冠状动脉旁路术围术期肺动脉血浆一氧化氮合成酶活性与一氧化氮浓度的变化

目的 研究冠状动脉旁路术围术期肺动脉血浆一氧化氮合成酶（NOS）活性和一氧化氮（NO）浓度的变化。方法 选择30例冠状动脉旁路手术（CABG）病人,在围术期抽取肺动脉血测定NOS和NO值。结果 肺动脉血浆中NOS和NO水平虽有明显变化（P＜0．05）,但NO浓度与NOS活性的增减并不一致：当NOS活性降低时,NO浓度增高;反之当NOS活性显著增高时,NO浓度降低。结论 在行CABG围术期中,肺动脉血浆中内源性NO分泌无法满足应激时自身保护对其的需要。     

Effect of methylprednisolone on myocardial preservation during coronary artery surgery

It has been proposed that a single preoperative dose of a corticosteroid may protect the myocardium from ischemic injury during open heart surgery. To test this hypothesis, a prospective, randomized, double blind study was carried out in ninety-five patients undergoing coronary bypass surgery using intermittent ischemic arrest with systemic and local hypothermia. Half the patients received 2 gm (approximately 30 mg/kg) of methylprednisolone 2 hours prior to the initiation of cardiopulmonary bypass and the other half received a placebo.Postoperative electrocardiograms and blood levels of serum creatine phosphokinase (CPK), lactic dehydrogenase (LDH), and serum glutamic oxalacetic transaminase (SGOT) were compared in the two groups. No apparent difference was noted in the number of patients with significantly elevated levels of CPK, LDH, or SGOT or in the number with positive isoenzyme patterns of CPK and LDH. Moreover, there was no significant difference in the mean values of CPK, LDH, or SGOT between the two groups.The number of patients with electrocardiographic evidence of myocardial injury (10 per cent) was the same in both groups and no difference was noted in (1) the ease with which patients could be weaned from cardiopulmonary bypass, (2) postoperative arrhythmias, (3) postoperative bleeding, (4) postoperative respiratory insufficiency, and (5) length of hospital stay.It is concluded that a single preoperative dose of 2 gm of methylprednisolone offers no demonstrable protection to the myocardium from the effects of ischemia during coronary artery bypass surgery.     

Coronary artery surgery and direct coronary artery thrombolysis during acute myocardial infarction

Twelve patients underwent direct coronary artery streptokinase thrombolysis during acute evolving myocardial infarction. Ten patients had restoration of orthograde pulmonary blood flow. Eight patients had significant myocardial salvage and clinical stabilization. Nine patients had subsequent coronary artery bypass surgery with no major hematological or cardiac complications. Five of these had surgery performed immediately. Two patients with no myocardial salvage after streptokinase had urgent surgery because of other critical coronary lesions. Seven patients with thrombolytic salvage of myocardium underwent urgent coronary artery bypass surgery without incident. The occurrence of two reinfarctions in streptokinase-improved patients waiting for surgery suggests that delay is unwarranted and coronary bypass surgery is needed to insure success.     

Glucose-insulin-potassium infusion for myocardial protection during off-pump coronary artery surgery

BACKGROUND: The purpose of this randomized, double-blind, placebo-controlled pilot study was to determine the effectiveness of an intravenous glucose-insulin-potassium (GIK) infusion in preventing myocardial damage and maintaining cardiac performance in patients undergoing "off-pump" myocardial revascularization. METHODS: Forty-six adult patients undergoing elective off-pump coronary artery bypass received either normal saline or a GIK infusion immediately after the induction of anesthesia through the first 12 hours of intensive care unit convalescence. Measurements of blood glucose, circulating creatine kinase MB and troponin I concentrations, as well as cardiac index (CI) and mixed venous oxygen saturation (SvO2), were obtained immediately before starting the infusion (baseline) and at 6, 12, and 24 hours post-initial coronary artery occlusion. RESULTS: Five patients (8%) requiring cardiopulmonary bypass were excluded from data analysis. Twenty patients received saline. Twenty-one received GIK. Blood glucose was significantly higher in the GIK group. The concentration of circulating creatine kinase MB and troponin I significantly increased over time after off-pump coronary artery bypass, with no significant intergroup differences. Cardiac index and SvO2 did not differ significantly between groups. CONCLUSIONS: A GIK infusion protocol commonly used as an adjunct to reperfusion therapy for acute myocardial infarction causes insulin-resistant hyperglycemia in elective off-pump coronary artery bypass patients with no demonstrable benefit. The finding of significant release of cardio-specific enzymes in individual patients implies an ongoing need to develop more effective strategies for myocardial protection during off-pump coronary artery bypass.     

