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PubMed2002

Role of prostacyclin on microcirculation in endotoxin-induced gastroprotection in rats: a microdialysis study.

Numerous mechanisms relating to lipopolysaccharide- (LPS) induced gastroprotection have been proposed. The prostaglandin (PG) system is a promising candidate that has received considerable attention. However, the role of prostacyclin (PGI2) remains unclear. Adult, male Sprague-Dawley rats were divided into four groups: (1) control, n = 6; (2) LPS (LPS, 10 mg/kg, i.v.), n = 7; (3) LPS + indomethacin (Indo) (LPS, 10 mg/kg and indomethacin 5 mg/kg, i.v.), n = 7; and (4) Indo (indomethacin 5 mg/kg, i.v.), n = 7. Additionally, gastric microcirculation was investigated using in vivo microscopy. Tissue malondialdehyde (MDA) and glutathione levels were measured at the conclusion of the experiment. Specifically, microdialysis was used to measure the 6-keto-PGF1alpha, a stable metabolite of PGI2, while flow cytometry was used to measure the CD11b/CD18 expression of circulating neutrophils. Compared with LPS alone, LPS with Indo significantly impaired gastric microcirculation and systemic hemodynamics. LPS-induced gastroprotection was lost, as evidenced by the increased adherent leukocyte count, decreased flow velocity in the post-capillary venules, and increased tissue MDA production. Meanwhile, the luminal glucose and protein contents that comprised the gastric mucosa injury index were significantly increased. These effects of Indo are directly associated with the levels of PGI2 in gastric tissue, which increased with LPS alone and significantly decreased with a combination of LPS and Indo. This work demonstrates that PGI2 contributes to LPS-induced gastroprotection.

Animals↗

PubMed2002

Response of the rat cremaster microcirculation to hemorrhage in vivo: differential effects of intravenous anesthetic agents.

Anesthetic agents are known to have differential effects on both the systemic circulation and the microcirculation. The aim of this study was to compare the effects of several intravenous (i.v.) agents on the microcirculatory response to hemorrhage. Male Wistar rats (n = 52) were anesthetized i.v. either with propofol and fentanyl (propofol fentanyl), ketamine, or thiopental. Cardiovascular variables were monitored. The cremaster muscle was observed by using fluorescent intravital microscopy. FITC-BSA was administered (0.25 mL/100 g, i.a.) to determine macromolecular leak, an index of vessel integrity. Animals were further allocated into control (C), 10% hemorrhage (H), or hemorrhage re-infusion (H-R, removal of 10% blood volume and then re-infusion of saline and blood) groups. When systolic arterial pressure (SAP) was maintained after hemorrhage, constriction of A3 and A4 arterioles (5-30 microm) was accompanied by no change in the diameter of A1 (80-130 microm): most frequent with ketamine (A1: -1.7 +/- 1.2; A4: -13.9 +/- 2.7%; H and H-R: n = 9/11). With lower SAP, dilation of the A3 and A4 was accompanied by constriction of the A1: most frequent with propofol/fentanyl (A1: -8.0 +/- 2.5; A4; 35.1 +/- 9.4%; H and H-R: n = 6/11). No increases in macromolecular leak occurred with any anesthetic agent or in H or H-R groups. The response of cremaster muscle microcirculation to hemorrhage differs with different i.v. anesthetic agents. Dilation of small arterioles is the predominant response with propofol/fentanyl and constriction of small arterioles with ketamine.

Anesthetics, Intravenous↗

PubMed2003

Endothelium-dependent vasodilation in the skin microcirculation of patients with septic shock.

