Increase In Tissue Blood Flow Research Articles

Rapid Cardiotonic Effects of Lipid Emulsion Infusion*

Bolus infusion of lipid emulsion can reverse cardiac pharmacotoxicity caused by local anesthetics and other lipophilic drugs. The mechanisms of this effect are not completely elucidated. The authors test the hypothesis that lipid emulsion infusion exerts direct, positive inotropic effects. Prospective, randomized animal study. University research laboratory. Adult male Sprague-Dawley rats. Rats anesthetized with isoflurane were given intravenous infusions (9 mL/kg over 1 min) of either 20% soybean oil-based emulsion or saline. Arterial pressure and aortic flow were measured continuously in intact animals. Lipid infusion increased aortic flow and arterial pressure faster and to a greater degree than did the same volume of saline infusion. Isolated rat hearts were studied using an isovolumetric, constant flow, nonrecirculating system. Left ventricular pressure was monitored. The infusion of lipid emulsion in the isolated heart dose-dependently increased rate pressure product, dP/dt, -dP/dt, and myocardial oxygen demand. Lipid emulsion exerts rapid, positive inotropic and positive lusitropic effects in both intact animal and isolated heart models. We hypothesize that this inotropy and the resulting increase in tissue blood flow contribute to the phenomenon of lipid reversal of cardiac toxicity caused by drug overdose.

ON NO—The Continuing Story of Nitric Oxide, Diabetes, and Cardiovascular Disease

Nitric oxide (NO) is a simple chemical compound—1 nitrogen and 1 oxygen atom coupled together—with complex biological actions (1,2). A singularly prominent feature of NO is its ability to cause vasodilation, a quality that is used pharmacologically when treating ischemic heart disease with NO precursors such as nitroglycerin. In 1980, Furchgott and Zawadzki (3) showed that vascular relaxation induced by acetylcholine was dependent on the presence of endothelium and provided evidence for the release of a volatile humoral factor. This substance, later called endothelium-derived relaxing factor and now recognized as NO (4), is a significant component of the insulin-signaling cascade (Fig. 1), executing microvascular vasodilation stimulated by local NO production from the vascular endothelium (5). Vasodilation has the potential to decrease systemic blood pressure and increase local tissue blood flow in tissues such as muscle. The combination of decreased blood pressure and increased tissue blood flow, together with specific beneficial endothelial effects, may serve to prevent hypertension, cardiovascular disease, and insulin resistance (5,6). However, these effects remain exquisitely sensitive to impaired insulin signaling within the endogenous cardiovascular NO system and appear to be compromised in the presence of insulin resistance (7). So there is evidence that impaired NO-dependent vasodilation causes hypertension and insulin resistance and vice versa: that insulin resistance, such as that observed in diabetes, the metabolic syndrome, and hypertension, …

Effect of vibration on muscle perfusion: a systematic review

Vibration has become of increasing interest to health professionals, primarily owing to reports that vibration can increase tissue blood flow. The aim of this review was to investigate the available scientific evidence on the effects of exogenous vibration on skeletal muscle perfusion. The databases searched from inception to December 2010 included Ovid MEDLINE, EMBASE, CINAHL via EbscoHost and CENTRAL. Experimental and observational studies, where exogenous vibration was an intervention, were included in this review. The main outcomes of interest were muscle blood volume, blood flow, blood flow velocity, arterial diameter and muscle temperature. One reviewer selected studies for inclusion, extracted data and assessed the quality of the eligible studies. Percentage change in muscle perfusion outcome was the measure of treatment effect, and regression analysis was used to investigate associations between vibratory load and muscle perfusion. Twenty-two studies with a total of 302 participants were included in this review. Muscle blood volume increased with vibration in five of nine studies and decreased in two studies; muscle blood flow velocity increased with vibration in five of six studies; muscle blood flow increased with vibration in two of three studies; vibration had a positive effect on arterial diameter in three of three studies; vibration had no effect on muscle temperature in two of two studies. The magnitude of increase in muscle perfusion was positively associated with vibratory load (P<0·001). We conclude that vibration increases muscle perfusion with the magnitude of increase positively related to the vibratory load applied.

