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PubMed2000

Lowering reperfusion pressure reduces the injury after pulmonary ischemia.

BACKGROUND: Controlled reperfusion with a modified solution limits pulmonary injury following ischemia. Our initial studies infused this modified reperfusate at a pressure of 40 to 50 mm Hg to insure distribution. However, perhaps a lower pressure, which is closer to the normal physiologic pressure in the lung, would improve results by decreasing sheer stress. METHODS: Fifteen adult pigs underwent 2 hours of lung ischemia by clamping the left bronchus and pulmonary artery. Five (group 1) then underwent uncontrolled reperfusion by removing the vascular clamps and allowing unmodified blood to reperfuse the lung at a pulmonary artery pressure of 20 to 30 mm Hg. The other 10 pigs underwent controlled reperfusion by mixing blood from the femoral artery with a crystalloid solution, and infusing this modified reperfusate into the ischemic lung through the pulmonary artery for 10 minutes before removing the arterial clamp. In 5 (group 2), the modified solution was infused at a pressure of 40 to 50 mm Hg, and in 5 (group 3) 20 to 30 mm Hg. Lung function was assessed 60 minutes after reperfusion and expressed as percentage of control. RESULTS: Compared to uncontrolled reperfusion (group 1), controlled reperfusion at a pressure of 40 to 50 mm Hg (group 2) significantly improved postreperfusion pulmonary compliance (77% versus 86%; p<0.001 versus group 1), and arterial/alveolar ratio (a/A) ratio (27% versus 52%; p<0.001 versus group 1); as well as decreased pulmonary vascular resistance (PVR) (198% versus 154%; p<0.001 versus group 1), lung water (84.3% versus 83.5%; p<0.001 versus group 1), and myeloperoxidase (0.35 versus 0.23 optical density/min/mg protein). Reducing the pressure of the modified reperfusate to 20 to 30 mm Hg further improved postreperfusion compliance (92%+/-1%; p<0.001 versus groups 1 and 2) and a/A ratio (76%+/-1%; p<0.001 versus groups 1 and 2); and lowered PVR (133%+/-2%; p<0.001 versus groups 1 and 2), lung water (82.7%+/-0.1%; p<0.001 versus groups 1 and 2), and myeloperoxidase (0.16%+/-0.01%; p<0.001 versus groups 1 and 2). CONCLUSIONS: After 2 hours of pulmonary ischemia, a severe lung injury occurs following uncontrolled reperfusion, controlled reperfusion with a modified solution reduces this reperfusion injury, and lowering the pressure of the modified reperfusate to more physiologic levels (20 to 30 mm Hg) further reduces the reperfusion injury improving pulmonary function.

Animals↗

PubMed1991

Superoxide anion release (O2-) after ischemia and reperfusion.

Neutrophils have been implicated as mediators of the reperfusion injury following ischemia. In order to measure neutrophil activation, O2- was determined after 2 hr of ischemia followed by 1 hr of reperfusion (no clinical reperfusion injury) and 3 hr of ischemia followed by 1 hr of reperfusion (significant clinical reperfusion injury). Using New Zealand white rabbits, baseline blood samples were drawn from an ear artery. The right iliac and femoral arteries were exposed and clamped. Just prior to clamp release, blood was obtained from the right iliac vein (ischemia). After 1 hr of reperfusion, blood was again taken from the right iliac vein (reperfusion). Neutrophils were isolated from the blood samples. O2- was determined by the reduction of cytochrome c using a spectrophotometer. In the 2-hr group, results (expressed as mumole O2-/min/2 x 10(6) cells) were: baseline, 0.337 +/- 0.025; ischemia, 0.512 +/- 0.039;* and reperfusion, 0.634 +/- 0.064*. (*P less than .05 as compared to baseline). In the 3-hr group, results were: baseline, 0.391 +/- 0.038; ischemia, 0.413 +/- 0.051; and reperfusion, 0.258 +/- 0.043** (**P less than 0.05 as compared to 2 hr reperfusion). A significant increase in O2- was seen after 2 hr of ischemia followed by 1 hr of reperfusion. However, little O2- increase was seen after 3 hr of ischemia and a significant O2- decrease was seen after 1 hr of reperfusion. We conclude: (1) Neutrophil O2- is stimulated early in ischemia followed by reperfusion; (2) after reperfusion injury occurs (3 hr), neutrophils have been activated and O2- can no longer be stimulated; and (3) O2- in this model may be involved in the clinical reperfusion injury seen.

Animals↗

PubMed1993

Myocardial infarct extension during reperfusion after coronary artery occlusion: pathologic evidence.