The evidence for endothelial dysfunction in sepsis is mostly restricted to animal models. We investigated endothelial function in the skin microcirculation of eight patients hospitalized for septic shock in an intensive care unit (ICU). All patients required adrenergic support. Twelve hemodynamically stable ICU patients without sepsis who did not receive any vasoactive medication were used as controls. The two groups were of similar age and sex ratio. For additional reference, 16 healthy, nonsmoking subjects matched for age and sex to the first two groups were also studied. The evaluation of endothelial function was based on the comparison of skin blood flow responses to iontophoretically applied acetylcholine (Ach, an endothelium-dependent vasodilator) and sodium nitroprusside (SNP, an endothelium-independent vasodilator). Skin blood flow was measured on the volar face of the forearm using laser Doppler imaging. Before application of Ach or SNP, the mean baseline skin blood flow was below 100 perfusion units (PU) in all subjects and did not differ between groups. The maximal increase in blood flow elicited by both agents was significantly depressed in the patients with sepsis (Ach: 167 +/- 63 PU; SNP: 138 +/- 34 PU, mean +/- SD) compared with the ICU control patients (Ach: 291 +/- 135 PU, P < 0.05; SNP: 261 +/- 121 PU, P < 0.01) and the healthy, nonsmoking groups (Ach: 336 +/- 98 PU, P < 0.01; SNP: 304 +/- 81 PU, P < 0.01). The ratio of responses to Ach and SNP did not significantly differ between groups (septic: 1.22 +/- 0.40; ICU control 1.18 +/- 0.46, healthy, nonsmoking 1.12 +/- 0.24, P = 0.86). Thus, sepsis was not associated with a selective depression of the endothelium-dependent response. These results suggest that the capacity of the endothelium to produce signals for vasorelaxation remains intact in the skin microcirculation of patients with septic shock.

Acetylcholine↗

PubMed2003

Effects of early and late intravenous norepinephrine infusion on cerebral perfusion, microcirculation, brain-tissue oxygenation, and edema formation in brain-injured rats.

OBJECTIVES: Reduction of cerebral perfusion during the early phase after traumatic brain injury is followed by a later phase of normal to increased perfusion. Thus, pharmacologically elevating mean arterial blood pressure with the aim of improving cerebral perfusion may exert different time-dependent effects on cortical perfusion, microcirculation, tissue oxygenation and brain edema formation after traumatic brain injury. DESIGN: Randomized, placebo-controlled trial. SETTING: Experimental laboratory at a university hospital. SUBJECTS: A total of 37 male Sprague-Dawley rats subjected to a focal cortical contusion. INTERVENTIONS: At 4 or 24 hrs after focal traumatic brain injury, mean arterial blood pressure was increased to 120 mm Hg for 90 mins by infusing norepinephrine. In rats receiving physiologic saline, mean arterial blood pressure remained unchanged. In the first series, pericontusional cortical perfusion was measured using the laser Doppler flowmetry scanning technique before injury and before, during, and after the infusion period. In a second series, intracranial and cerebral perfusion pressure and intraparenchymal perfusion and tissue oxygen measured within the contused and pericontusional cortex were recorded continuously before, during, and after norepinephrine infusion. Changes in cortical microcirculation were investigated by orthogonal polarization spectral imaging. At the end of each experiment, hemispheric swelling and water content were determined gravimetrically. MEASUREMENTS AND MAIN RESULTS: At 4 and 24 hrs after traumatic brain injury, intravenous norepinephrine significantly increased pericontusional cortical perfusion, which was also reflected by an increase in diameters and flow velocities of pericontusional arterioles and venules. Cerebral perfusion pressure and intraparenchymal perfusion and tissue oxygen were significantly increased during norepinephrine infusion at 4 and 24 hrs. Hemispheric swelling and water content showed no difference between the groups. CONCLUSIONS: After cortical impact injury, early and late intravenous norepinephrine infusion pressure-dependently increased cerebral perfusion and tissue oxygenation without aggravating or reducing brain edema formation. Future studies are warranted to determine long-term changes of short and prolonged norepinephrine-induced increases in mean arterial blood pressure and cerebral perfusion pressure.

Animals↗

PubMed2005

Activated protein C improves the visceral microcirculation by attenuating the leukocyte-endothelial interaction in a rat lipopolysaccharide model.