Detection of myocardial perfusion abnormalities using ultra-low radiation dose regadenoson stress multidetector computed tomography

The ability of multidetector computed tomography (MDCT) to detect stress-induced myocardial perfusion abnormalities is of great clinical interest as a potential tool for the combined evaluation of coronary stenosis and its significance. However, stress testing requires repeated scanning that is associated with additional radiation exposure and iodine contrast. Our goal was to determine the effects of reduced tube voltage and contrast dose on the ability to detect perfusion abnormalities. We studied 40 patients referred for coronary CT angiography (CTA) who agreed to undergo additional imaging after administration of an A(2A)-agonist (regadenoson 0.4 mg). Images were acquired at rest and during hyperemia with prospective gating with 120 kV tube voltage with 80-90 mL of contrast in 20 patients (group 1) and 100 kV with 55-70 mL of contrast in the remaining 20patients (group 2). Custom 3D analysis software was used to define 3D myocardial segments and measure x-ray attenuation in each segment. In each group of patients, myocardial attenuation was averaged for segments supplied by coronary arteries with stenosis causing >50% luminal narrowing on coronary CTA and separately for segments supplied by arteries without significant stenosis. Coronary CTA detected stenosis >50% in 23 of 120 coronary arteries in 16 of 40 patients. In all patients combined, myocardial attenuation increased from 86 ± 9 at rest to 110 ± 17 HU with stress, reflecting an increase in tissue blood flow, despite the decrease in left ventricular cavity attenuation (347 ± 72 to 281 ± 55 HU), reflecting an increase in cardiac output. Importantly, in both groups, myocardial attenuation was equally reduced in segments supplied by diseased arteries (group 1: 119 ± 19 vs 103 ± 14 HU, P < 0.05; group 2: 108 ± 20 vs 97 ± 16 HU, P < 0.05), despite the 74% reduction in radiation (from 7.4 ± 2.8 to 1.9 ± 0.45 mSv) and the 28% reduction in contrast dose (from 84 ± 7 to 60 ±7 mL) (both P < 0.05). Regadenoson stress MDCT imaging can detect hypoperfused myocardium even when imaging settings are optimized to provide a significant reduction in radiation and contrast doses.

Mild elevation of body temperature reduces tumor interstitial fluid pressure and hypoxia and enhances efficacy of radiotherapy in murine tumor models.

Human and rodent solid tumors often exhibit elevated interstitial fluid pressure (IFP). This condition is recognized as a prognostic indicator for reduced responses to therapy and decreased disease-free survival rate. In the present study, we tested whether induction of a thermoregulatory-mediated increase in tissue blood flow, induced by exposure of mice to mild environmental heat stress, could influence IFP and other vascular parameters within tumors. Using several murine tumor models, we found that heating results in a sustained reduction in tumor IFP correlating with increased tumor vascular perfusion (measured by fluorescent imaging of perfused vessels, laser Doppler flowmetry, and MRI) as well as a sustained reduction in tumor hypoxia. Furthermore, when radiation therapy was administered 24 hours postheating, we observed a significant improvement in efficacy that may be a result of the sustained reduction in tumor hypoxia. These data suggest, for the first time, that environmental manipulation of normal vasomotor function is capable of achieving therapeutically beneficial changes in IFP and microvascular function in the tumor microenvironment.

Noninvasively measuring the hemodynamic effects of massage on skeletal muscle: A novel hybrid near-infrared diffuse optical instrument

Increase in tissue blood flow is one of the most acknowledged potential effects of massage; however, actual research studies examining this phenomenon are inconsistent and inconclusive. One possible reason for continued uncertainty regarding this topic is methodology, specifically how tissue blood flow is measured because limitations exist in previously utilized technologies. Near-infrared spectroscopy (NIRS) affords massage researchers a versatile and non-invasive measurement option by providing dynamic information on oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, and blood oxygen saturation in deep tissue. Near-infrared diffuse correlation spectroscopy (DCS) is an innovative technique for continuous non-invasive measurement of blood flow in deep tissue. The combination of these two technologies has resulted in a novel hybrid diffuse optical instrument for simultaneous measurement of limb muscle blood flow and oxygenation. The purposes of this short report are to review previous blood flow measurement techniques and limitations in massage therapy research, introduce a novel hybrid near-infrared diffuse optical instrument that addresses previous limitations in the assessment of hemodynamic properties, outline a proposed massage therapy pilot study utilizing the novel measurement technology, and present sample data from a pilot participant using the introduced novel technology.