Activation of endothelial nitric oxide synthase in contralateral testis during unilateral testicular torsion in rats

There are controversies about the injury of the contralateral testis during unilateral testicular torsion (UTT). An autonomic reflex arc between bilateral testes has been proposed. The authors focused on the involvement of nitric oxide (NO) in the contralateral testis during UTT. Eight-week-old male Wistar rats underwent unilateral torsion (1 h)-detorsion (up to 24 h). NO synthase (NOS) activity was detected as NADPH-diaphorase activity after fixation by paraformaldehyde. N-nitro-L-Arginine methyl ester (L-NAME, 20 mg/kg) was injected intravenously to the other group of rats. To evaluate the testicular injury, proteolysis of alpha-fodrin production was detected by Western blotting. Apoptosis of the germ cells was evaluated by TUNEL. Long-term effect on spermatogenesis was evaluated by flow cytometry at 60 days after UTT. Transient activation of NOS was detected following the proteolysis of alpha-fodrin in the contralateral testis. L-NAME inhibited these alterations. NADPH-diaphorase activity and eNOS immunoreactivity were co-localized in the endothelial cells. These reactions were not observed in other organs. There was neither enhanced apoptosis nor deteriorated spermatogenesis in the contralateral testis during and 60 days after UTT. In the contralateral testis, eNOS-derived NO regulates the vasomotor function against unilateral testicular torsion, whereas it acts slightly cytotoxic. These results suggest the possible involvement of a testis-specific neurovasomotor reflex between the bilateral testes.     

Exhaled nitric oxide as a marker of lung injury in coronary artery bypass surgery

Background. Exhaled nitric oxide (NO) concentrations have beensuggested as a marker of disease onset and severity in a numberof inflammatory conditions such as acute asthma. Known markersof the onset of acute lung injury require invasive tests andlaboratory based analysis and have limited clinical applicability.We performed a study of the use of exhaled NO as a marker ofdeveloping acute lung injury during and after coronary arterybypass grafting in patients requiring cardiopulmonary bypass. Methods. Mixed expired air samples were taken from the patientbreathing system and analysed for exhaled NO using chemiluminescenceanalysis. Results. Exhaled nitric oxide concentrations in expired gascorrelated with the Pa_O2/FI_O2 ratio (r=0.23, P<0.01). Therewas a non-significant trend towards a reduction in exhaled NOlevels from after induction of anaesthesia to post-bypass timepoints, with the lowest exhaled NO concentrations occurringat this time (P=0.07). There was no correlation between meanarterial pressure (r=–0.1, P=0.54) or mean pulmonary arterypressure (r=–0.1, P=0.67) and expired NO levels. Conclusions. Further work is required to test whether exhaledNO concentration may be useful in diagnosing the onset of acutelung injury in patients undergoing coronary artery bypass grafting. Br J Anaesth 2002; 89: 247–50     

Plasma concentrations of nitric oxide products and cognitive dysfunction following coronary artery bypass surgery