OBJECTIVE: Abnormalities in the vascular endothelial function play an important role in the development of septic organ dysfunction. The aim of the study was to examine the effect of recombinant human activated protein C on leukocyte-endothelial interaction in endotoxemia. DESIGN: Experimental animal model of sepsis. SETTING: University research laboratory. SUBJECTS: Normal Wistar rats. Each animal was infused with 4.5 mg/kg lipopolysaccharide to simulate severe sepsis. INTERVENTIONS: Rats were injected with endotoxin simultaneously with either a low or a high dose of recombinant human activated protein C (n = 7). One, 2, and 3 hrs after injection, mesenteric microcirculation was observed under intravital microscopy. In another series, tumor necrosis factor, interleukin-6, alanine transaminase, and blood urea nitrogen levels were evaluated (n = 5). MEASUREMENTS AND MAIN RESULTS: The adhesive leukocyte count on the endothelium was significantly suppressed in both high-dose and low-dose groups (p < .01 and .05, respectively). The bleeding events decreased in the low-dose treatment group compared with both the control (p < .05) and high-dose group (p < .05). Microcirculatory flow as expressed by red blood cell velocity was maintained better in the low-dose group. Comparison of cytokine levels showed a significant decrease in the treatment groups. Organ damage markers were also suppressed in the treatment groups (p < .05) CONCLUSIONS: Recombinant human activated protein C demonstrated a protective effect on microcirculation through the inhibition of leukocyte-endothelial interaction and suppression of inflammatory cytokine production.

Alanine Transaminase↗

PubMed2006

Microcirculation during cardiac arrest and resuscitation.

OBJECTIVE: Direct observations of the microcirculation using orthogonal polarization spectral imaging have attracted attention and revealed that, especially in cardiogenic and distributive shock, there is discordance between the macrocirculation and the microcirculation. We evaluated serial changes and the effects of epinephrine on microcirculatory blood flow in the most severe form of circulatory failure, namely, cardiac arrest. DESIGN AND SETTING: : Controlled laboratory animal study. SUBJECTS AND INTERVENTIONS: A total of 15 pigs were subjected to 5 mins of ventricular fibrillation and 5 mins of precordial compression before electrical defibrillation was attempted. In a subset, six animals received 1 mg of epinephrine after 1 min of precordial compression. MEASUREMENTS AND MAIN RESULTS: Microcirculatory blood flow was visualized in the sublingual mucosa at baseline and 0.5, 1, and 5 mins of ventricular fibrillation, at 1 and 5 mins of precordial compression, and at 1 and 5 mins after return of spontaneous circulation. In addition, coronary perfusion pressure was recorded. Microcirculatory blood flow decreased dramatically in the 0.5 min after the onset of ventricular fibrillation. Precordial compression partially restored microcirculatory blood flow in each animal but to a significantly greater extent in animals that achieved return of spontaneous circulation. These changes were paralleled by similar changes in coronary perfusion pressure. Both variables were highly correlated. Administration of epinephrine resulted in a massive reduction of microcirculatory blood flow that lasted for >/=5 mins. CONCLUSIONS: In this model, microcirculatory blood flow was highly correlated with macrocirculatory hemodynamics, including coronary perfusion pressure in distinction with septic shock. Administration of epinephrine dramatically decreased microcirculatory blood flow.

Animals↗

PubMed2005

Endogenous estrogens increase postischemic hyperemia in the skin microcirculation.