Cilostazol Increases Tissue Blood Flow in Contracting Rabbit Gastrocnemius Muscle

The mechanisms underlying the ability of cilostazol to improve walking distance in patients with intermittent claudication (IC) are not fully understood, but may be related to its phosphodiesterase type 3 (PDE3) and adenosine uptake inhibition. In the present study the effect of cilostazol on blood flow and interstitial adenosine concentration was compared with that of the PDE3 inhibitor, milrinone, and the adenosine uptake inhibitor, draflazine. Rabbit gastrocnemius muscle blood flow was measured under resting, contracting and ischemic conditions. Interstitial adenosine was sampled by microdialysis. None of the drugs affected tissue blood flow at rest. Blood flow in electrically stimulated muscle was 2- to 3-fold higher in vehicle-, milrinone- and draflazine-treated animals. However, cilostazol caused an 8-fold increase. Ligation of the femoral artery decreased blood flow in the stimulated muscle in all groups to a similar degree. Cilostazol and draflazine increased the dialysate adenosine concentration during the first 10 min of muscle contraction, but had no effect during ischemia, most likely because of the high AMP deaminase activity in skeletal muscle. Cilostazol increases blood flow in the gastrocnemius muscle during contraction and it is this effect that may be partially responsible for the improved walking distance in IC patients. (Circ J 2010; 74: 181 - 187).

Epinephrine in Local Anesthetic Cancels Increase in Tongue Mucosal Blood Flow after Stellate Ganglion Block in Rabbit

The goal of this study was to compare oral mucosal blood flow and duration of anesthetic action after stellate ganglion block (SGB) using lidocaine, with or without epinephrine, and discuss the effect of epinephrine on SGB. Duration of anesthetic action was defined as elapsed time from finish of injection to recovery of common carotid blood flow (CCBF) to within+/-5% of respective control value. Male Japan White rabbits were anesthetized with isoflurane and mechanically ventilated. Common carotid blood flow and tongue mucosal tissue blood flow (TMBF) were measured with an ultrasound flowmeter and laser Doppler flowmeter, respectively. End-tidal partial pressure of carbon dioxide (ETCO(2)) and hemodynamic variables were continuously monitored, including heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP). For SGB, the tip of the needle was placed on the left transverse process of the cervical vertebra, 1-2 mm caudal to the cricoid cartilage. Either 0.1 ml of 1% lidocaine (Group L) or 1% lidocaine containing 10 mug/ml epinephrine (Group LE) was injected for SGB. There were no differences in values at immediately before SGB and at the time when maximal change in CCBF was observed after SGB for ETCO(2), HR, SBP, DBP or MAP in either group. CCBF showed a significant increase in Group L after SGB. In contrast, CCBF only showed a slight increase in Group LE. TMBF showed a significant increase in Group L after SGB, but not in Group LE. No differences in time required for maximal effect were observed between the two groups. In contrast, duration of anesthetic action in Group LE was significantly longer than that in Group L. Addition of epinephrine to local anesthetic solutions is not suitable for SGB, as it may not facilitate an increase in tissue blood flow, which is the primary objective of SGB.

Nitroglycerin as a Modulator of Hemoglobin Function.