BACKGROUND AND OBJECTIVE: Prospective longitudinal studies now indicate that cognitive dysfunction following coronary artery bypass surgery (CABG) is both common and persistent. This dysfunction is due in part to the inflammatory response and cerebral ischaemia-reperfusion, with nitric oxide (NO) as an important mediator of both. We hypothesized that a clinically significant association exists between plasma concentrations of nitrate/nitrite (NO3-/NO2-) and cognitive dysfunction after CABG. METHODS: Cognitive assessment was performed on 36 adult patients the day before CABG, on the fourth postoperative day and 3 months postoperatively. Patient spouses (n = 10) were also studied. RESULTS: A new cognitive deficit was present in 22/36 (62%) 4 days postoperatively and in 16/35 (49%) of patients, 3 months postoperatively. Patients who had cognitive dysfunction 3 months postoperatively were more likely to have cognitive dysfunction and increased plasma NO3-/NO2- concentrations compared to the non-deficit group preoperatively (22.6 (9.2) vs. 27.6 (8.4)) (P = 0.002). Plasma NOx (NO3- plus NO2-) concentrations were greater in patients with cognitive dysfunction 3 months postoperatively, 2 h (24.2 (6.3) vs. 19.1 (5.2)) (P = 0.002), and 12 h postoperatively (24.8 (7.6) vs. 18.8 (5.6)) (P = 0.001). There was, however, a time course similarity in NOx elevations for both deficit and non-deficit groups. CONCLUSIONS: Perioperative plasma NOx concentrations do not serve as an effective biomarker of cognitive deficit after CABG.     

Pravastatin attenuates lower torso ischaemia-reperfusion-induced lung injury by upregulating constitutive endothelial nitric oxide synthase.

OBJECTIVES: to elicit whether pre-treatment with pravastatin will prevent or ameliorate the acute lung injury that occurs following lower torso ischaemia-reperfusion (IR) in an experimental animal model. MATERIALS AND METHODS: male Sprague-Dawley rats were randomised into three groups (n=7/group). The control group underwent a sham laparotomy and aortic dissection. The second group underwent infrarenal aortic cross clamping for 30 min followed by reperfusion for 120 min. The third group pre-treated with pravastatin sodium (0.4 mg/kg/day over 5 days) were again subjected to an ischaemia-reperfusion (IR) injury. The parameters used to assess lung injury included: Wet to dry lung weight ratio (W:D), myeloperoxidase activity (MPO), protein concentration (BALprot) and neutrophil count (BAL PMN) of bronchoaveolar lavage fluid. Western blotting was used to determine the expression of constitutive endothelial nitric oxide synthase (ecNOS) within lung tissue. RESULTS: IR causes an acute lung injury as indicated by statistically significant differences in W:D lung weight ratios, MPO activity, neutrophil count and BALprotein concentration in the IR group over that of controls. Pre-treatment with pravastatin attenuated this neutrophil infiltration and microvascular leakage. The pravastatin group showed a marked increased expression of ecNOS over that of the IR group and controls. CONCLUSION: this data indicates that pre-treatment with pravastatin protects against ischaemia-reperfusion induced lung injury in an experimental animal model. We believe that its mechanism of action involves an upregulation of ecNOS, which increases basal expression of nitric oxide providing protective effects on the pulmonary circulation against microvascular injury.     

Propofol attenuates myocardial lipid peroxidation during coronary artery bypass grafting surgery

Background. Propofol can scavenge free radicals because it hasa chemical structure similar to antioxidants. Methods. We examined if free radical scavenging occurs withpropofol during CABG operations. We studied 24 patients undergoingCABG surgery for triple vessel disease, randomized into twogroups. After induction of anaesthesia with fentanyl 10 µgkg^–1 and midazolam 0.1 mg kg^–1, patients in thefentanyl group (n=14) received fentanyl infusion 10–30µg kg^–1 h^–1 and patients in the propofol group(n=10) received propofol infusion 3–6 mg kg^–1 h^–1for maintenance of anaesthesia. Atrial tissue biopsies weretaken during cannulation for bypass, 45 min after cross-clampinsertion, 5 min after unclamping, and in the decannulationperiod. Lipid peroxidation was assessed by measurement of thiobarbituricacid reactive substances (TBARS) in the atrial tissue samples. Results. Lipid peroxidation in the propofol group was less thanin the fentanyl group (P<0.05) in all sampling periods. Lipidperoxidation in the fentanyl group increased significantly duringcardiopulmonary bypass (CPB) (P<0.05), but no increase wasfound in the propofol group (P>0.05). Conclusion. In clinical doses, propofol strongly attenuateslipid peroxidation during CABG surgery. Br J Anaesth 2002; 89: 242–6     