Estrogens have been recognized as a major regulator of vascular tone and structure, particularly in the skin. The objective of this study was to investigate the effects of endogenous estrogens on the skin microcirculation. Skin blood flow was measured at the forearm at rest and during postischemic hyperemia using laser Doppler flowmetry in 32 healthy women (mean age 34.5 +/- 3.9 years) involved in an in-vitro fertilization program. Women were treated for 10 to 12 days with gonadotropin-releasing hormone agonist (total dose 40.3 +/- 3.3 mg) and human menopausal gonadotropin (1942 +/- 801 IE) or follicle-stimulating hormone (2544 +/- 1071 IE) according to individual estrogen levels. Plasma estrogen levels increased from 132 +/- 90 pmol/L (36 +/- 25 pg/mL) to 8471 +/- 4386 pmol/L (2308 +/- 1195 pg/mL) during treatment (P < 0.0001). Maximal hyperemic blood flow increased from 353 +/- 81% before treatment to 516 +/- 144% after hormonal stimulation (P < 0.0001), whereas basal skin flow was not altered. This study shows that endogenous estrogens enhance the postischemic hyperemic response of the skin microcirculation.

Adult↗

PubMed2006

A novel approach to the study of human microcirculation: Reactivity to locally applied angiotensin II in the conjunctival microvascular bed.

OBJECTIVE: To develop a state-of-the-art, computer-assisted intravital microscopy protocol to evaluate directly the effects of topically applied drugs on conjunctival arteriolar and venular diameters. METHODS: Fifty-one normotensive volunteers were studied. Video-recordings of the bulbar conjunctival microcirculation were made before and following eye drops containing angiotensin II (AngII) (0.001% w/w, or 0.01%) or phenylephrine (0.25%). The computer-assisted analyses of arteriolar and venular diameters were performed off-line. In different protocols the microvascular reactivity to the different eye drops were compared. RESULTS: AngII (0.01%) eye drops, but not AngII (0.001%), induced significant constriction in both arterioles (median, 19%) and venules (13%). Phenylephrine eye drops (pharmacological control) induced similar arteriolar (18%) and venular (12%) constrictions. Repeated AngII challenges with a 30-min interval revealed reproducible vasoconstriction responses (median arteriolar constriction, 11 and 17%, respectively; NS). The vasoconstriction responses following AngII challenges on two consecutive days revealed reproducible responses (median arteriolar constriction, 13 and 11%, respectively; NS). CONCLUSIONS: The present results demonstrate that the proposed model for noninvasive intravital video-microscopy of the conjunctival microcirculation is sensitive for measuring direct arteriolar and venular reactivity following topically applied drugs. We consider this model a valuable tool for sophisticated research on in-vivo microvascular reactivity in humans.

Administration, Topical↗

PubMed2003

Oxygenation and microcirculation during skin stretching in undermined and nonundermined skin.

The aim of this experimental study was to assess the skin microcirculation of undermined and nonundermined wound edges closed with a skin-stretching device. In eight piglets, 9 x 9-cm wounds were created on both flanks by excision of the skin and the subcutaneous layer down to the muscular fascia, with general anesthesia. On one flank, the surrounding skin was completely undermined. For a period of 30 minutes, wound closure was performed with a stretching device, using the principle of load cycling. The device stretched the skin and moved the opposing wound edges toward each other. During this period, laser Doppler flowmetry and transcutaneous oximetry were simultaneously used to monitor microcirculation and oxygenation in the stretched skin of both flanks. Undermining of the surrounding skin produced a 12 percent decrease in the laser Doppler flowmetry signal and a 21 percent decrease in the transcutaneous oximetry value. Skin stretching resulted in decreases in the laser Doppler flowmetry signals and the transcutaneous oximetry values, whether or not the skin was undermined. Releasing the stretching device resulted in rapid normalization of the laser Doppler flowmetry values in undermined and nonundermined skin and a slow return of the transcutaneous oximetry values to close to baseline levels in nonundermined skin. The transcutaneous oximetry values in undermined skin did not return to baseline levels; each period of skin stretching resulted in an additional decrease in the transcutaneous oximetry values. Stretching of undermined skin for 30 minutes produced a significant (p < 0.0001) decrease in skin oxygenation. As a result, 50 percent of the undermined stretched skin demonstrated skin necrosis at the wound edges, which was still present after 1 week. Wound healing in the nonundermined stretched skin proceeded without problems. It is concluded from these experiments that the viability of undermined skin becomes compromised as a result of significantly decreased oxygen availability in the skin during and after stretching. Consequently, it is recommended that skin stretching be performed on nonundermined skin, rather than undermined skin. In addition, when skin is stretched to close a large defect, it is logical to use cyclic loading, so that recuperation of the skin circulation can occur. Furthermore, laser Doppler flowmetry seemed to produce atypical signals in monitoring of skin viability of wound edges closed with a skin-stretching device.