Recent evidence suggests that oxygen acts as an allosteric modulator of nitric oxide (NO) binding to hemoglobin. This may have important physiological implications. Those effects, thought by some to be mediated by nitrosylation of the conserved cysteine β93 residues (S-nitrosohemoglobin; SNO-Hb), may also have therapeutic relevance in sickle cell disease and potentially be a useful strategy in controlling vasoactive effects of hemoglobin-based blood substitutes. Nitroglycerin (NTG), the classic vasodilator drug, acts in part through metabolism to NO. Normal (AA) and sickle (SS) blood suspensions were treated with nitroglycerin from 0.03 to 300 μM for periods up to 3.25 hours. Such treatment significantly lowered the oxygen affinity (increases P50, PO2 at which hemoglobin is half-saturated with O2) of both AA and SS red cells. The decrease in oxygen affinity is greater when oxygenated cells are treated than deoxygenated cells, with changes in P50 as great as 7.4 mm Hg in the AA cells and 9.9 mm Hg in the SS cells. Those shifts occur within 15 minutes, before significant increases in methemoglobin levels. This is opposite to what has been seen with other NO donors (2-(N,N-diethylamino)-diazenolate-2-oxide, S-nitrosocysteine, and sodium trioxodinitrate), where increased oxygen affinity occurs. Other classic NO donors also yielded significant methemoglobin formation within 15 minutes. In vivo effects of NTG infusion up to 1 μg/kg/min fail to demonstrate any change in P50 or methemoglobin in study subjects with normal AA erythrocytes. (Shigihara A. Masui1994;43:222) In addition, NTG has been shown to enhance oxygen release from erythrocytes without significantly increasing tissue blood flow in the hepatic microcirculation in a rat model. (Kosaka H, et al. Nat Med1997;3:456) Furthermore, a study in a dog model demonstrated NTG-induced enhanced oxygen unloading in the ischemic microcirculation. (Bin JP, et al. Circulation2006;113:2502) Elevated tandem erythrocyte S-nitrosothiol content, reflecting mainly SNO-Hb, was also noted. However, SNO-Hb increases oxygen affinity (Bonaventura C, et al. J Biol Chem1999;274:24742) and cannot explain the increased oxygen unloading. The effect of NTG on erythrocytes in our in vitro study model mimics in vivo results in the microcirculation (as opposed to the macrovascular circulation) and demonstrates that the reported enhanced oxygen unloading is due to a decrease in oxygen affinity of hemoglobin. Other biotransformation products of NTG may account for these effects as opposed to SNO-Hb. This study demonstrates that selective NO donors (i.e., NTG) may target erythrocytes for enhanced R (oxyhemoglobin) to T (deoxyhemoglobin) transformations specifically in the microcirculation and thereby improve tissue oxygenation.

Propagation of calcium waves along endothelium of hamster feed arteries

An increase in tissue blood flow requires relaxation of smooth muscle cells along entire branches of the resistance vasculature. Whereas the spread of hyperpolarization along the endothelium can coordinate smooth muscle cell relaxation, complementary signaling events have been implicated in the conduction of vasodilation. We tested the hypothesis that Ca(2+) waves propagate from cell to cell along the endothelium of feed arteries exhibiting spontaneous vasomotor tone. Feed arteries of the hamster retractor muscle were isolated, pressurized to 75 mmHg at 37 degrees C, and developed myogenic tone spontaneously. Smooth muscle cells and endothelial cells were loaded with the Ca(2+) indicator Fluo-4. An acetylcholine stimulus was delivered locally using microiontophoresis (1-microm pipette tip, 1 microA, 1 s), and Ca(2+) signaling within and along respective cell layers was determined using laser-scanning confocal microscopy. Acetylcholine triggered an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) of endothelial cells at the site of stimulation that preceded two distinct events: 1) a rapid synchronous decrease in smooth muscle [Ca(2+)](i) along the entire vessel and 2) an ensuing Ca(2+) wave that propagated bidirectionally along the endothelium at approximately 111 microm/s for distances exceeding 1 mm. Maximal dilation of vessels with either nifedipine (1 microM) or sodium nitroprusside (SNP, 100 microM) reduced the distance that Ca(2+) waves traveled to approximately 300 microm (P < 0.05). Thus Ca(2+) waves propagate along the endothelium of resistance vessels with vasomotor tone, and this signaling pathway is compromised during maximal dilation with nifedipine or SNP.

