Ischemia-reperfusion Injury In Dogs Research Articles

Quantitative evaluation of renal parenchymal perfusion using contrast-enhanced ultrasonography in renal ischemia-reperfusion injury in dogs.

This study evaluated whether renal perfusion changes can be noninvasively estimated by using contrast-enhanced ultrasonography (CEUS) in renal ischemia-reperfusion injury and investigated the correlation between renal perfusion measured by CEUS and necrosis and apoptosis of renal tubular epithelial cells. In six dogs with experimentally induced renal ischemia-reperfusion injury, changes in time to peak intensity, peak intensity, and area under the curve were measured on CEUS. Peak intensity and area under the curve of the renal cortex began to decrease on day 1 (about 20% lower than baseline) and reached the lowest levels (about 50% of baseline) on day 4. They then gradually increased until day 10, at which time peak intensity was about 87% and area under the curve was about 95% of baseline; neither fully recovered. Both parameters were strongly correlated with the necrosis scores on histopathologic examination on day 4 (r = −0.810 of peak intensity and r = −0.886 of area under the curve). CEUS allowed quantitative evaluation of perfusion changes in acute renal ischemia-reperfusion injury, and CEUS results were correlated with renal tubular damage on histopathologic examination. Thus, CEUS could be a noninvasive, quantitative diagnostic method for determining progress of renal ischemia-reperfusion injury.

Roles of endothelial nitric oxide synthase (eNOS) and mitochondrial permeability transition pore (MPTP) in epoxyeicosatrienoic acid (EET)-induced cardioprotection against infarction in intact rat hearts

We previously demonstrated that 11,12 and 14,15-epoxeicosatrienoic acids (EETs) produce cardioprotection against ischemia-reperfusion injury in dogs and rats. Several signaling mechanisms have been implicated in the cardioprotective actions of the EETs; however, their mechanisms remain largely elusive. Since nitric oxide (NO) plays a significant role in cardioprotection and EETs have been demonstrated to induce NO production in various tissues, we hypothesized that NO is involved in mediating the EET actions in cardioprotection. To test this hypothesis, we used an in vivo rat model of infarction in which intact rat hearts were subjected to 30-min occlusion of the left coronary artery and 2-hr reperfusion. 11,12-EET or 14,15-EET (2.5mg/kg) administered 10min prior to the occlusion reduced infarct size, expressed as a percentage of the AAR (IS/AAR), from 63.9±0.8% (control) to 45.3±1.2% and 45.5±1.7%, respectively. A nonselective nitric oxide synthase (NOS) inhibitor, L-NAME (1.0mg/kg) or a selective endothelial NOS inhibitor, L-NIO (0.30mg/kg) alone did not affect IS/AAR but they completely abolished the cardioprotective effects of the EETs. On the other hand, a selective neuronal NOS inhibitor, nNOS I (0.03mg/kg) and a selective inducible NOS inhibitor, 1400W (0.10mg/kg) did not affect IS/AAR or block the cardioprotective effects of the EETs. Administration of 11,12-EET (2.5mg/kg) to the rats also transiently increased the plasma NO concentration. 14,15-EET (10μM) induced the phosphorylation of eNOS (Ser1177) as well as a transient increase of NO production in rat cardiomyoblast cell line (H9c2 cells). When 11,12-EET or 14,15-EET was administered at 5min prior to reperfusion, infarct size was also reduced to 42.8±2.2% and 42.6±1.9%, respectively. Interestingly, L-NAME (1.0mg/kg) and a mitochondrial KATP channel blocker, 5-HD (10mg/kg) did not abolish while a sarcolemmal KATP channel blocker, HMR 1098 (6.0mg/kg) and a mitochondrial permeability transition pore (MPTP) opener, atractyloside (5.0mg/kg) completely abolished the cardioprotection produced by the EETs. 14,15-EET (1.5mg/kg) with an inhibitor of MPTP opening, cyclosporin A (CsA, 1.0mg/kg) produced a greater reduction of infarct size than their individual administration. Conversely, an EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 2.5mg/kg) completely abolished the cardioprotective effects of CsA, suggesting a role of MPTP in mediating the EET actions. Taken together, these results suggest that the cardioprotective effects of the EETs in an acute ischemia-reperfusion model are mediated by distinct mediators depending on the time of EET administration. The cardioprotective effects of EETs administered prior to ischemia were regulated by the activation of eNOS and increased NO production, while sarcKATP channels and MPTP were involved in the beneficial effects of the EETs when administered just prior to reperfusion.