OBJECTIVES: The goal of this study was to demonstrate myocardial infarct extension during reperfusion within the same animal. BACKGROUND: Whether myocardial reperfusion can result in the extension of myocardial necrosis remains controversial. The transformation of reversibly injured myocytes into irreversibly damaged cells after reperfusion has been difficult to demonstrate pathologically. METHODS: New Zealand White rabbits (Group I, n = 10) were subjected to 30 min of coronary artery occlusion and 180 min of reperfusion. Horseradish peroxidase, a tracer protein that permeates the sarcolemma of irreversibly injured myocytes, was used to quantitate myocyte necrosis at the beginning of reperfusion. Within the same heart, infarct size was measured after 180 min of reperfusion by triphenyltetrazolium chloride (TTC) staining. In separate experiments to demonstrate the validity of the model, rabbits were subjected to 30 min of coronary occlusion, followed by intravenous infusion of horseradish peroxidase and rapid induction of death (Group II) or 30 min of occlusion, 180 min of reperfusion with horseradish peroxidase administered after 180 min of reperfusion and TTC staining after induced death (Group III). RESULTS: In Group I, infarct size at the onset of reperfusion, delineated by horseradish peroxidase, measured 45.3 +/- 2.8% of the area of risk and was significantly less than TTC-delineated infarct size after 180 min of reperfusion (59.8 +/- 3.3%, p = 0.0002). By electron microscopy, border areas within the ischemic bed demonstrated irreversibly injured horseradish peroxidase-positive myocytes adjacent to irreversibly injured horseradish peroxidase-negative myocytes, suggesting that further cell death occurred during reperfusion. In Group II, infarcts delineated by horseradish peroxidase after 30 min of coronary occlusion were similar in size to infarcts measured by this tracer in Group I. In Group III, infarcts delineated by horseradish peroxidase at 180 min of reperfusion were similar in size to infarcts measured by TTC and similar to TTC-delineated infarcts measured at 180 min of reperfusion in Group I. CONCLUSIONS: These results provide evidence that there is a subset of myocytes in border areas within the ischemic region that are viable at the beginning of reperfusion but subsequently progress to irreversible injury during the reperfusion period.

Animals↗

PubMed2000

Early assessment of skeletal muscle damage after ischaemia-reperfusion injury using Tc-99m-glucarate.

PURPOSE: After acute arterial obstruction of the lower extremity, muscle damage is the critical determinant for clinical outcome. The extent of muscle damage and limb viability are currently assessed by clinical examination, which is inaccurate. Tc-99m-pyrophosphate (PYP) has been applied for imaging ischaemia-reperfusion damage. More recently, a new imaging agent, Tc-99m-glucarate (GLUC), was introduced for delineating early myocardial infarction after ischaemia-reperfusion. The aim of this study was to determine if GLUC could delineate early skeletal muscle damage after ischaemia-reperfusion. Both tracers were used in a novel murine model of hindlimb ischaemia-reperfusion. METHODS: In anaesthetised mice, ischaemia of one hindlimb was maintained for 2, 3 and 4h using a tourniquet, followed by a reperfusion period of 1h. Additionally, reperfusion periods of 3, 24 and 96h were studied after 3h of ischaemia. PYP or GLUC was injected 45min before end of reperfusion. Concentrations of both agents were determined in blood, reperfused and contralateral muscle. Reperfused-to-contralateral muscle ratios were calculated. In separate experiments, muscle biopsies were obtained for histologic examination. RESULTS: Ischaemia and reperfusion damage was demonstrated histologically. Using scintigraphy GLUC depicted reperfusion significantly better than PYP. After 2, 3 and 4h of ischaemia, the reperfused-to-contralateral ratios for GLUC were 10.7+/-0.9, 8.9+/-0.9 and 8.6+/-1.1, as compared to 4.5+/-0.7, 4.9+/-0.4 and 4.5+/-0.4 for PYP (P<0.05 at all points). For longer periods of reperfusion, the ratios for GLUC decreased to similar levels as observed for PYP. CONCLUSION: The present study indicates that GLUC is a specific early marker of myocyte necrosis after ischaemia-reperfusion. GLUC may become an useful agent for clinical, early, non-invasive monitoring of skeletal muscle damage after ischaemia-reperfusion.

Animals↗

PubMed1997

Beneficial effects of 3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase in a rat model of splanchnic artery occlusion and reperfusion.

1. Peroxynitrite, a potent cytotoxic oxidant formed by the reaction of nitric oxide with superoxide anion, and hydroxyl radical, formed in the iron-catalysed Fenton reaction, are important mediators of reperfusion injury. In in vitro studies, DNA single strand breakage, triggered by peroxynitrite or by hydroxyl radical, activates the nuclear enzyme poly (ADP-ribose) synthetase (PARS), with consequent cytotoxic effects. Using 3-aminobenzamide, an inhibitor of PARS, we investigated the role of PARS in the pathogenesis of splanchnic artery occlusion shock. 2. Splanchnic artery occlusion and reperfusion shock (SAO/R) was induced in rats by clamping both the superior mesenteric artery and the coeliac trunk for 45 min, followed by release of the clamp (reperfusion). At 60 min after reperfusion, animals were killed for histological examination and biochemical studies. 3. SAO/R rats developed a significant fall in mean arterial blood pressure, significant increase of tissue myeloperoxidase activity and marked histological injury to the distal ileum. SAO/R was also associated with a significant mortality (0% survival at 2 h after reperfusion). 4. There was a marked increase in the oxidation of dihydrorhodamine 123 to rhodamine (a marker of peroxynitrite-induced oxidative processes) in the plasma of the SAO/R rats, starting early after reperfusion, but not during ischaemia alone. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, a specific 'footprint' of peroxynitrite, in the necrotic ileum in shocked rats, as measured at 60 min after the start of reperfusion. 5. In addition, in ex vivo studies in aortic rings from shocked rats, we found reduced contractions to noradrenaline and reduced responsiveness to a relaxant effect to acetylcholine (vascular hyporeactivity and endothelial dysfunction, respectively). 6. In a separate set of studies, using a 4000 Dalton fluorescent dextran tracer, we investigated the changes in epithelial permeability associated with SAO/R. Ten minutes of reperfusion, after 30 min of splanchnic artery ischaemia, resulted in a marked increase in epithelial permeability. 7. There was a significant increase in PARS activity in the intestinal epithelial cells, as measured 10 min after reperfusion ex vivo. 3-Aminobenzamide, a pharmacological inhibitor of PARS (applied at 10 mg kg(-1), i.v., 5 min before reperfusion, followed by an infusion of 10 mg kg(-1) h(-1)), significantly reduced ischaemia/reperfusion injury in the bowel, as evaluated by histological examination. Also it significantly improved mean arterial blood pressure, improved contractile responsiveness to noradrenaline, enhanced the endothelium-dependent relaxations and reduced the reperfusion-induced increase in epithelial permeability. 8. 3-Aminobenzamide also prevented the infiltration of neutrophils into the reperfused intestine, as evidenced by reduced myeloperoxidase activity. It improved the histological status of the reperfused tissues, reduced the production of peroxynitrite in the late phase of reperfusion and improved survival. 9. In conclusion, our study demonstrates that the PARS inhibitor 3-aminobenzamide exerts multiple protective effects in splanchnic artery occlusion/reperfusion shock. We suggest that peroxynitrite and/or hydroxyl radical, produced during the reperfusion phase, trigger DNA strand breakage, PARS activation and subsequent cellular dysfunction. The vascular endothelium is likely to represent an important cellular site of protection by 3-aminobenzamide in SAO shock.