Effects of different resuscitation fluids on tissue blood flow and oxidant injury in experimental rhabdomyolysis

This study was performed to evaluate the effects of 0.9% saline (SAL), 0.9% saline + sodium bicarbonate + mannitol (SAL/BIC/MAN), and hypertonic saline-dextran (HSD) on hemodynamic variables, tissue blood flow, and oxidant injuries in experimental traumatic rhabdomyolysis (TR) in rats subjected allogeneic muscle extract infusion. Prospective, randomized, experimental. Physiology experiment laboratory. Male Sprague-Dawley rats, weighing 250-300 g. All groups (n = 8 each) underwent femoral artery and vein catheterization. The animals in the TR, SAL, SAL/BIC/MAN, and HSD groups received an infusion of 2 mL of autologous muscle extract for 60 mins. After autologous muscle extract infusion, the SAL and HSD groups received 30 mL/kg 0.9% saline for 30 mins or 4 mL/kg HSD for 5 mins, respectively. The SAL/BIC/MAN group received 30 mL/kg 0.9% saline for 30 mins plus a bolus of 1 g/kg mannitol and a bolus of 2 mEq/kg sodium bicarbonate diluted in 1 mL of saline. At 2 hrs of autologous muscle extract infusion, erythrocyte flows in liver and kidney were measured by using a laser Doppler flowmeter. Then, blood samples and kidney and liver biopsies were taken to measure levels of glutathione and malondialdehyde. TR caused decreases in mean arterial pressure, tissue blood flow, and tissue glutathione and an increase in malondialdehyde. Rats in the HSD group had significant metabolic acidosis. SAL resuscitation did not correct tissue blood flow and prevent oxidant injury. HSD increased tissue blood flow, mean arterial pressure, and liver and kidney glutathione and decreased serum, liver, and kidney malondialdehyde. SAL/BIC/MAN resuscitation corrected all oxidant damage variables but did not increase tissue blood flow. SAL/BIC/MAN preserved serum malondialdehyde and liver glutathione better than the HSD did. HSD prevented oxidant injury and restored tissue blood flow but increased metabolic acidosis that followed autologous muscle extract infusion. SAL/BIC/MAN seems to be more effective than HSD in decreasing oxidant injury. Further research on the effects of the solute overload and metabolic acidosis due to HSD resuscitation on renal function in experimental rhabdomyolysis is warranted.

Ocular blood flow changes after dynamic exercise in humans

To investigate control mechanisms for ocular blood flow changes after dynamic exercise using two different methods. Changes over time in the tissue blood flow in the retina and choroid-retina of healthy volunteers were determined after dynamic exercise (Master's double two-step test), using scanning laser Doppler flowmetry (SLDF) and laser speckle flowgraphy (LSFG). Changes in intraocular pressure (IOP), blood pressure, plasma CO(2) gas concentration (pCO(2)), and levels of nitric oxide (NO) metabolites were examined. Retinal blood flow measured by SLDF increased significantly only at 15 min after exercise. In contrast, normalized blur (NB) values in the choroid-retina, obtained by LSFG, increased significantly up to 60 min after exercise. Ocular perfusion pressure (OPP), calculated from IOP and blood pressure, increased significantly immediately and 15 min after exercise. The plasma NO metabolite levels increased significantly, although pCO(2) levels were unchanged. Dynamic exercise changes OPP and produces increased tissue blood flow in the retina in the immediate postexercise period, while blood flow increases more persistently in the choroid-retina. Difference in control of blood flow in these two regions may be related to stronger autoregulatory mechanism of blood flow in the retina. Nitric oxide may play a role in the regulation of blood flow.

Garlic supplementation increases peripheral blood flow: a role for interleukin-6?

