameter during anesthesia. It is concluded that vasomotion is regulated by a mechanism that modulates smooth muscle cell activity through the endothelium.

Acetylcholine↗
PubMed1994

Hemodilution and blood substitutes.

The primary consequence of the substitution or replacement of blood with a surrogate is the dilution of the original constituents. This hemodilution produces systemic and microvascular phenomena that underlie all forms of blood replacement and provides a physiological reference for comparison for blood substitutes. The basic features of hemodilution become evident when the procedure is carried out in isovolemic and isoocotic conditions where blood viscosity and oxygen carrying capacity are changed. Blood viscosity is decreased, which redistributes macro and microcirculatory blood pressure increasing the arterio/venular pressure difference and central venous pressure, which improves cardiac filling and cardiac output and therefore blood flow velocity. These effects coupled to the oxygen carried by the diluted blood maintains the rate of oxygen delivery to the microcirculation up to hematocrit reductions of one third. The increased flow velocity counteracts the diffusive losses of oxygen from the microvessels. The increased flow velocity increases shear stress at the vessel wall lowering the tendency of activated leukocytes to adhere. Hemodilution with dextran 70 also maintains functional capillary density to hematocrit decreases of one half. Hemodilution with alpha alpha-hemoglobin presents all the features found with non-oxygen carrying colloids, however the increased oxygen carrying capacity is not fully exploited because systemic and microvascular effects due to colloids do not develop to the same extent.

Biological Transport↗
PubMed1994

Functional capillary density changes during blood substitution with alpha alpha Hb and dextran 70: influence on oxygen delivery.

The effectiveness of a blood substitute is ultimately determined by the rate at which O2 arrives to the capillaries and the functional capillary density i.e., the number of flowing capillaries per unit volume of tissue. We use this rationale to analyze the effectiveness of isovolemic blood substitution with alpha alpha Hb (3,5-bis(dibromosalicyl)fumarate) compared to isooncotic and isovolemic hemodilution with dextran 70. Progressive hemodilution with each solution was performed in the awake hamster skinfold model by simultaneous isovolemic exchange of blood until the systemic hematocrit was reduced to 30% of control. Systemic hematocrit, blood pressure, heart rate were monitored. To determine O2 delivery at the microcirculatory level, functional capillary density, RBC velocity, RBC flux, capillary hematocrit were measured. Functional capillary density was maintained during moderate hemodilution with dextran 70, whereas alpha alpha Hb exchange caused a gradual reduction in the number of flowing capillaries. O2 delivery to tissue was calculated from total O2 content (RBC and plasma Hb or RBC only), blood flow, and functional capillary density. Our findings suggest that augmentation of the O2 content of blood with alpha alpha Hb substitution produces similar results in terms of capillary O2 delivery and capacity as isovolemic and isooncotic hemodilution with dextran 70.

Animals↗
PubMed1993

Periodic hemodynamics (flow motion) in peripheral arterial occlusive disease.

PURPOSE: The occurrence of periodic blood flow variations (flow motion) in health and disease is controversially discussed. This is partly due to not reporting the incidence and to performing the analysis solely visually. We have therefore studied flow motion with computerized methods. METHODS: We used a computerized Prony spectral line estimator program to analyze the frequencies of resting skin blood flow variations, as determined by laser Doppler flowmetry on the thumb and great toe, in 50 male control subjects (group a), in 50 patients with mild peripheral arterial occlusive disease (PAOD stages I and II; group b), and in 25 patients with severe PAOD (stages III and IV; group c). RESULTS: The median ankle/arm pressure ratio was 1.10 in the control group, 0.72 in the mild PAOD group, and 0.66 in the severe PAOD group. Slow wave flow motion was detected in 19% of all thumbs from groups a and b (systolic arm pressures > 100 mm Hg) and in 12% of the toes in the control group. Patients with mild PAOD exhibited slow wave flow motion in 46% of the toes. Patients with severe PAOD showed slow waves in 77% of the toes. The median flow motion frequencies were about 1.6 cycles/min for groups a and b, when present. The median frequency in group c was significantly higher at 4.0 cycles/min, though still in the range of slow waves. The median peak-to-through amplitude was between 17% and 20% of mean flow for all groups. CONCLUSIONS: We conclude that evaluation of flow motion requires computerized frequency analysis and that slow wave flow motion is a perfusion pattern characteristic of PAOD rather than of normal perfusion states. This finding has potential implications for diagnostic and therapeutic approaches in arterial occlusive disease.

Arterial Occlusive Diseases↗
PubMed1993

Microvessel PO2 measurements by phosphorescence decay method.

A system is described for the in vivo noninvasive measurement of intravascular PO2 at the microscopic level. Under special circumstances the method can also be used to measure interstitial PO2. The PO2 determination is based on the O2-dependent quenching of phosphorescence of palladium-porphyrins bound to albumin. This compound was injected intravenously in the dosage of 30 mg/kg body wt and dissolved in saline to a concentration of 15 mg/ml. The phosphorescence emission was excited by epi-illumination with a strobe xenon arc and measured by a photomultiplier in a well-defined tissue area as small as 15 x 30 microns. A selected portion of the phosphorescence decay was fitted by a single exponential, and the Stern-Volmer equation was used to calculate PO2. Calibration was performed in vitro using saline and blood and was in agreement with previous reports. In vivo observations were made in normal tissue regions from the unanesthetized hamster transparent skin fold chamber preparation. The method allows PO2 determinations, in the range of 0-80 mmHg, in microvessels with diameters of 15-100 microns. Simultaneous transillumination of the tissue also allows measurement of vessel diameter and red blood cell velocity in the same vessels.