Animals↗

PubMed2004

Effect of L-arginine on leukocyte adhesion in ischemia-reperfusion injury.

Nitric oxide has been reported to be beneficial in preserving muscle viability following ischemia-reperfusion injury. The purpose of this study was to evaluate the influence of nitric oxide via L-arginine on leukocyte adhesion following ischemia-reperfusion injury. Intravital videomicroscopy of rat gracilis muscle was used to quantify changes in leukocyte adherence. The gracilis muscle was raised on its vascular pedicle in 48 male Wistar rats. The animals were assigned to one of five groups: (1) nonischemic control; (2) ischemia-reperfusion; (3) ischemia-reperfusion and L-arginine; (4) ischemia-reperfusion and Nomega-nitro-L-arginine methyl ester (L-NAME); and (5) ischemia-reperfusion, L-NAME, and L-arginine. All groups that included ischemia-reperfusion were subjected to 4 hours of global ischemia followed by 2 hours of reperfusion. L-Arginine (10 mg/kg) and L-NAME (10 mg/kg) were infused into the contralateral femoral vein beginning 5 minutes before reperfusion, for a total of 30 minutes. The number of adherent leukocytes was counted at baseline and at 5, 15, 30, 60, and 120 minutes after reperfusion (reported as mean change from baseline, +/- SEM). Groups were compared by repeated-measures analysis of variance (five groups, five times). P < or =0.05 was accepted as significant. L-Arginine significantly reduced leukocyte adherence to venular endothelium during reperfusion when compared with the ischemia-reperfusion group (1.39 +/- 0.92 versus 12.78 +/- 1.43 at 2 hours, p < 0.05). Administration of L-NAME with L-arginine showed no significant difference in adherent leukocytes when compared with the ischemia-reperfusion group (10.28 +/- 2.03 at 2 hours). The nitric oxide substrate L-arginine appears to reduce the deleterious neutrophil-endothelial adhesion associated with ischemia-reperfusion injury. L-NAME (nitric oxide synthesis inhibitor) given concomitantly with L-arginine reversed the beneficial effect of L-arginine alone, indicating that L-arginine may be acting via a nitric oxide synthase pathway. These results suggest an important role for nitric oxide in decreasing the neutrophil-endothelial interaction associated with ischemia-reperfusion injury.

Animals↗

PubMed2005

Reperfusion of pulmonary arteriovenous malformations after embolotherapy.

PURPOSE: To describe the mechanisms and risk factors associated with reperfusion of successfully treated pulmonary arteriovenous malformations (PAVMs) after embolotherapy. MATERIALS AND METHODS: Among 112 consecutive patients with PAVMs treated by embolotherapy, 19 patients were identified who had 33 angiographically confirmed reperfused PAVMs. A retrospective analysis of computed tomography (CT) and angiography was performed in patients with documented reperfused PAVMs in which reperfused PAVMs were compared with nonreperfused PAVMs. CT images were examined for persistence of the aneurysm and/or draining vein after initial embolotherapy and correlated with angiography to determine the mechanism of reperfusion. PAVM and embolic agent characteristics (eg, feeding artery size and number; PAVM location; coil size, number, and location) were evaluated for association with reperfusion. The outcomes of repeat embolotherapy for reperfused PAVMs were evaluated. RESULTS: The PAVM aneurysm and/or draining vein persisted on CT after initial embolotherapy in all reperfused PAVMs and resolved in all nonreperfused PAVMs (in patients with nondiffuse PAVMs). Recanalization was the mechanism of reperfusion in 88%. Reperfusion was associated with the use of a single coil (P < .0001), oversized coils (P < .0001), coil placement more than 1 cm from the aneurysm (P < .0001), and increased feeding artery size (P < .001). Repeat embolotherapy for reperfused PAVMs was technically successful in 94% of cases. In the remaining 6% of cases, insufficient feeding artery length prevented safe repeat treatment. After a mean follow-up of 41 months, 42% of reperfused PAVMs in our series have been successfully treated again and occluded. CONCLUSIONS: Recanalization is the most common mechanism of PAVM reperfusion. Increased feeding artery diameter, low number of coils, use of oversized coils, and proximal coil placement within the feeding artery are associated with reperfusion. Distal coil placement facilitates repeat embolization if reperfusion occurs.