Comparison of Neutron Activated and Radiolabeled Microsphere Methods for Measurement of Transmural Myocardial Blood Flow in Dogs

The 'gold standard' radioactive microsphere (RM) technique for measurement of organ blood flow under various experimental conditions is inaccessible to many researchers due to increasing environmental concerns regarding safety and disposal of low-level radioactive waste materials. A new method using neutron activated microspheres (NAM) has recently been described. We compared regional myocardial blood flows using the new formulation STERIspheres (NAM; 15.0 +/- 0.1 [SD] microm; density 1.5 gr/mL) with RM (15.0 +/- 0.1 [SD] microm; density 1.5 gr/mL) under different experimental conditions during acute ischemia-reperfusion injury in dogs. Random paired combinations of four different RM and NAM were co-injected into the left atrium during autoregulation, coronary occlusion and flow-mediated hyperemia (reperfusion) in the same animal. The left ventricle was divided into non-ischemic and ischemic regions and further subdivided into endocardial, mid-myocardial and epicardial portions. After gamma-counting, blood and myocardial tissue samples (n = 180) were dried and then shipped to a core facility for neutron activation and analysis. NAM-RM blood flow data were directly compared by ANOVA and regression analysis; Bland and Altman analysis was also performed to assess mean differences in blood flow with NAM-RM. A direct relation for blood flow between NAM-RM was observed; the slope of the relation (1.17 RM +/- 0.04 [SEE]) was different from unity but the intercept (0.06 +/- 0.06 [SEE]) was not different from the origin. Intermethod mean differences were minimal between NAM-RM in the low to normal range of blood flow and were increased at the higher blood flow levels the latter being of minor physiological consequence. A direct relation for endo/epicardial blood flow ratios between NAM-RM was also observed; the slope of the relation (0.98 RM +/- 0.04 [SEE]) and the intercept (0.03 +/- 0.06 [SEE]) were not different from unity or the origin, respectively. RESULTS show that in addition to limiting production of radioactive waste materials, NAM accurately measure myocardial blood flow, endocardial/epicardial and ischemic/non-ischemic blood flow distributions over a wide range. We compared myocardial blood flows using paired combinations of neutron activated (NAM) and the 'gold standard' radiolabeled microspheres (RM) co-injected during autoregulation, coronary occlusion and flow-mediated hyperemia in an in situ canine ischemia-reperfusion preparation. A direct relation for blood flow and endo/epicardial blood flow ratios between NAM-RM was observed; intermethod mean differences between NAM-RM were minimal in the low to normal blood flow range but increased at higher blood flow levels. These results indicate that NAM accurately measure myocardial blood flow and its transmural distribution in addition to limiting unnecessary production of radioactive laboratory waste products.

Effect of FR167653 on pancreatic ischemia-reperfusion injury in dogs

Background. The role of inflammatory cytokines is still unclear in ischemia-reperfusion injury of the pancreas. We investigated the effect of FR167653 (FR), a newly developed compound that is a potent suppressor of interleukin (IL)-1β and tumor necrosis factor (TNF)-α on ischemia-reperfusion injury of the isolated pancreatic tail in dogs. Methods. The tail of the pancreas was subjected to ischemia for 90 minutes. During occlusion of the vascular inflow, the head of the pancreas was removed. A control group (n = 14) and an FR treatment group (n = 11) were evaluated for survival rate, tissue blood flow, arterial oxygen pressure (Pao2), serum amylase and lipase levels, glucose and insulin, liver enzymes, creatinine, IL-1β mRNA in the peripheral blood, and histopathology. Results. Six of the 14 control animals and 2 of the 11 FR-treated animals died. The FR treatment group showed lower amylase (P=.037) and lipase (P =.030) levels, lower IL-1β mRNA expression (P =.033), and less pancreatic tissue damage (P =.041) than did the control group, but there was no remarkable change in endocrine function (P =.422). Pao2 during the acute phase in the FR treatment group was maintained (P=.009), but pulmonary tissue was damaged. Results of biochemical and histologic examinations of the liver and kidneys were unremarkable. Conclusions. FR ameliorates ischemia-reperfusion injury of the pancreas and reduces the production of inflammatory cytokines that may contribute to secondary damage to distant organs. (Surgery 2001;129:309-17)

Effect of Lazaroid U-74389G on Pulmonary Ischemia - Reperfusion Injury in Dogs

Lipid peroxidation induced by oxygen free radicals is a contributing factor in ischemia-reperfusion injury. Lazaroid U-74389G (LAZ-G) is a group of new synthetic 21-aminosteroids and inhibits irondependent lipid peroxidation. We investigated the effects of LAZ-G on pulmonary ischemia-reperfusion injury in dogs. Twenty dogs were divided into three groups. In the LAZ-G group (

A spontaneous nitric oxide donor ameliorates small bowel ischemia-reperfusion injury in dogs.

Nitric oxide (NO) appears to play an important role in tissue injury during reperfusion. FK409 is the first spontaneous NO donor that increases plasma guanosine 3',5'-cyclic monophosphate. We investigated the effects of the NO donor FK409 (FK) on ischemia-reperfusion injury in a canine warm ischemia model. Fourteen adult mongrel dogs were divided into two groups: the control group and the FK group, which received FK. The superior mesenteric artery and vein were both clamped for 2 h and then reperfused for 12 h. Arterial and intramucosal pH were well maintained in the FK group in comparison with the control group. Histologically, ischemia-reperfusion injury was significantly more severe in the control group than in the FK group. The serum NO levels were significantly higher in the FK group than in the control group during FK administration. FK409 has protective effects on ischemia-reperfusion injury of the small intestine due to NO release.

