Role of nitric oxide in regulation of coronary blood flow during myocardial ischemia in dogs

Objectives. This study was undertaken to examine whether nitric oxide released in ischemic myocardium decreases the coronary vascular resistance and attenuates the severity of contractile and metabolic dysfunction.Background. Endothelium-derived relaxing factor, recently identified as nitric oxide, is a potent relaxant of coronary smooth muscle.Methods. The left anrterior descending coronary artery was perfused through an extracorporeal bypass tube placed in the carotid artery in 56 open chest dogs. After hemodynamic stabilization, we occluded this bypass tube to decrease coronary blood flow to one third of the control flow. Thereafter, we maintained a constant coronary perfusion pressure(40.9 ± 3.1mm Hg).Results. Under ischemic conditions, the coronary arteriovenous differences in nitrate and nitrite (end products of nitric oxide) increased (from 3.5 ± 0.4 [mean ± SEM] to 12.9 ± 2.1 μmol/liter, p < 0.01). ⁰-Monomethyl -arginine (3 μg/kg body weight per min, intracoronary) decreased the coronary arteriovenous differences in nitrate and nitrite (5.0 ± 0.9 μmol/liter, p < 0.05) and coronary blood flow (from 29.8 ± 0.5 to 18.1 ± 1.1 ml/100 g per min, p < 0.001). Fractional shortening (from 3.7 ± 1.0 to −1.3 ± 0.7%, p < 0.001) and lactate extraction ration (from −44.0 ± 4.1 to −59.2 ± 4.9%, p < 0.005) of the perfused area also decreased. These values were restored by the concomitant administration of -arginine. Blood flow to the endomyocardium was decreased relative to the epimyocardium. A reduction in coronary blood flow and worsening of myocardial contractile and metabolic functions due to the administration of ^G-monomethyl -arginine during ischemia were observed in denervated hearts. A reduction in coronary blood flow in ischemic myocardium was observed with the administration of ^W-nitro- -arginene methyl ester as well, although neither ^W-nitro- -arginine methyl ester nor ^G-monomethyl -arginine changed coronary blood flow and myocardial contractile and metabolic functions in the nonischemic myocardium. The cyclic guanosine monophosphate content of epicardial coronary artery increased due to myocardial ischemia; this increased was attenuated with ^G-monomethyl -arginine treatment.Conclusions. We conclude that endogenous nitric oxide predominantly decreases the coronary vascular resistance of ischemic endomyocardium, thereby improving myocardial contractility and metabolic function.     

Bacteria in Crohn's disease: mechanisms of inflammation and therapeutic implications

Microbial agents are implicated in each of the most prevalent etiologic hypotheses of Crohn's disease. Although chronic infection with a specific, persistent pathogen cannot be excluded, it is more likely that Crohn's disease is caused by an overly aggressive immune response to normal commensal enteric bacteria. The complex, predominantly anaerobic microbiota in the distal ileum and colon provide a constant source of antigens and adjuvants that stimulate chronic immune-mediated inflammation in genetically susceptible hosts. Host genetic susceptibility in the form of defective mucosal barrier function, bacterial killing or processing can lead to enhanced exposure to luminal bacteria and their immunologically active components, whereas defective immunoregulation can lead to lack of appropriate immunosuppression. Either process can lead to overly aggressive T-cell responses to normal bacteria that causes tissue damage. Transient infection with pathogenic organisms could serve as environmental triggers to initiate inflammatory responses that are perpetuated in susceptible hosts by commensal microbial antigens. In addition, commensal bacteria such as Escherichia coli recovered from the ileum of patients with recurrent Crohn's disease after resection can contain virulence factors that mediate epithelial attachment, invasion, and resistance to killing. Finally, Western diet, antibiotic use, hygiene, and public health practices may have altered the balance of beneficial versus aggressive microbial species. Crohn's disease patients exhibit enhanced humoral and T-cell responses to common commensal bacterial and fungal antigens. These observations may help identify clinically relevant patient subsets and suggest novel therapeutic approaches to restore a beneficial balance of enteric microbiota, enhanced microbial killing, and inhibit aggressive T-cell responses to microbial antigens.     