Differential nitric oxide synthase expression during hepatic ischemia-reperfusion

BACKGROUND: In recent years the important role of nitric oxide in hepatic ischemia-reperfusion injury has been increasingly recognised. The prevailing consensus is that reperfusion injury may be partly the result of decreased production of nitric oxide from endothelial nitric oxide synthase and excessive production of nitric oxide from the inducible isoform. We therefore undertook this study to characterize the expression of different nitric oxide synthase isoforms during hepatic reperfusion. METHODS: Male Wistar rats (n = 6) were subjected to 45 minutes of partial hepatic ischemia (left lateral and median lobes) followed by 6 hours of reperfusion. Control animals (n = 6) were subjected to sham laparotomy. The expression of endothelial and inducible nitric oxide synthase was examined using immunohistochemistry and Western blotting. Liver sections were also stained with nitrotyrosine antibody, a specific marker of protein damage induced by peroxynitrite (a highly reactive free radical formed from nitric oxide). RESULTS: Liver sections from all the control animals showed normal expression of the endothelial isoform and no expression of inducible nitric oxide synthase. Livers from all the animals subjected to hepatic ischemia showed decreased expression of endothelial nitric oxide synthase, and all but one animal from this group showed expression of the inducible isoform both in inflammatory cells and in hepatocytes. Western blotting confirmed these findings. Staining with the antinitrotyrosine antibody was also confined to five liver sections from animals subjected to hepatic ischemia. CONCLUSIONS: During the reperfusion period after hepatic ischemia, endothelial nitric oxide synthase is downregulated while inducible nitric oxide synthase is expressed in both hepatocytes and inflammatory cells. The presence of nitrotyrosine in livers subjected to hepatic ischemia-reperfusion suggests that the expression of inducible nitric oxide synthase plays an important role in mediating reperfusion injury in this model.     

Response to nitric oxide during adult cardiac surgery.

Pulmonary hypertension is associated with significant morbidity and mortality in adult cardiac surgery patients. Inhaled nitric oxide is known to be a selective pulmonary vasodilator in this setting. However, it is not known which cardiac surgery patients benefit most from nitric oxide therapy. This study sought to prospectively determine whether a patient's baseline pulmonary vascular resistance could be used to predict responsiveness to inhaled nitric oxide therapy. Subjects were 30 consecutive cardiac surgery patients with pulmonary hypertension immediately prior to induction of anesthesia. There were 2 study groups: Group 1 (n = 15) had an initial pulmonary vascular resistance between 125 and 300 dyn-s/cm5, while group 2 (n = 15) had an initial pulmonary vascular resistance of greater than 300 dyn-s/cm5. Both groups were empirically treated with inhaled nitric oxide (30 ppm) upon separation from bypass. The conduct of anesthesia, surgery, and cardiopulmonary bypass were controlled. A therapeutic algorithm dictated the use of vasoactive substances for all patients. Heart rate, mean arterial pressure, pulmonary vascular resistance, peripheral vascular resistance, cardiac index, and right ventricular ejection fraction were monitored throughout the operative experience. Patients with a higher initial pulmonary vascular resistance had a significantly greater percent reduction in pulmonary vascular resistance after the initiation of nitric oxide therapy. This study suggests that pulmonary vascular resistance is more dramatically affected by inhaled nitric oxide in cardiac surgery patients with a greater degree of pulmonary hypertension.     

Activation of complement and leukocyte receptors during on- and off pump coronary artery bypass surgery.