There is considerable epidemiological and clinical evidence that regular garlic supplementation reduces cardiovascular risk. In this study, we have investigated the hypothesis that dietary garlic supplementation increases tissue blood flow and this is mediated by the vasodilatory actions of interleukin-6 (IL-6). Venous occlusion plethysmography was used to measure resting calf blood flow before and after oral administration of 600 mg of garlic tablets once daily for 7 days in 13 young healthy female volunteers (treatment group) and 13 female controls matched for age and body mass index (BMI). Blood samples were obtained at the time of plethysmography to measure plasma levels of IL-6, nitrate, nitrite and c-GMP. In the treatment group, calf blood flow increased significantly from 3.01 (2.56 to 3.3) ml min -1 100 mL -1 of tissue before garlic to 3.46 (3.0 to 4.03) ml min -1 100 mL -1 of tissue after 7 days of garlic ( P = 0.001). Plasma IL-6 concentrations increased significantly from 54.6 (32.3 to 151.6) mcg/mL before to 151 (135.75 to 422.3) mcg/mL after 7 days of garlic ( P = 0.02). However, there was no significant change in the plasma levels of nitrate, nitrite and c-GMP after the garlic ( P = 0.4, 0.9 and 0.65 respectively). In the control group, resting calf blood flow and plasma levels of IL-6, nitrite, nitrate and c-GMP remained unchanged after 7 days ( P = 0.62, 0.92, 0.28 and 0.35 respectively). Calf blood flow showed a non-linear correlation with plasma IL-6 levels after garlic supplementation (r = 0.86, p = <0.001) but not before. There was no significant relationship between blood flow and plasma nitrate, nitrite and c-GMP in either groups and between blood flow and IL-6 in the control group. These data suggest that garlic supplementation increases resting tissue blood flow and this may be mediated by IL-6.

Increased pressure during retrograde cerebral perfusion in an acute porcine model improves brain tissue perfusion without increase in tissue edema

Background. There is a significant lack of scientific data to support the clinically accepted view that 25 to 30 mm Hg is the maximum safe perfusion pressure during retrograde cerebral perfusion (RCP). This study was designed to investigate whether perfusion pressure greater than 30 mm Hg during RCP is beneficial to the brain during prolonged HCA in an acute porcine model. Methods. Sixteen pigs underwent 120 minutes of circulatory arrest in conjunction with RCP at a perfusion pressure of either 23 to 29 mm Hg (group L, n = 8) or 34 to 40 mm Hg (group H, n = 8) at 15°C, followed by 60 minutes of normothermic cardiopulmonary bypass. Cortical blood flow and oxygenation were measured continuously with a laser flowmeter and near-infrared spectroscopy, respectively. Tissue water content was measured at the end of the experiments. Results. Brain tissue blood flow was significantly higher in group H than in group L (16.8% ± 4.1% vs 4.8% ± 0.9% of baseline, p < 0.01) during RCP. Brain oxygen extraction in group L reached a maximum (∼70%) immediately after starting RCP, whereas in group H it increased gradually and reached a maximum at 120 minutes of RCP, indicating a greater supply of oxygen to tissue in group H than in group L. After RCP, the ability of brain tissue to use oxygen was better preserved in group H than in group L, as indicated by tissue oxygen saturation and the deoxyhemoglobin level. There was no significant increase in tissue water content in either group (group H 79.2% ± 0.3%, group L 79.1% ± 0.4%) relative to normal control pigs (78.7% ± 0.1%). Conclusions. In this acute porcine model, increasing perfusion pressure from 23–29 to 34–40 mm Hg during RCP increases tissue blood flow and provides better tissue oxygenation, without increasing tissue edema. The optimal perfusion pressure for RCP needs to be further investigated.

Sonography of the Patellar Tendon and Adjacent Structures in Pediatric and Adult Patients