Endothelial and myocardial injury during ischemia and reperfusion: pathogenesis and therapeutic implications

Early reperfusion remains the most effective way of limiting myocardial necrosis and improving ventricular function in experimental models and human patients. However, the introduction of oxygen and cellular elements, especially the neutrophil, into the ischemic zone may initiate a deleterious cascade of events that limits myocardial salvage after reperfusion. Although the pathogenesis of reperfusion injury remains controversial, recent studies have suggested that the endothelium may play a critical role. Endothelial cells maintain flow in the microcirculation by secreting a number of vasodilatory compounds and substances that prevent plugging of capillaries by inhibiting neutrophil adherence and platelet aggregation. Reperfusion of ischemic myocardium accelerates structural and functional changes in endothelial cells, resulting in a progressive decrease in microcirculatory flow ("no reflow" phenomenon). Numerous studies suggest that activated neutrophils mediate vascular damage by releasing reactive oxygen species and potent proteolytic enzymes. The administration of therapeutic agents that limit endothelial disruption and neutrophil plugging has shown promising results in limiting myocardial reperfusion injury in experimental models.     

Role of adenosine in coronary blood flow regulation after reductions in perfusion pressure

We employed intracoronary infusion of adenosine deaminase to test the hypothesis that endogenous adenosine contributes to regulation of coronary blood flow following acute reductions in coronary artery pressure. In 16 closed-chest anesthetized dogs, we perfused the left circumflex coronary artery from a pressurized arterial reservoir and measured coronary blood flow following changes in perfusion pressure before and 10 minutes after the start of intracoronary adenosine deaminase, 5 U/min per kg body weight. Parallel studies showed that this dose of enzyme resulted in cardiac lymph adenosine deaminase concentrations of 3.2 +/- 0.4 U/ml. Adenosine deaminase abolished the vasodilator response to intracoronary adenosine, 4 and 8 micrograms, but had no effect on the vasodilator response to intracoronary papaverine, 200 and 300 micrograms, demonstrating enzyme efficacy and specificity. Additional experiments demonstrated that adenosine deaminase reversibly attenuated myocardial reactive hyperemia following 5- and 10-second coronary occlusions by 30% (P less than 0.05), evidence that the infused enzyme effectively degraded endogenous adenosine. However, adenosine deaminase did not alter the time course for coronary autoregulation or the steady state autoregulatory flow response over the pressure range between 125 and 75 mm Hg. Further, adenosine deaminase did not alter steady state coronary flow when perfusion pressure was reduced below the range for effective autoregulation (60-40 mm Hg). Such results show that adenosine is not essential for either coronary autoregulation or for the maintenance of coronary vasodilation when autoregulatory vasodilator reserve is expended.     

Depression in coronary artery disease: novel pathophysiologic mechanisms and therapeutic implications

Depression is a common comorbid condition in patients with coronary artery disease and a well-documented risk factor for recurrent cardiac events and mortality. The exact mechanisms underlying the interplay between depression and ischemic heart disease remain poorly understood and the same is true for the most effective depression treatment for cardiac patients. This review summarizes current knowledge regarding the prognostic role of depression in patients with coronary artery disease, the pathophysiologic pathways involved, and the effects of antidepressant therapy on cardiovascular disease outcomes. With recent evidence suggesting that selective serotonin reuptake inhibitors may improve survival after myocardial infarction in patients with depression, diagnosis and treatment of this co-morbidity may be essential for the clinical management of coronary artery disease.     

Nutrient myocardial blood flow in experimental myocardial ischemia. Effects of intraaortic balloon counterpulsation and coronary reperfusion.

This experimental study was designed to evaluate the effect of intraaortic balloon pumping (IABP) upon nutrient myocardial blood flow (NMBF) following acute myocardial ischemia in dogs, but also to determine whether IABP improves NMBF following revascularization. Localized myocardial ischemia was produced by ligation of one or two small branches of the circumflex coronary artery combined with a three hour snare occlusion of the left anterior descending coronary artery distal to the first septal branch. NMBF was measured by NaI131 washout at three points corresponding to the peripheral, intermediate, and central zones of the infarct. Occlusion of the coronary arteries reduced NMBF. Release of occlusion after three hours, or the equivalent of coronary artery revascularization, increased NMBF but did not restore it to control levels. The increase in flow was more marked in the peripheral zones of ischemia. IABP increased NMBF significantly both during and after release of occlusion. The effect was sustained after cessation of IABP only when the latter was maintained during the period of reperfusion. The results indicate that NMBF, defined by washout of a locally injected tracer, was improved by both IABP and reperfusion. The beneficial effect was maximal when the two techniques were combined.     