Adult↗

PubMed1991

The cardioprotective effect of gamma-glutamylcysteine ethyl ester during coronary reperfusion in canine hearts.

1. The cardioprotective effect of gamma-glutamylcysteine ethyl ester was investigated on ischaemia-reperfusion-induced myocardial damage in anaesthetized dogs. 2. Open chest anaesthetized dogs were divided into four groups: 2 h occlusion of the left anterior descending coronary artery (LAD); 2 h LAD occlusion followed by 1 h reperfusion; 2 h LAD occlusion followed by 1 h reperfusion with administration of gamma-glutamylcysteine ethyl ester (10 mg kg-1 just before reperfusion); 2 h LAD occlusion followed by 1 h reperfusion with administration of GSH (the reduced form of glutathione, 10 mg kg-1 just before reperfusion). 3. After occlusion or reperfusion, heart mitochondria were prepared from the normal area and the occluded or the reperfused area, and mitochondrial function (rate of oxygen consumption in State III, and respiratory control index) was measured polarographically. 4. Mitochondrial GSH and GSSG (the oxidized form of glutathione) concentrations, and activities of glutathione peroxidase and glutathione reductase were measured. 5. Two h of LAD occlusion induced mitochondrial dysfunction with depletion of mitochondrial GSH concentration. One h of reperfusion after 2 h LAD occlusion induced significant mitochondrial dysfunction associated with a marked depletion of mitochondrial GSH concentration. 6. gamma-Glutamylcysteine ethyl ester reduced mitochondrial dysfunction and depletion of mitochondrial GSH concentration after 2 h LAD occlusion and 1 h reperfusion. In contrast, GSH did not prevent depletion of mitochondrial GSH concentration and mitochondrial dysfunction after 2 h LAD occlusion followed by 1 h reperfusion. 7. The activities of glutathione peroxidase and glutathione reductase did not change significantly in each group. 8. One h of reperfusion after 2 h occlusion of LAD induced ventricular arrhythmias. gamma-Glutamylcysteine ethyl ester markedly reduced the development of reperfusion arrhythmias, whilst GSH showed no protective effect.9. Gamma-Glutamylcysteine ethyl ester maintained mitochondrial GSH concentration, prevented reperfusion myocardial damage, and reduced reperfusion arrhythmias.

Animals↗

PubMed2000

Impact of community intervention to reduce patient delay time on use of reperfusion therapy for acute myocardial infarction: rapid early action for coronary treatment (REACT) trial. REACT Study Group.

BACKGROUND: Reperfusion therapy for acute myocardial infarction (AMI) is a time-dependent intervention that can reduce infarct-related morbidity and mortality. Out-of-hospital patient delay from symptom onset until emergency department (ED) presentation may reduce the expected benefit of reperfusion therapy. OBJECTIVE: To determine the impact of a community educational intervention to reduce patient delay time on the use of reperfusion therapy for AMI. METHODS: This was a randomized, controlled community-based trial to enhance patient recognition of AMI symptoms and encourage early ED presentation with resultant increased reperfusion therapy rates for AMI. The study took place in 44 hospitals in 20 pair-matched communities in five U.S. geographic regions. Eligible study subjects were non-institutionalized patients without chest injury (aged > or =30 years) who were admitted to participating hospitals and who received a hospital discharge diagnosis of AMI (ICD 410); n = 4,885. For outcome assessment, patients were excluded if they were without survival data (n = 402), enrolled in thrombolytic trials (n = 61), receiving reperfusion therapy >12 hours after ED arrival (n = 628), or missing symptom onset or reperfusion times (n = 781). The applied intervention was an educational program targeting community organizations and the general public, high-risk patients, and health professionals in target communities. The primary outcome was a change in the proportion of AMI patients receiving early reperfusion therapy (i.e., within one hour of ED arrival or within six hours of symptom onset). Trends in reperfusion therapy rates were determined after adjustment for patient demographics, presenting blood pressure, cardiac history, and insurance status. Four-month baseline was compared with the 18-month intervention period. RESULTS: Of 3,013 selected AMI patients, 40% received reperfusion therapy. Eighteen percent received therapy within one hour of ED arrival (46% of treated patients), and 32% within six hours of symptom onset (80% of treated patients). No significant difference in the trends in reperfusion therapy rates was attributable to the intervention, although increases in early reperfusion therapy rates were noted during the first six months of the intervention. A significant association of early reperfusion therapy use with ambulance use was identified. CONCLUSIONS: Community-wide educational efforts to enhance patient response to AMI symptoms may not translate into sustained changes in reperfusion practices. However, an increased odds for early reperfusion therapy use during the initiation of the intervention and the association of early therapy with ambulance use suggest that reperfusion therapy rates can be enhanced.

Adult↗

PubMed1993

Myocardial hypertrophy in the ischemic zone induced by exercise in rats after coronary reperfusion.