1535 he patellar tendon and its adjacent soft tissue and bony structures may be affected by a number of conditions, most of which are thought to be related to trauma. The patellar tendon is readily seen on sonography because of its superficial location. Patellar tendon abnormalities have been given a number of different labels with a confusing overlap in terminology. This pictorial essay illustrates both normal and abnormal appearances of the patellar tendon on sonography and describes the more common conditions affecting it. Sonographic Technique The patellar tendon is readily examined on sonography with high-frequency linear array transducers. Transducers up to 20 MHz are now available and may be desirable to achieve high spatial resolution. However, acoustic penetration may be limited, and these transducers are expensive and not widely available. In practice, excellent patellar tendon sonography can be performed with 7to 10-MHz transducers. The knee is examined in a flexed or semiflexed position, and comparison may be made with the contralateral side. Longitudinal and transverse images of the tendon are obtained with electronic focusing at the appropriate depth [1]. An acoustic standoff pad can be used to help visualize more superficial structures in greater detail and can also facilitate direct palpation during real-time scanning. Power Doppler sonography can be used to examine for increased tissue blood flow associated with patellar tendon abnormality [2].

Involvement of the Endothelin System in Experimental Critical Hind Limb Ischemia

Endothelin- (ET-1) is involved in the pathogenesis of several ischemic diseases. We investigated the hypotheses that ET-1 is involved in the pathogenesis of experimental critical hind limb ischemia and that ET-1 receptor antagonists have a protective effect. Critical hind limb ischemia was achieved by exclusion of the femoral artery and embolization of collateral vessels in rats. The induction of endothelin system components by ischemia was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) (mRNAs) and immunoassay (peptides) in the plasma and ischemic muscles 5 hr (H5), 5 days (D5) and 14 days (D14) after ischemia. Two groups of rats received 100 mg/kg/day of either Bosentan, a mixed ET(A/B) receptor antagonist (n = 12), or LU 135252, a selective ET(A) receptor antagonist (n = 9), and a control group without treatment (n = 12) served as control. Muscle blood flow and ischemia were monitored in the ischemic limb by laser Doppler and phosphorylase activity, respectively. The procedure induced an 80% decrease in muscle blood flow and complete suppression of phosphorylase activity without necrosis. At day 14, the tissue blood flow remained reduced by 70% and phosphorylase activity was suppressed completely. There was up-regulation of preproendothelin-1, preproET-3, endothelin converting enzyme-1, and ET(A). ET(B) receptor mRNAs in ischemic muscle at day 5 and day 14 was accompanied by an increase in muscle concentration of ET-1 at day 5, without significant changes in plasma endothelin. Treatment with Bosentan and LU 135252 increased tissue blood flow and reduced muscle ischemia at day 14. Tissue production of ET- 1 is up-regulated in experimental critical hind limb ischemia. Inhibition of the endothelin system by a mixed ET(A/B) receptor antagonist may protect, at least in part, against muscle injury.

Effects of norepinephrine on the distribution of intestinal blood flow and tissue adenosine triphosphate content in endotoxic shock.

To investigate, during endotoxic shock, the effect of a treatment of norepinephrine (NE) administration on the distribution of blood flow and adenosine triphosphate (ATP) content in the intestinal wall. Randomized controlled trial. Animal laboratory. Domestic pigs. A total of 18 pigs were anesthetized with ketamine and pentobarbital, mechanically ventilated, hemodynamically monitored, and then challenged with a continuous infusion of Escherichia coli endotoxin (ET) (15 microg/kg) for 2 hrs. Three groups of six animals were studied; one served as time control, one group received ET and fluid resuscitation, and a third group received ET, fluid resuscitation, and a perfusion of NE to maintain constant mean arterial pressure (MAP). Cardiac output, mesenteric arterial blood flow, MAP, pulmonary pressure, and portal pressure were measured. Intestinal mucosal intracellular pH (pHi) was determined with saline-filled balloon tonometers. Tissue blood flows to the intestinal mucosa and to the muscular layer were independently measured with fluorescent microspheres, using the arterial reference sample method. Measurements were performed before and 3 hrs after the start of the ET challenge. At the end of the experiments, muscularis and mucosal samples were quickly frozen for further enzymatic ATP measurements. ET administration with fluid resuscitation induced a distributive shock with increased mucosal blood flow and decreased muscularis blood flow, whereas pHi decreased and mucosal ATP content was significantly lower than in the control group. In the group receiving ET plus NE, MAP remained constant, mucosal blood flow did not increase, and mucosal ATP content was equal to the time control group. Meanwhile, mucosal acidosis was not prevented. Normodynamic endotoxic shock may induce an alteration in mucosal oxygenation, despite an increased tissue blood flow. A treatment of NE combined with fluid resuscitation has complex effects on tissue blood flow, ATP content, and pHi.