Animals↗

PubMed2005

Effects of colloid resuscitation on peripheral microcirculation, hemodynamics, and colloidal osmotic pressure during acute severe hemorrhage in rabbits.

We examined the effects of hydroxyethyl starch (HES) on the microcirculation, hemodynamics, and colloidal osmotic pressure in a rabbit model of hemorrhagic shock. A total of 40 rabbits was anesthetized with pentobarbital and isoflurane, and they were mechanically ventilated. An ear chamber was prepared to examine blood vessels by intravital microscopy. Shock was induced by removing nearly half of the circulating blood volume. Twenty rabbits received 20 mL of HES by intravenous infusion immediately after blood letting. Additional HES was then administered intravenously to a total volume of 100 mL. The other 20 rabbits (control) were intravenously given 40 mL of lactated Ringer's solution (LR), followed by additional LR to a total volume of 200 mL, administered under the same conditions as HES. After blood letting, arteriolar diameter decreased similarly in the the HES and LR groups (HES, 40.5% +/- 14.8% of the baseline value versus LR, 43.3% +/- 13.1%). After the completion of infusion, arteriolar diameter significantly recovered to 90.8% +/- 10.2% of the baseline value in the HES group as compared with only 62.6% +/- 10.7% in the LR group (P < 0.005). Recovery of arterial blood flow velocity and blood flow rate was also significantly better in the HES group than in the LR group (P < 0.005). Mean arteriolar pressure, central venous pressure, and plasma colloid osmotic pressure after the completion of infusion were significantly greater in the HES group than in the LR group (P < 0.005). We conclude that intravenous infusion of HES effectively maintains the microcirculation, hemodynamics, and colloidal osmotic pressure in a rabbit model of acute severe hemorrhage.

Animals↗

PubMed2006

Pretreatment of sivelestat sodium hydrate improves the lung microcirculation and alveolar damage in lipopolysaccharide-induced acute lung inflammation in hamsters.

Damage to the lung microcirculation and alveoli caused by activated leukocytes is known to play an important role in the development of acute lung injury (ALI). The aim of this study is to evaluate the difference in the effect of pretreatment and posttreatment of a synthetic neutrophil elastase inhibitor sivelestat on ALI. Hamsters were instilled with 10.0 mg/kg of lipopolysaccharide (LPS) intratracheally for 1 h to simulate ALI. Two milligrams per kilogram of sivelestat was injected intraperitoneally either previously or after LPS infusion. One and 24 hours after the infusion of LPS, pulmonary microcirculation was observed under the intravital microscopy. In another series, the blood cell counts were evaluated. The adhesive leukocyte count on the endothelium was significantly lower in pretreatment group compared with control group (P < 0.01), whereas the difference was not significant in the posttreatment group. Similarly, the number of obstructed capillary was significantly lower in the pretreatment group (P < 0.01). The width of interstitium was significantly lower in the pretreatment and posttreatment group (P < 0.01 and 0.05, respectively). A comparison of white blood cell counts showed a better maintenance in pretreatment group (P < 0.05). Pretreatment of sivelestat demonstrated a protective effect on both intravascular and extravascular damage in the lung, whereas posttreatment only suppressed the latter damage.

Acute Disease↗

PubMed2003

Different radiogenic effects on microcirculation in healthy pancreas and in pancreatic carcinoma of the rat.