BACKGROUND: Factors influencing left ventricular (LV) remodeling after coronary artery reperfusion, including adaptive changes in the infarcted region and the role of exercise, have not been well defined. The common application of early reperfusion by thrombolysis after acute myocardial infarction lends potential significance to such remodeling, and a rat model with 45 minutes of regional ischemia followed by reperfusion was developed to study these events. We postulated that the effects of reperfusion in altering LV morphology would be further modified by exercise training, including induction of hypertrophic changes in the outer region of the nontransmural infarction. METHODS AND RESULTS: Female Sprague-Dawley rats were subjected either to 15 minutes of left anterior descending coronary artery occlusion followed by reperfusion or to sham operation, and at 5 days after the operation, animals were randomly assigned to sedentary conditions or to 3 weeks of swimming exercise. Animals completing the experiment included a reperfused sedentary group (n = 21), a reperfused exercised group (n = 20), a sham-operated group (n = 10), and a sham-operated group subjected to exercise (sham exercised group, n = 9). In addition, in seven rats, myocardial infarction was produced by permanent coronary occlusion, and the animals remained sedentary (permanent occlusion group). In each group, the morphology of the noninfarcted (septal) and the infarcted (anterolateral) regions of the left ventricle was examined 26 days after surgery from midventricular transverse sections 25 microns thick taken after perfusion fixation of the heart at an aortic pressure of 60 mm Hg and an LV cavity pressure of 10 mm Hg. Compared with the permanent occlusion group, LV cavity area in the sedentary reperfused group was smaller (33.5 versus 53.2 mm2, p < 0.001), the infarcted wall was thicker (1.36 versus 0.53 mm, p < 0.001), and the septal wall also was thicker (1.95 versus 1.62 mm, p < 0.05), whereas compared with the sham-operated group, the LV cavity area was increased, and infarcted wall thickness was reduced (both p < 0.01). Reperfusion resulted in less transmurality of infarction compared with permanent occlusion (38.3% versus 69.5%, p < 0.001), with increased subepicardial area in the infarcted zone after reperfusion (7.5 versus 1.9 mm2, p < 0.001). In the reperfused exercised group, transmurality was further decreased compared with the reperfused sedentary group (31.5% versus 38.3%, p < 0.05), and the viable subepicardial area of the infarct zone increased by 32%. CONCLUSIONS: Important remodeling of global and regional LV morphology was evident at 26 days in sedentary rats after 45 minutes of coronary occlusion with reperfusion compared with rats with permanent coronary occlusion, with reduced infarct transmurality and less LV dilation in the reperfused group. Exercise after reperfusion further affected ventricular remodeling by causing hypertrophy with increased wall thickness of the surviving subepicardium of the infarcted zone.

Animals↗

PubMed1993

Receptor-mediated cardioprotective effects of endogenous adenosine are exerted primarily during reperfusion after coronary occlusion in the rabbit.

BACKGROUND: We hypothesized that: (1) endogenous adenosine released during ischemia/reperfusion reduces infarct size and preserves postischemic myocardial blood flow by receptor-mediated mechanisms and (2) this cardioprotection is exerted predominantly during reperfusion. METHODS AND RESULTS: Sixty-one anesthetized open-chest rabbits subjected to 30 minutes of coronary occlusion and 120 minutes of reperfusion were randomized to six groups: group 1, saline (Vehicle) (n = 10) to allow receptor interaction of endogenous adenosine (Ado) during ischemia/reperfusion; group 2, Ado-receptor blockade during both ischemia and reperfusion with intravenous 8-p-sulfophenyltheophyl-line (10 mg/kg) (SPTIR, n = 10); group 3, Ado-receptor blockade in multiple doses during both ischemia and reperfusion (MSPTIR, n = 11); group 4, blockade during reperfusion (SPTR, n = 10); group 5, blockade during reperfusion with PD115,199 (6 mg/kg) (PDR, n = 10); and group 6, blockade after 30 minutes of reperfusion (SPT30R, n = 10) to allow adenosine receptor interaction during early reperfusion. Transmural myocardial blood flow in the area at risk (Ar) (15-microns radiolabeled microspheres) was reduced by 96.7% in all groups, from 137.9 +/- 15.5 to 4.5 +/- 1.4 mL.min-1 x 100 g-1 (P < .001). MSPTIR, SPTIR, and SPTR significantly attenuated reactive hyperemia at 15 minutes of reperfusion (144 +/- 18, 141 +/- 22, and 144 +/- 20 mL.min-1 x 100 g-1, respectively) compared with Vehicle (257 +/- 40 mL.min-1 x 100 g-1, P < .05). This attenuation was more pronounced in the necrotic zone than in the nonnecrotic zone. Reactive hyperemia at 15 minutes of reperfusion in SPT30R group was comparable to the Vehicle group. At 120 minutes of reperfusion, blood flow in Ar was significantly less in MSPTIR (77 +/- 10), SPTIR (82 +/- 9), and SPTR (80 +/- 11) compared with Vehicle (140 +/- 12) and SPT30R (105 +/- 24 mL.min-1 x 100 g-1). Infarct size (by triphenyltetrazolium chloride), expressed as a percent of Ar, was largest in the multiple-dose group with blockade during both ischemia and reperfusion (MSPTIR, 51.9 +/- 2.3%) and was significantly increased also in single-dose SPTIR (39.1 +/- 2.2%) compared with 25.7 +/- 1.7% in the Vehicle group (P < .05). Ado-receptor blockade only during reperfusion was associated with 14% smaller infarct size in the SPTR group than the MSPTIR group (P < .05). In contrast, Ado-receptor blockade after 30 minutes of reperfusion (SPT30R) did not increase infarct size (27.9 +/- 2.2%), which was comparable to infarct size in the Vehicle group. CONCLUSIONS: We conclude that: (1) endogenous adenosine released from the myocardium during ischemia/reperfusion reduces infarct size by receptor-mediated mechanisms and (2) Ado-mediated cardioprotection is most pronounced during the early phase of reperfusion.