Revascularization using the short gastric vessels of the gastric tube after subtotal esophagectomy for intrathoracic esophageal carcinoma

Background: Maintaining sufficient blood flow to the substitutive organ after esophagectomy is essential to decrease the risk of anastomotic leakage.Study Design: Forty-one patients underwent subtotal esophagectomy for intrathoracic esophageal carcinoma and reconstruction using the gastric tube. Additional vascular anastomosis between the short gastric vessels and the vessels in the neck was performed in 15 patients. Tissue blood flow was measured by laser Doppler flowmetry before and after vascular anastomosis. The incidence of anastomotic leakage in the revascularization group was compared with that in the remaining 26 patients.Results: Venous anastomosis was performed in 14 patients and arterial anastomosis in 9. There was a significant increase in tissue blood flow after venous anastomosis alone (mean percent increase: 36%; p < 0.01), and after arterial and venous anastomoses (mean percent increase: 108%; p < 0.01). No anastomotic leakage was observed in the revascularization group; six patients (23.1%) in the control group had leakage (p < 0.05). Patients in the revascularization group started taking a meal 10.0 ± 0.4 days postoperatively, compared with 15.1 ± 1.8 days in the control group (p < 0.05).Conclusions: Additional vascular anastomosis in esophageal reconstruction after subtotal esophagectomy achieved good results. This procedure can reduce the risk of anastomotic leakage and may be useful for esophageal reconstruction.

Additional microvascular anastomosis in reconstruction after total esophagectomy for cervical esophageal carcinoma

Background: Maintaining sufficient blood flow to the substitute organ after total esophagectomy is essential for decreasing the risk of anastomotic leakage. Additional venous, or arterial and venous, anastomoses between the vessels of the gastric tube and the vessels in the neck after total esophagectomy are described for 11 patients with cervical esophageal carcinoma. Methods: The tissue blood flow was measured by laser Doppler flowmetry before and after anastomosis. Venous anastomosis was performed for all 11 patients, and arterial anastomosis was added for 7 patients. Results: A significant increase in tissue blood flow was observed after venous anastomosis alone (mean, 19%; P <0.05) and after arterial and venous anastomoses (mean 43%; P <0.01). There was no anastomotic leakage or hospital death. Conclusions: This procedure may reduce the risk of anastomotic leakage especially in the case of pharyngogastrostomy following total esophagectomy.

Nitrosation of Uric Acid by Peroxynitrite: FORMATION OF A VASOACTIVE NITRIC OXIDE DONOR

Peroxynitrite (ONOO-), formed by the reaction between nitric oxide (. NO) and superoxide, has been implicated in the etiology of numerous disease processes. Low molecular weight antioxidants, including uric acid, may minimize ONOO---mediated damage to tissues. The tissue-sparing effects of uric acid are typically attributed to oxidant scavenging; however, little attention has been paid to the biology of the reaction products. In this study, a previously unidentified uric acid derivative was detected in ONOO--treated human plasma. The product of the uric acid/ONOO- reaction resulted in endothelium-independent vasorelaxation of rat thoracic aorta, with an EC50 value in the range of 0.03-0.3 microM. Oxyhemoglobin, a .NO scavenger, completely attenuated detectable .NO release and vascular relaxation. Uric acid plus decomposed ONOO- neither released .NO nor altered vascular reactivity. Electrochemical quantification of .NO confirmed that the uric acid/ONOO- reaction resulted in spontaneous (thiol-independent) and protracted (t1/2 approximately 125 min) release of .NO. Mass spectroscopic analysis indicated that the product was a nitrated uric acid derivative. The uric acid nitration/nitrosation product may play a pivotal role in human pathophysiology by releasing .NO, which could decrease vascular tone, increase tissue blood flow, and thereby constitute a role for uric acid not previously described.