Coronary vasospasm and the regulation of coronary blood flow

Under physiologic conditions, epicardial arteries contribute minimally to coronary vascular resistance. However, in the presence of endothelial dysfunction, stimuli that normally produce vasodilation may instead cause constriction. Examples include neural release of acetylcholine or norepinephrine, platelet activation and production of serotonin and thrombin, and release of local factors such as bradykinin. This shift from a primary endothelial-mediated vasodilator influence to one of endothelial dysfunction and unchecked vasoconstriction is precisely the milieu in which coronary vasospasm is observed. This condition, which typically occurs during periods of relatively sedentary activity, is associated with focal and transient obstruction of an epicardial arterial segment resulting in characteristic echocardiographic changes and symptoms of myocardial ischemia. This review highlights the current understanding of mechanisms regulating the coronary circulation during health and examines the pathophysiologic changes that occur with coronary spasm. Genetic and other predisposing conditions are addressed, as well as novel therapies based on recent mechanistic insights of the coronary contractile dysfunction associated with coronary spasm.     

Role of interleukin 18 in acute lung inflammation induced by gut ischemia reperfusion

AIM: To study the changes of endogenous interleukin 18 (IL-18) levels and evaluate the role of IL-18 on lung injury following gut ischemia/reperfusion. METHODS: A superior mesenteric artery occlusion model was selected for this research. The mice were randomly divided into four groups: Sham operation (sham), ischemia (0.5 h) followed by different times of reperfusion (I/R), and I/R pretreated with exogenous IL-18 (I/R+IL-18) or IL-18 neutralizing antibody (I/R+IL-18Ab) 15 min before ischemia. Serum IL-18 levels were detected by Western blot and ELISA, and the levels of IL-18 in lung tissue were evaluated by immunohistochemical staining. For the study of pulmonary inflammation, the lung myeloperoxidase (MPO) contents and morphological changes were evaluated. RESULTS: Gut ischemia/reperfusion induced rapid increase of serum IL-18 levels, peaked at 1 h after reperfusion and then declined. The levels of IL-18 in lung tissue were gradually enhanced as the progress of reperfusion. Compared with I/R group, exogenous administration of IL-18 (I/R+IL-18) further remarkably enhanced the pulmonary MPO activity and inflammatory cell infiltration, and in I/R+IL-18Ab group, the content of MPO were significantly reduced and lung inflammation was also decreased. CONCLUSION: Gut ischemia/reperfusion induces the increase of IL-18 expression, which may make IL-18 act as an important proinflammatory cytokine and contribute to gut ischemia/reperfusion-induced lung inflammation.     

Role of leukocytes in coronary vascular endothelial injury due to ischemia and reperfusion

A possible cause of the coronary endothelial injury that occurs with ischemia and reperfusion is the local accumulation of leukocytes during these events. To investigate the role of leukocytes in coronary endothelial injury, we tested the effect of leukocyte removal by filtering on coronary endothelial function in a canine model of regional myocardial ischemia and reperfusion. Blood was supplied to the left anterior descending and circumflex arteries of anesthetized dogs via an extracorporeal circulation. A 60-minute left anterior descending occlusion was followed by 120 minutes of reperfusion either with (n = 6) or without (n = 6) leukocyte filters in the extracorporeal circuit. Regional myocardial blood flow was measured with radiolabeled microspheres. Radiolabeled autologous transferrin (113mIn) and erythrocytes (99mTc) were given intravenously during reperfusion for assessment of microvascular permeability. Left anterior descending and circumflex coronary artery rings were assessed in vitro for endothelium-dependent dilation to acetylcholine, ADP, and thrombin. In unfiltered dogs, ischemia and reperfusion increased the protein leak index of ischemic myocardium 2.3-fold compared with that of nonischemic myocardium (2.3 +/- 0.5 to 5.2 +/- 1.6, p less than 0.05). In filtered dogs, there was no difference in the protein leak index of nonischemic versus ischemic myocardium (1.5 +/- 0.4 versus 1.9 +/- 0.5, p = NS). There was impaired left anterior descending coronary artery relaxation (versus circumflex) in response to endothelium-dependent vasodilators in vitro. However, relaxation was not consistently improved by leukocyte filtering. We conclude that leukocytes are responsible for the endothelial injury secondary to ischemia and reperfusion in the coronary microvasculature but have little or no effect on the endothelial injury in epicardial coronary arteries.     