Adenosine↗

PubMed2005

[Beneficial effects of Tong-xin-luo (herb) on myocardial no-reflow after acute myocardial infarction and reperfusion: experiment of mini-swine model].

OBJECTIVE: To evaluate the beneficial effects of Tong-xin-luo on myocardial no-reflow after acute myocardial infarction (AMI) and reperfusion. METHODS: Forty mini-swine were randomized into 5 equal groups: control group, low-dose group (pretreated with Tong-xin-luo 0.05 g.kg(-1).d(-1) for 3 days), medium-dose group (pretreated with Tong-xin-luo 0.2 g .kg(-1).d(-1) for 3 days), high-dose group (pretreated with Tong-xin-luo 0.5 g.kg(-1).d(-1) for 3 days), and sham-operation group. The swine in the former four groups were subjected to 3 hours of coronary occlusion followed by 60 minutes of reperfusion. Left ventricle systolic pressure (LVSP), left ventricle end diastolic pressure (LVEDP), rate of maximum pressure change in left ventricle (+/- dp/dt(max)), cardiac output (CO), and heart rate (HR) were measured 5 min before AMI in all groups and 180 min after AMI and 60 min after reperfusion in the groups 1-4. Coronary blood volume (CBV) was recorded 5 min before AMI in all groups and immediately and 60 min after reperfusion in the group 1-4. Myocardial contrast echography (MCE) was used before AMI, 3 h after AMI, and 60 min after reperfusion in the group 1-4 so as to calculate the left ventricle wall area (LVWA), ligation area (LS), and %LA. Sixty minutes after reperfusion thioflavin-S was injected into the left ventricle to dye the reperfusion area, then the descending anterior branch was re-ligated at the original site and Evan's blue was injected into the left ventricle to dye the area outside the reperfusion area blue. The heart was taken out immediately to undergo pathological examination and calculation of LVWA, LS, area of no-reflow (SNR), LA, ANR. necrosis area (NS), and NA. RESULTS: (1) In the control group, systolic and diastolic blood pressures (SBP and DBP), LVSP, +/- dp/dt(max), and CO significantly decreased (P < 0.05 or P < 0.01), while LVEDP significantly increased (P < 0.01) 3 hour after AMI, and then LVSP was significantly recovered while +/- dp/dt(max) further significantly decreased (both P < 0.05) 60 minutes after reperfusion. In the 3 Tongxinluo groups, the changes of LVSP, +/- dp/dt(max), CO and LVEDP were the same as those in the control group 3 hours after AMI, and 60 minutes after reperfusion, +/- dp/dt(max), CO and LVEDP were recovered significantly in the high-dose group to degrees better than those in the control group (all P < 0.05). (2) In the control group, the LS values measured by MCE in vivo and by pathological evaluation were similar (P > 0.05), and the SNR was 78.5% by MCE in vivo and was 82.3% by pathological evaluation with the final NS reaching 98.5% of LS. There was no significant difference in LS by both MCE and pathological evaluation between the Tongxinluo groups and control group, though the values of SNR by both methods in the medium and high-dose groups were 41.1% and 42.4% and 24.1% and 25.0% respectively, all significantly lower than those in the control group and low-dose group (P < 0.05 or P < 0.01) with the values in the high-dose group being significantly lower than those in the median-dose group (P < 0.05 and P < 0.01). The final NS of pathological evaluation was also significantly decreased to 90.2%and 81.2% of LS (P < 0.05). In the control group, CBV was significantly decreased to 45.8% and 50.6% of the baseline value immediately at the beginning of reperfusion and 60 minutes after reperfusion (both P < 0.01). In the high-dose group, CBV was also significantly decreased to 76% and 73.5% of the baseline value immediately at the beginning of reperfusion and 60 minutes after reperfusion (both P < 0.05), however, both significantly higher than those in the control group (both P < 0.01). CONCLUSION: Tongxinluo is effective in preventing myocardial no-reflow, improving left ventricular function and reducing infarct area during AMI and reperfusion.

Animals↗

PubMed1975

Coronary hemodynamics during reperfusion following acute coronary ligation in dogs.