OBJECTIVE: To compare the radiogenic effects on microcirculation in healthy and malignant pancreatic tissue. SUMMARY BACKGROUND DATA: Vascular injury is an important effect of radiotherapy, which has been suggested for antiangiogenic tumor therapy. METHODS: An established model of duct-like pancreatic cancer (DSL6A) was used. Investigation was performed in 12 healthy and 24 tumor-bearing Lewis rats. The tumors were locally irradiated with 15 Gy in 12 animals 4 weeks after intraperitoneal inoculation. Additionally, local radiation of the normal pancreas was performed in six healthy animals. Intravital microscopy of tumor and normal pancreatic microcirculation was performed 5 days after radiation. Relevant parameters were erythrocyte velocity and functional vessel density. Tumor apoptosis and the fraction of vital tumor cells were estimated histologically 5 and 12 days after radiation. RESULTS: Local radiation with 15 Gy caused a pronounced impairment of blood flow and functional capillary density in the normal pancreas 5 days after radiation, while the tumor blood flow was not significantly changed. A significant reduction in the fraction of vital tumor cells and a significant increase in tumor apoptosis were observed 12 days after radiation. CONCLUSIONS: Local radiation impairs blood flow in healthy pancreas but not in pancreatic cancer tissue. Tumor cell death is the leading consequence of radiation injury in malignant pancreatic tissue without affecting the vascular system of the tumor. The authors conclude that external beam radiation does not appear to be a useful adjunct for a vascular-targeted therapy in pancreatic carcinoma but causes distinct hypoperfusion in the healthy pancreas.

Animals↗

PubMed2005

Heat shock preconditioning reduces ischemic tissue necrosis by heat shock protein (HSP)-32-mediated improvement of the microcirculation rather than induction of ischemic tolerance.

INTRODUCTION: Supraphysiologic stress induces a heat shock response, which may exert protection against ischemic necrosis. Herein we analyzed in vivo whether the induction of heat shock protein (HSP) 32 improves survival of chronically ischemic myocutaneous tissue, and whether this is based on amelioration of microvascular perfusion or induction of ischemic tolerance. METHODS: The dorsal skin of mice was subjected to local heat preconditioning (n = 8) 24 hours before surgery. In additional heat-preconditioned animals (n = 8), HSP-32 was inhibited by tin-protoporphyrin-IX. Unconditioned animals served as controls (n = 8). A random-pattern myocutaneous flap was elevated in the back of the animals and fixed into a dorsal skinfold chamber. The microcirculation, edema formation, apoptotic cell death, and tissue necrosis were analyzed over a 10-day period using intravital fluorescence microscopy. RESULTS: HSP-32 protein expression was observed only in heat-preconditioned but not in unconditioned flaps. Heat preconditioning induced arteriolar dilation, which was associated with a significant improvement of both arteriolar blood flow and capillary perfusion in the distal part of the flap. Further, heat shock reduced interstitial edema formation, attenuated apoptotic cell death, and almost completely abrogated the development of flap necrosis (4% +/- 1% versus controls: 53% +/- 5%; P[r] < 0.001). Most strikingly, inhibition of HSP-32 by tin-protoporphyrin-IX completely blunted the preconditioning-induced improvement of microcirculation and resulted in manifestation of 72% +/- 4% necrosis. CONCLUSION: Local heat preconditioning of myocutaneous tissue markedly increases flap survival by maintaining adequate nutritive perfusion rather than inducing ischemic tolerance. The protection is caused by the increased arteriolar blood flow due to significant arteriolar dilation, which is mediated through the carbon monoxide-associated vasoactive properties of HSP-32.

Analysis of Variance↗

PubMed2005

Kupffer cell ablation improves hepatic microcirculation after trauma and sepsis.