Spontaneous nitric oxide (FK409) ameliorates pulmonary ischemia-reperfusion injury in dogs

Spontaneous nitric oxide (FK409) ameliorates pulmonary ischemia-reperfusion injury in dogs

The Effects of Steroids on Pulmonary Ischemia-Reperfusion Injury in Dogs.

We evaluated the effects of steroids on pulmonary ischemia-reperfusion injury in an in situ warm ischemia canine model. Fourteen dogs were divided into two groups : the control group and the steroid-treated group, which received 30mg/kg methylprednisolone 15 minutes before ischemia and 15 minutes before reperfusion. Warm ischemia was induced for 3 hours. The cardiac output (CO), left pulmonary vascular resistance (L-PVR), arterial partial pressure of oxygen (PaO2), and blood levels of interleukin-1β (IL-1β) mRNA were measured. A histologic study was performed and polymorphonuclear neutrophils (PMNs) were counted. The CO and PMNs after 30 minutes of reperfusion were significantly (p<0.05) better in the steroid-treated group than in the control group. The L-PVR after 30 minutes of reperfusion was better in the steroid-treated group than in the control group. The histologic damage was reduced in the steroid-treated group compared to the control group. IL-1β mRNA blood levels were lower in the steroid-treated group than in the control group. Steroids apparently produce a protective effect on ischemia-reperfusion injury of the lung.

The effect of FR167653 on small bowel ischemia-reperfusion injury in dogs

The effect of FR167653 on small bowel ischemia-reperfusion injury in dogs

Role of platelets in myocardial ischemia-reperfusion injury in dogs.

We investigated the involvement of circulating platelets in myocardial ischemia-reperfusion injury in canine autoperfused heart-lung preparations using filters to deplete platelets and/or leukocytes. The left anterior descending (LAD) coronary artery was occluded for 40 min, followed by 40 min reperfusion, in 3 groups: a leukocyte-platelet-depleted (LPD) group, in which both leukocytes and platelets were depleted; a leukocyte-depleted (LD) group, in which leukocytes alone were depleted; and a control group. There were no differences in hemodynamics or arrhythmias among groups before or during coronary occlusion. After reperfusion, the maximum rate of change in left ventricular pressure during systole and diastole was significantly higher in the LPD group than in the control and LD groups. The LPD group also showed gradual recovery of regional myocardial function and a decrease in the frequency of premature ventricular contractions. The LD group showed a slight improvement in cardiac function and arrhythmias compared with the control group. Although there was no significant difference in the pulmonary arterial plasma level of thromboxane B2 at any stage among groups, the control group showed an increase after reperfusion. These results suggest that platelets are important in reperfusion injury and that the depletion of both leukocytes and platelets effectively protects against reperfusion injury.

Trandolapril plus verapamil inhibits the coronary vasospasm induced by hypoxia following ischemia-reperfusion injury in dogs

1. 1. Dogs were exposed to hypoxemia followed by a coronary angiogram at three different times: under control conditions, after ischemia-reperfusion injury, then 30 min later. 2. 2. In the study group, the dogs were treated with trandolapril (0.05 mg/kg) and verapamil (0.1 mg/ kg) just prior to the final hypoxic challenge. 3. 3. Under control conditions, the left anterior descending coronary artery (LAD) dilated in response to hypoxia. Following ischemia-reperfusion injury, however, it constricted significantly in response. 4. 4. In the control group, repeat hypoxia 30 min later resulted in vasoconstriction of the LAD which was comparable to the preceding response. 5. 5. However, in the study group, treatment with trandolapril plus verapamil inhibited the vasoconstriction in response to repeat hypoxia.

Effects of amlodipine on myocardial ischemia-reperfusion injury in dogs

The effects of the dihydropyridine calcium channel blocker amodipine on subendocardial segment shortening (%SS), regional myocardial blood flow, myocardial high-energy phosphate levels and tissue water Content were compared with those of a saline-treated group of barbital-anesthetized dogs subjected to a 45-minute coronary artery occlusion followed by 60 minutes of reperfusion. Saline or amlodipine (200 μg/kg administered intravenously) was given 15 minutes before coronary occlusion. There were no significant differences between groups in ischemic bed size or hemodynamies although dP/dt was higher after amlodipine administration. Subspicardial collateral blood flow was higher in the amlodipine group during coronary occlusion. After occlusion, %SS in the ischemic region was markedly decreased in both series and passive systolic lengthening resulted. Despite similar decreases In %SS during occlusion, the amlodipine-treated dogs showed a marked improvement in myocardial segment function of the ischemic reperfused region throughout 60 minutes of reperfusion compared with same-treated dogs. In addition, amlodipine prevented the rebound increase in phosphoaeathne and attenuated the loss of adenine nucleotides and increase in tissue water in the ischemic reperfused area at 60 minutes of reperfusion. These results suggest that amlodipine has a favorable effect on the functional and metabolic recovery of the ischemic reperfused myocardium and may have potential as a therapeutic agent for the treatment of coronary artery disease. The mechanism of action of amlodipine in this model is unknown but may be partially related to a drug-induced increase in coronary collateral blood flow or a decrease in afterload.