The coronary hemodynamic effects of re-establishing blood flow to ischemic myocardium and the regional distribution of myocardial flow during reperfusion were studied in anesthetized open-chest dogs. A large portion of the left ventricular wall was rendered ischemic by occlusion of the left anterior descending coronary artery for 2 hours. During reperfusion of the LAD, coronary resistance in the reperfused vasculature increased progressively for the first 3 hours, while resistance in the intact LC vasculature was unchanged. Minimal resistances in the reperfused vascular bed, calculated from mean aortic pressure and peak coronary reactive hyperemic blood flow following a 90 sec. LAD occlusion, were elevated significantly during reperfusion. The increased minimal resistance values, which reflect the passive physical component of resistance, indicate structural changes in the reperfused vascular bed which were evident shortly after the initiation of reperfusion and persisted throughout the experimental period. Coronary resistances (RH) in the reperfused (LAD) and intact (LC) vasculatures during the reactive hyperemia following 10 sec. coronary occlusions were evaluated. During reperfusion, RH in the reperfused vasculature increased progressively while RH in the intact bed was unchanged. The marked increase in RH in the LAD indicates that the reactive hyperemic flow response to a consistent period of coronary occlusion progressively diminished, and reflects a gradual reduction in the vasodilatory potential of the reperfused coronary circulation. The regional distribution of myocardial blood flow following 5 minutes, 2 hours, and 4 hours of reperfusion was measured with multiple injections of radioactive microspheres. These measurements demonstrated a progressive reduction of blood flow to the reperfused myocardium with no significant change in flow to the control myocardium. In contrast to the uniform transmural distribution of flow in the normal myocardium, the reperfused region showed a distinctly nonuniform distribution of flow after 2 hours and 4 hours of reperfusion, with more severe reduction of flow to the endocardial layer. These studies would suggest that rechannelling blood flow distal to an acute coronary occlusion in human subjects might not in itself be capable of reversing the myocardial injury. It is hoped that additional therapeutic measures might be applied to salvage the injured myocardium.

Animals↗

PubMed1995

Preconditioning of perfused rat heart inhibits reperfusion-induced release of inositol(1,4,5)trisphosphate.

Preconditioning the heart by brief episodes of ischemia and reperfusion can be cardioprotective to injury from subsequent sustained ischemia and reperfusion. Such protective effects include the reduction of reperfusion-induced arrhythmias. We have previously reported a rapid rise in the second messenger inositol(1,4,5) trisphosphate with post-ischemic reperfusion, which has been implicated in the generation of reperfusion-induced arrhythmia. Given the possible importance of inositol(1,4,5)trisphosphate, studies were performed in isolated perfused rat hearts to determine if preconditioning could reduce the reperfusion-induced rise in inositol(1,4,5) trisphosphate. [3H]Inositol labeled hearts underwent 20 min global ischemia with or without 2 min reperfusion. This was preceded by preconditioning of two or three cycles of 2 or 5 min ischemia separated by 5 or 10 min reperfusion, or by time matched control perfusions. Two min reperfusion following 20 min ischemia in time matched controls caused an increase of [3H]inositol(1,4,5)trisphosphate from 20 +/- 3 cpm/mg protein to 52 +/- 5 cpm/mg protein (mean +/- S.E.M. n = 4, P < 0.01). Preconditioning of three cycles of 5 min ischemia and 5 min reperfusion inhibited the 2 min reperfusion-induced rise in [3H]inositol(1,4,5)trisphosphate (26 +/- 4 cpm/mg protein. P < 0.01 relative to non-preconditioned hearts), however protocols that involved either fewer ischemic cycles or shorter ischemic periods were ineffective. Preconditioning did not affect myocardial ATP levels or norepinephrine release with sustained ischemia and reperfusion. Inhibition of the reperfusion-induced rise in inositol(1,4,5) trisphosphate may provide an explanation for the inhibitory effects of preconditioning on reperfusion-induced arrhythmias.

Adenosine Triphosphate↗

PubMed1996

Transient reperfusion with acidic solution affects postischemic functional recovery: studies in the isolated working rat heart.

This isolated working rat heart study was designed to investigate the effect of duration of reperfusion and degree of acidity of the reperfusate on myocardial protection. The experimental time course was as follows: 20 minutes of perfusion with the heart working, 3 minutes of infusion with the St. Thomas' Hospital cardioplegic solution followed by global ischemia for 33 minutes at 37 degrees C, and 20 minutes of Langendorff reperfusion followed by 20 minutes of working perfusion. During the initial 3 minutes of Langendorff reperfusion, the pH of the reperfusate was changed to 5.6, 6.8, and 7.5 by addition of sodium hydroxide into Krebs-Henseleit nonbicarbonate HEPES buffer. A respiratory acidic reperfusate was used for the initial 0.5, 1, 2, 3, 5, and 15 minutes during reperfusion. The results were as follows: (1) Reperfusion with a mildly acidic solution (i.e., pH 6.8) yielded better recovery than reperfusion with solutions having pH levels of 5.8 or 7.5. (2) Reperfusion for less than 3 minutes with a reperfusate having a pH level of 6.8 provided better recovery, although reperfusion for longer than 3 minutes exacerbated reperfusion injury. In conclusion, the effects of reperfusion with acidic solution were influenced by degree and duration with biphasic response characteristics.

Analysis of Variance↗

PubMed1994

Brief perfusion with diluted whole blood after global myocardial ischaemia increases reperfusion injury.