Streptokinase improves reperfusion blood flow after coronary artery occlusion

Streptokinase is an effective thrombolytic agent which, with early restoration of coronary blood flow, has the potential for limiting infarct size. Distinct from thrombolysis, we studied the effects of streptokinase on reperfusion coronary blood flow and infarct size. Open-chest anesthetized canines underwent a 90 minute snare occlusion of the left circumflex coronary artery followed by release and reperfusion through a critical stenosis for 6 hours. The animals were assigned randomly to two groups. Intracoronary streptokinase [group 1 (n = 8): 6000 IU/kg in 3 ml of saline] or saline [group 2 (n = 8): 3 ml of saline] was infused at 0.05 ml/min for 60 minutes beginning 30 minutes before reperfusion. Coronary blood flow was stable in group 1 during reperfusion, while in group 2 it fell during 6 hours of reperfusion (30 +/- 4 ml/min to 18 +/- 2 ml/min, P = 0.05). The ST-segment elevation on the limb lead II electrocardiogram 15 minutes after coronary artery occlusion was similar in both groups (group 1: 3.9 +/- 0.6 mV, group 2: 2.3 +/- 0.5 mV), suggesting the extent of myocardial ischemia was also similar in both groups. The infarct sizes were similar when expressed both as a percent of the total left ventricular mass [(IZ/LV) group 1: 17 +/- 2.5%, group 2: 17.5 +/- 2.5%] or as a percent of the area at risk of infarction [(IZ/AR) group 1: 39 +/- 6%, group 2: 39 +/- 5%]. In both groups, the mass of left ventricle dependent on the blood flow distribution of the left circumflex coronary artery was similar when compared to total left ventricular mass [(AR/LV) group 1: 41 +/- 3%, group 2: 44 +/- 4%]. These results demonstrate that streptokinase maintains reperfusion coronary blood flow through a critical stenosis at a rate similar to baseline levels. Despite the fact that coronary blood flow remained stable with streptokinase during reperfusion, infarct size was not limited after 90 minutes of fixed coronary artery occlusion in this canine model of myocardial injury.     

Late coronary artery reperfusion: benefits and mechanisms

In patients with acute myocardial infarction (AMI), coronary artery reperfusion beyond 4 to 6 h after the onset of symptoms is believed to have little or no effect on infarct size. However, benefits have been demonstrated even when reperfusion is performed late and without significant myocardial salvage. Late reperfusion prevents infarct expansion and left ventricular remodelling. The mechanism is multifactorial and partially related to salvage of small islets of still viable myocytes within the scar. Other benefits of late reperfusion are electrical stability and prevention of arrhythmias. The survival benefits of reperfusion are strongly dependent on the time after the onset of symptoms until treatment (better outcomes are obtained with earlier reperfusion). Based on the demonstration of a significant reduction in mortality, the current practice is to perform reperfusion up to 12 h after the onset of symptoms. The survival benefits of reperfusion performed 13 to 24 h after the onset of AMI are less certain; however, large AMIs, particularly anterior infarcts, have the maximum risk of remodelling. Thus, benefits of reperfusion on left ventricular remodelling, arrhythmogenicity and prevention of congestive heart failure justify reperfusion in this group of patients up to 24 h after the onset of symptoms.     

Possible role of prostaglandins in the regulation of coronary blood flow

Summary Prostaglandins may represent one group of local chemical factors that control coronary perfusion and adapt it to the metabolic demands of the heart. Present study summarizes the current knowledge in this field with particular reference to prostacyclin (PGI₂). The major biosynthetic pathways and their modification by drugs are briefly outlined. The sources and fates of cardiac prostaglandins are described and possible mechanisms of action discussed in both physiological and pathophysiological (myocardial ischemia) situations. Attention is focussed on the interplay between catecholamines, adenosine and PGI₂. A model is presented, based on the hypothesis that adenosine from myocardial metabolism and PGI₂ from vascular sites are acting in concert to antagonize sympathetic metabolic and vasoconstrictory influences and to maintain an adequate blood supply to the heart.