Animals↗
PubMed1993

Neurogenic modulation of periodic hemodynamics in rabbit skeletal muscle.

We characterized the effect of various forms of neural blockade and vasopressin infusion on regular slow-wave flux oscillation (RSWFO). RSWFO, measured with laser-Doppler flowmetry (LDF), was induced by local reduction of arterial pressure in the gastrocnemius muscle of 30 New Zealand White rabbits. At normal median femoral arterial mean pressure, LDF only showed irregular variations. With an intact innervation, RSWFO was maximal at a median femoral mean pressure of 30 mmHg (range 25-53), the median frequency was 1.7 cycles/min (range 1.0-3.0), and the maximum amplitude was 50% (range 19-119). Application of lidocaine to the sciatic nerve, or cutting of this nerve, when arterial pressure was reduced, resulted in disappearance of slow waves in all cases. Intravenous application of guanethidine resulted in a significant reduction of the flux oscillation amplitude from 47 to 10% (P < 0.001). In an additional nine animals with sciatic denervation and local blood pressure reduction, RSWFO could be induced by intravenous vasopressin infusion. These results offer a new pathophysiological concept of periodic hemodynamics as a locally controlled and, with intact innervation, a neurally modulated mechanism for blood flow redistribution in cases of reduced blood pressure and flow.

Animals↗
PubMed1993

Effect of oxymetazoline on nasal and sinus mucosal blood flow in the rabbit as measured with laser-Doppler flowmetry.

The effect of topical oxymetazoline hydrochloride on the blood flow of the nasal and sinus mucosa of the rabbit was measured by laser-Doppler flowmetry. Oxymetazoline, the active component in clinically used nose drops, induced a dose-dependent decrease of the nasal mucosal blood flow. This effect has previously been shown in humans and suggests the presence of alpha 2-adrenoceptors in the nasal mucosa of the rabbit. Doses of oxymetazoline used clinically in humans induced a 50% reduction of blood flow in rabbits. Rhythmic variations in blood flow were seen in 30% of the rabbits after administration of oxymetazoline. Additionally, oxymetazoline induced a dose-dependent decrease of the mucosal blood flow in the maxillary sinus when the drug was applied in the nose. A vasoconstricting effect of oxymetazoline on the arteries penetrating the maxillary sinus ostium is a possible explanation. This can have positive as well as negative consequences on acute sinus infections.

Administration, Intranasal↗
PubMed1993

Effect of leukocyte adhesion and microvascular permeability on capillary perfusion during ischemia-reperfusion injury in hamster cheek pouch.

The role of leukocyte sticking and permeability changes in the variation of perfused capillaries induced by ischemia reperfusion was studied in the hamster cheek pouch microcirculation. The drugs utilized were the antiperoxidative agents allopurinol, the calcium antagonists verapamil and diltiazem, and phenidone and adenosine, which inhibit leukotriene formation as well as leukocyte adhesion to the endothelium. The microvasculature was visualized by a fluorescence technique. Ischemia was induced by clamping the cheek pouch for 30 minutes followed by 30 minutes of reperfusion. The increase in permeability, the perfused capillary length and the number of adhering leukocytes to venular vessel wall were measured. Ischemia and reperfusion were associated with increased permeability, increased number of leukocytes sticking to the venular wall, and decreased number of functional capillaries. Microvascular injury evidenced by increased permeability was apparent in the first 5 min of ischemia. All the drugs decreased the number of leukocytes sticking to the venular wall; allopurinol, verapamil and adenosine reduced the increase in permeability, whereas phenidone and diltiazem were effective only during ischemia. In addition verapamil and adenosine preserved capillary blood flow during reperfusion. In conclusion, leukocyte sticking is correlated with increased microvascular permeability, but not with decreased perfusion of the capillary bed. These data suggest that leukocytes did not play a prominent role in the reduction of functional capillaries at the end of reperfusion.

Adenosine↗
PubMed1993

Biological zero of laser Doppler fluxmetry: microcirculatory correlates in the hamster cheek pouch during flow and no flow conditions.

The microcirculation of the hamster cheek pouch was visualized by the intravenous injection of FITC-dextran 150,000 during normal flow conditions and when flow was interrupted by clamping proximal to the pouch. Laser Doppler fluxmetry (LDF) was used to evaluate flow during control, 30 min of occlusion and after reperfusion. Intravital video recordings of the microcirculation during occlusion show that blood moves between the different arteriolar segments after occlusion and during the whole period of no flow. This motion was oscillatory in nature, had maximum velocity of order of 30 microns sec-1, and was related to progressive decrease of arteriolar diameter. The LDF output was in the range of 60-100 AU during control. This value fell in the range of 5-25 +/- 15% AU during occlusion and was assumed to constitute the biological zero for this system. The variability of the LDF signals was characterized by the autoregressive modeling power spectrum technique. The power spectra during control, occlusion, and reperfusion were similar, suggesting that motion of blood not related to perfusion or blood flow is present in all conditions. These findings suggest that the biological zero arises from signals that are not flow related and that it should be subtracted from the flow signal.

Animals↗