OBJECTIVES: In vivo studies indicate that blood components, especially leucocytes, contribute to reperfusion injury after myocardial ischaemia. This study was designed to: (1) develop a small animal heart model of ischaemia-reperfusion that demonstrates the contribution of blood to reperfusion injury; (2) determine when the presence of blood in the heart--that is, during ischaemia or during early reperfusion--caused greater dysfunction; and (3) attempt to limit the blood contribution to reperfusion injury by leucocyte depletion. METHODS: Adult rat hearts were perfused in situ with a Krebs-albumin red cell solution (K2RBC), then isolated. Cardiac pump function was assessed with an intraventricular balloon as left ventricular developed pressure and contractility (dP/dt). Group I served as a non-ischaemic control group. Group II was subjected to global, no flow ischaemia for 30 min followed by 45 min reperfusion. In group III, diluted whole blood replaced the K2RBC for five min immediately before ischaemia. In group IV, diluted whole blood was perfused during the first five min reperfusion. In group V, the hearts were reperfused with leucocyte poor diluted whole blood. RESULTS: Pre-ischaemic pump function values were similar to other blood perfused, isolated heart models. Group I showed no increase in coronary resistance or decrease in pump function with time or in response to diluted whole blood. After 35 min reperfusion, the recovery (% control) of dP/dt in group II was 56(12), in group III it was 39(15) and in group IV it was only 19(6) (p < 0.05). Large increases in coronary vascular resistance, oedema, and contracture during reperfusion were also seen in group IV. When leucocytes were depleted from the diluted whole blood (group V), the recoveries were similar to reperfusion without diluted whole blood (group II). CONCLUSIONS: Thirty min of global, normothermic ischaemia caused significant cardiac dysfunction early during reperfusion. Perfusion with unstimulated blood for a limited period further impaired the recovery of function and enhanced myocardial oedema. Dysfunction was particularly evident when diluted whole blood was perfused during the first minutes of reperfusion. The leucocyte depletion studies suggest that leucocytes are necessary, but may not be sufficient, to demonstrate the blood contribution to reperfusion injury.

Animals↗

PubMed1995

Pharmacological evidence for the persistent activation of ATP-sensitive K+ channels in early phase of reperfusion and its protective role against myocardial stunning.

BACKGROUND: The activation of cardiac ATP-sensitive potassium channels is reported to protect myocardium during ischemia. However, the behavior and role of this channel during reperfusion remain uncertain. METHODS AND RESULTS: Guinea pig right ventricular walls were studied by use of microelectrodes and a force transducer. Each preparation was perfused via the coronary artery at a constant flow rate and was stimulated at 3 Hz. In the first protocol, the preparation was subjected to 10 minutes of no-flow ischemia, which was followed by 60 minutes of reperfusion. Introduction of ischemia shortened the action potential duration (APD) to 58.7 +/- 3.1% of the preischemic values, in association with a decrease in the resting membrane potential (by 12 +/- 0.8 mV) and action potential amplitude (by 34.6 +/- 1.8 mV). On reperfusion, although the APD was restored, it remained shortened for up to approximately 30 minutes of reperfusion. In the presence of glibenclamide (10 mumol/L), the shortening of the APD during ischemia was significantly attenuated and the restoration of APD after reperfusion was significantly facilitated. When glibenclamide was applied from the onset of reperfusion, the persistent APD shortening was significantly suppressed. The developed tension decreased during ischemia and recovered after 60 minutes of reperfusion (up to 92.0 +/- 6.4% of preischemic values) in the untreated preparations. The application of glibenclamide that was started before ischemia or from the onset of reperfusion significantly suppressed the recovery of contractility (P < .05 versus untreated preparations). In the second series of experiments, 20 minutes of no-flow ischemia and 60 minutes of reperfusion were applied. This protocol produced a sustained contractile dysfunction after reperfusion (to 34.0 +/- 3.2% of preischemic values). In the presence of cromakalim (2 mumol/L), the APD shortening was enhanced during both ischemia and the early reperfusion period. Cromakalim significantly improved the contractile recovery (to 79.3 +/- 4.1% of preischemic values, P < .05 versus untreated preparations). The application of cromakalim that was started from the onset of reperfusion also improved the contractile recovery during this phase and this effect was associated with enhanced APD shortening. However, the cromakalim-treated preparations demonstrated a higher incidence of ventricular fibrillation during reperfusion. CONCLUSIONS: Cardiac ATP-sensitive potassium channels are activated by ischemia, and a fraction of these channels remains activated during the early reperfusion phase. The resulting shortening of the APD prevents the heart from developing myocardial stunning.

Action Potentials↗

PubMed1990

Microvasculature sparing with controlled reperfusion of ischemic myocardium.

Reperfusion of ischemic myocardium may result in further ultrastructural damage to cardiac fibers, a phenomenon known as reperfusion injury. We have recently shown that controlled reperfusion, with maintenance of reperfusion flow rates near preischemia levels, prevents much of this reperfusion damage. This observation suggests that mechanical damage to the myocardial microvasculature is important in the pathogenesis of reperfusion injury. In this study, we have used electron microscopy to examine the microcirculation of ischemic, reperfused pig myocardium under conditions of uncontrolled and controlled reperfusion. Animals receiving uncontrolled reperfusion (reperfusion flow 3-4 times preischemia levels) showed ultrastructural damage to myocardial capillaries after 1 hour of ischemia and 2 hours of reperfusion. This damage was manifested as depletion of endothelial cell pinocytotic vesicles, plugging of capillaries by erythrocytes, leukocytes, and fibrin-containing microthrombi, and perivascular microhemorrhages. None of these changes were found in animals receiving controlled coronary artery reperfusion. We conclude that mechanical damage to the myocardial microvasculature is important in the pathogenesis of reperfusion injury and that such damage is obviated under conditions of controlled coronary artery flow during reperfusion.

Animals↗