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Zusammenfassung Prostaglandine können als eine Gruppe chemischer Substanzen angesehen werden, die lokal entstehen und die koronare Perfusion an die Stoffwechselerfordernisse des Herzens anpassen. Vorliegende Arbeit gibt eine Zusammenfassung des heutigen Wissensstandes auf diesem Gebiet unter besonderer Berücksichtigung von Prostacyclin (PGI₂). Neben Biosynthese und Metabolismus sowie ihrer Beeinflussung durch Pharmaka werden kardiale und koronare Wirkungen von PGI₂ beschrieben und mögliche Wirkungsmechanismen der Substanz unter physiologischen und pathophysiologischen (myokardiale Ischämie) Bedingungen diskutiert. Im Mittelpunkt stehen Wechselwirkungen zwischen PGI₂, Adenosin und Katecholaminen und ihre möglichen Konsequenzen für die Regulation des koronaren Tonus. Hierzu wird ein Modell vorgestellt, bei dem die direkt-vasokonstriktorischen und stoffwechselsteigernden Katecholaminwirkungen durch Bildung von PGI₂ im Gefäßbereich und Adenosin im Herzmuskelstoffwechsel funktionell antagonisiert werden.

     

Intramyocardial diversion of coronary blood flow: Effects of isoproterenol-induced subendocardial ischemia

Isoproterenol was found to have produced adverse reactions in eight of our patients. All demonstrated large negative ST segment shifts. In experimental studies in rats, the J-shift of the electrocardiogram was sensitive to low doses of isoproterenol. Combined use of a nitrate and beta-blocker completely reversed the significant negative J-shift depression induced by isoproterenol.Dog studies using platinum electrodes to measure intramyocardial oxygen tension at the epicardium and endocardium documented an intracardiac diversion of blood flow between the subendocardium and subepicardium. Isoproterenol diverted blood flow away from the subendocardium, which is very vulnerable to ischemia and decreased perfusion. This isoproterenol-induced “coronary steal” is probably due to localized hypoxia at the subendocardium. Nitroglycerin and propranolol both selectively increased subendocardial blood flow with little effect at the subepicardium. The regulation of blood flow through the coronary circulation can be explained in part by an intramyocardial diversion phenomenon.     

直接经皮冠状动脉介入术中心肌再灌注损伤的机制与治疗策略

<正>再灌注治疗,包括静脉溶栓治疗、直接经皮冠状动脉介入治疗(primary percutaneous coronary intervention,PPCI)以及急诊冠状动脉搭桥术等,能使缺血心肌快速恢复血液灌流及氧供应,在过去的20年中显著降低了急性ST段抬高型心肌梗死(acute STsegment elevation myocardial infarction,STEMI)患者急性期病死率。其中,PPCI是STEMI再灌注治疗的首选治疗策略~([1])。然而,值得注意的是,PPCI术后心肌缺血再灌注使急性心肌梗死面积减小的同时也     

Regional redistribution of myocardial blood flow after coronary occlusion and reperfusion in the conscious dog

Early and late changes in regional myocardial blood flow distribution within the left circumflex coronary arterial bed after occlusion and after occlusion and reperfusion were compared with the extent of myocardial tissue necrosis. Radiolabeled microspheres, 15 μm, were used to study regional myocardial blood flow in conscious dogs at 5 minutes, 2 and 6 hours and 1 month after coronary occlusion. Blood flow was measured in conscious dogs whose hearts were reperfused for 72 hours after 2, 6 and 24 hours of occlusion. Blood flow was measured in four distinct transmural myocardial zones dellneated by dye injections and gross infarct features of the occluded left circumflex coronary bed. After occlusion, myocardial flow was redistributed from deep layers to outer layers, and within 6 hours after occlusion collateral flow was increased to the outer zones in excess of redlstributed flow. After reperfusion, blood flow greatly increased to regions containing predominantly normal tissue, and flow was redlstrlbuted away from the necrotic zones. The indigenous collateral circulation was a major determinant of infarct size in the occluded and reperfused myocardium. The concept of a migrating and narrowing marginal zone is discussed.     

Silent myocardial ischemia: prognostic significance and therapeutic implications

Evidence is now accumulating which strongly suggests that prognosis of patients with painless myocardial ischemia determined either by ambulatory ECG monitoring or exercise testing may be no different than the prognosis of patients who have overt clinical manifestations of myocardial ischemia associated with transient ischemic ECG changes. In my view the goal of therapy for patients with clinical manifestations of coronary artery disease should be the elimination of myocardial ischemia. Medical therapy, coronary angioplasty, or coronary artery surgery should be rendered and then followed by objective documentation of therapeutic efficacy.