BACKGROUND: Macrophages undergo maladaptive alterations after trauma. In this study, we assessed the role of Kupffer cells in hepatic microcirculatory response to endothelin-1 (ET-1) after femur fracture (FFx) and cecal ligation and puncture (CLP). METHODS: Sprague-Dawley rats (200-300 g) underwent sham, FFx, CLP, or FFx + CLP. To ablate Kupffer cells, group 1 animals were treated with gadolinium chloride, and group 2 animals received saline. Hepatic microcirculation was assessed by intravital microscopy. Liver mitochondrial redox state and tissue oxygen (tPo2) were determined by NADH and ruthenium fluorescence, respectively. Liver damage was estimated by alanine aminotransferase levels. Differences were assessed using analysis of variance followed by Student-Newman-Keuls post hoc test. RESULTS: After 10 minutes of ET-1, CLP and FFx + CLP caused significant reduction in hepatic perfusion index (2.5-fold and 5-fold vs. sham, p < 0.05, respectively), redox state (36% and 45% vs. sham, p < 0.01, respectively), tPo2 (10% and 12% vs. sham, p < 0.05, respectively), and more liver damage compared with sham and FFx-treated animals. Kupffer cell depletion restored microcirculation, redox state, and tPo2 and abrogated hepatocellular damage. CONCLUSION: Kupffer cells contribute directly to hepatic microcirculatory dysfunction and liver injury after inflammatory stress. Furthermore, Kupffer cell depletion ameliorates the microcirculatory perturbations of trauma and sepsis. Thus, modulation of Kupffer cell response may prove beneficial.

Animals↗

PubMed2006

In vivo visualization of the effect of polyclonal antithymocyte globulins on the microcirculation after ischemia/reperfusion in a primate model.

BACKGROUND: Ischemia-reperfusion injury (IRI) leads to increased leukocyte adherence enhancing acute cellular rejection and microvascular dysfunction. Polyclonal antithymocyte globulins (ATGs) induce T-cell depletion and functional impairment of nondepleted lymphocytes in peripheral blood. ATGs represent an important option in the treatment of acute cellular rejection but little is known about their effects on the microcirculation in IRI. METHODS: In a perfusion system, 19 cynomolgus monkeys were used to evaluate the influence of three different ATGs on the leukocyte-endothelium interaction after cold ischemia. ATGs were administered to human blood 30 min prior to reperfusion of primate extremities. Using intravital fluorescence microscopy the postreperfusion microcirculation of skeletal muscle was visualized. RESULTS: Significant differences were found between ATG-treated and ATG-free groups concerning blood flow velocity, leukocyte count, and leukocyte-endothelium interaction. ATGs reduced microvascular leukocyte adhesion, count, and blood flow impairment. CONCLUSION: ATGs have a favorable impact on early mechanisms of IRI. Due to reduced leukocyte adherence to the antigen-presenting endothelial cells, recognition events cannot take place in the posttransplant period of reperfusion. In addition to inhibiting acute transplant rejection, increase of posttransplant blood flow supports the use of ATGs as pretransplant induction therapy.

Animals↗

PubMed1976

Ultrastructure of the human dermal microcirculation: the horizontal plexus of the papillary dermis.

Electron microscopy was used to define the ultrastructure of the various segments of the human cutaneous microcirculation in normal forearem skin. The organization of the vessels in the horizontal plexus of the papillary dermis was reconstructed from 1-mum plasticembedded sections. Ultrathin sections were taken at 10- to 20-mum intervals over a distance of 450 mum. Arterioles were followed through the capillary bed to their venous connections. Terminal arterioles, arterial and venous capillaries, and postcapillary venules were identified on the basis of size, cellular composition of their walls, and their relationship to the other segments of the microvascular bed. The arterial segments were characterized by a homogeneous basement membrane and the venous segments by a multilaminated basement membrane. The elastic lamina in the arterioles was a discontinuous layer which gradually disappeared from the arteriolar wall to form an external sheath just before the arteriole connected with the arterial capillary segment. The vascular walls varied from 1 to 5 mum in all of the segments of the microvascular bed. Criteria are proposed for identifying the various segments of the microcirculation so that their roles in dermatoses and vascular malformations can be evaluated.

Basement Membrane↗

PubMed2005

Laser Doppler imager (LDI) scanner and intradermal injection for in vivo pharmacology in human skin microcirculation: responses to acetylcholine, endothelin-1 and their repeatability.

AIMS: The purpose of this study was to evaluate the repeatability of forearm skin blood flow responses to intradermal injections of acetylcholine (ACh) and endothelin-1 (ET-1) using a double injection technique (DIT) and a laser Doppler imager (LDI) scanner in the human skin microcirculation. METHODS: We used a laser Doppler imager (Moor LDI V3.01) to continuously monitor the change in skin blood flow during intradermal administration of physiological saline (0.9% NaCl), acetylcholine (ACh 10(-7), 10(-8), 10(-9) M) and endothelin-1 (ET-1 10(-14), 10(-16), 10(-18) M) in 10 healthy male subjects. Subjects were examined on 3 different days for assessment of interday and interobserver repeatability. Injections of either drug were randomly placed on different sites of the forearm. Laser Doppler images were collected before and after injection at 2.5 min intervals for 30 min. Data were analysed after the completion of each experiment using Moor Software V.3.01. Results are expressed as changes from baseline in arbitrary perfusion units (PU). RESULTS: ACh caused a significant vasodilation (P < 0.0001 anova, mean +/- SE: 766 +/- 152 PU, ACh 10(-9) M; 1868 +/- 360 PU, ACh 10(-8) M; 4188 +/- 848 PU, ACh 10(-7) M; mean of days 1 and 2, n = 10), and ET-1 induced a significant vasoconstrictive response (P < 0.0001 anova, -421 +/- 83 PU, ET-1 10(-18) M; -553 +/- 66 PU, ET-1 10(-16) M; -936 +/- 90 PU, ET-1 10(-14) M; mean of days 1 and 2, n = 10). There was no difference on the response to either drug on repeated days. Bland-Altman analyses showed a close agreement of responses between days with repeatability coefficients of 1625.4 PU for ACh, and 386.0 PU for ET-1 (95% CI: ACh, -1438 to 1747 PU, ET-1, -399 to 358 PU) and between observers with repeatability coefficients of 1057.2 PU for ACh and 255.8 PU for ET-1 (95% CI: ACh, -1024 to 1048 PU, ET-1, -252 to 249 PU). The variability between these responses was independent of average flux values for both ACh and ET-1. There was a significant correlation between responses measured in the same site, in the same individual on two different days by the same observer (ACh, r = 0.94, P < 0.0001; ET-1, r = 0.90, P < 0.0006), and between responses measured by two different observers (ACh, r = 0.94, P < 0.0001; ET-1, r = 0.91, P < 0.0003). CONCLUSION: We have shown that interday and intraobserver responses to intradermal injections of ET-1 and ACh, assessed using the DIT in combination with an LDI scanner, exhibited good reproducibility and may be a useful tool for studying the skin microcirculation in vivo.

Acetylcholine↗

PubMed1990

Pharmacodynamic measurements of methyl nicotinate percutaneous absorption: the effect of aging on microcirculation.

The penetration of drugs through aged skin is important both in terms of transdermal delivery to elicit systemic pharmacological effects, and for topical treatment. Cutaneous microcirculation efficiency, an integral parameter in the overall process of percutaneous absorption, was studied in young (20-34 years) and old (64-86 years) individuals. Cutaneous erythema as induced by topical administration of methyl nicotinate to the ventral forearm, was monitored non-invasively using laser-Doppler flowmetry. Dose-response behaviour was characterized by five parameters: (i) the time of onset of action; (ii) the time to reach maximum response; (iii) the magnitude of the maximum response; (iv) the area under the response-time curve; and (v) the time to decay to 75% of the maximum response. Additionally, the sensitivity and efficiency of the cutaneous microcirculation in both age groups was evaluated using a pharmacokinetic-pharmacodynamic model. Statistical analysis of all data showed no significant differences between the age groups for the same concentrations. The results indicate that microvessel reactivity to the applied stimulus is comparable in the ventral forearm of both young and old populations.

Adult↗