OBJECTIVE: The aim of this prospective, randomised study was to investigate the influence of extracorporeal circulation on the inflammatory response, our hypothesis being that off pump coronary artery bypass grafting (OFFCAB) procedures would generate less activation than on pump procedures (ONCAB). METHODS: Patients admitted for elective CABG were randomised to either ONCAB or OFFCAB surgery and blood samples were taken during and up to 24 h after the operation. We measured complement factors C5a and the terminal complement complex (TCC, C59-b), and the interleukins IL-6 and IL-8. Leukocytes were studied for cellular counts and adhesion molecules (CD11b, CD35 and CD62L) by flow cytometry. We included a combination of activity markers with different aspects of neutrophil function and combined these with in vitro activation. RESULTS: The complement factors C5a and TCC showed a more rapid (P=0.02, P<0.001) and TCC a more profound (P<0.001) increase in the ONCAB group than in the OFFCAB group during the operation, after that there were no inter-group differences. Cellular markers, cell counts and interleukin levels were activated by surgery but with no difference between groups. CONCLUSION: This prospective, randomised study showed less complement activation in low risk OFFCAB, compared to ONCAB patients.     

Localization of constitutive nitric oxide synthase isoforms and the nitric oxide target enzyme soluble guanylyl cyclase in the human bladder

PURPOSE: Nitric oxide is a free radical gas synthesized from L-arginine by a family of isoenzymes called nitric oxide synthase that has an important role in smooth muscle relaxation. L-arginine, the substrate for nitric oxide synthase, may be beneficial under pathophysiological conditions in the bladder, as in interstitial cystitis. We determined the localization of nitric oxide synthase and the target enzyme of NO, soluble guanylyl cyclase, in the human bladder. MATERIALS AND METHODS: Benign bladder tissues were obtained from 18 patients with localized superficial bladder tumors undergoing transurethral bladder resection. Histochemical nicotinamide adenine dinucleotide phosphate-diaphorase staining, nitric oxide synthase immunohistochemical testing and soluble guanylyl cyclase immunoreactivity studies were performed in all benign tissue specimens. RESULTS: A different pattern of nitric oxide synthase expression was confirmed by nicotinamide adenine dinucleotide phosphate-diaphorase staining and immunohistochemical testing for endothelial and neuronal nitric oxide synthase. In addition to endothelial nitric oxide synthase expression, detrusor smooth muscle was recognized as an important location of endothelial nitric oxide synthase, while the urothelium had only small endothelial nitric oxide synthase positive cell clusters. Neuronal nitric oxide synthase expression was only found in nitrinergic fibers of the submucosal surface and between muscle cells. Detrusor and vascular smooth muscle as well as interstitial cells, nerve fibers and transitional epithelium were recognized as targets of nitric oxide, as shown by soluble guanylyl cyclase expression. CONCLUSIONS: The distribution of constitutive nitric oxide synthase isoforms and soluble guanylyl cyclase provides evidence of nitric oxide-cyclic guanosine monophosphate mediated regulation of detrusor smooth muscle relaxation, neurotransmission and blood flow. Furthermore, the urothelium may also be a target of nitric oxide.     

大鼠肝缺血／再灌注后肝组织一氧化氮和不同亚型一氧化氮合酶的变化

目的探讨一氧化氮（NO）和一氧化氮合成酶（NOS）在肝缺血／再灌注（I／R）过程中的变化和作用。方法健康雄性SD大鼠24只，随机分为3组（每组8只）：①正常对照组，术中只分离肝周围韧带，不做肝门阻断及再灌注。②I/R组，进行45min的部分肝门阻断及60min的再灌注。③L-精氨酸（L—Arg）组，缺血前20min经阴茎背静脉注射L—Arg（300mg／kg），余同②组。实验结束后，取下腔静脉血2ml，并迅速切取缺血肝组织。检测血清丙氨酸转氨酶（ALT）、门冬氨酸转氨酶（AST）、乳酸脱氢酶（LDH）；测定肝组织中超氧化物歧化酶（SOD）、丙二醛（MDA）、黄嘌呤氧化酶（XOD）、一氧化氮（NO）和一氧化氯合成酶（NOS）等指标；观察光镜和电镜下肝组织学变化。结果与正常对照组相比，I／R组iNOS升高，NO降低；L-Arg组NO、eNOS均高于I／R组。2、3组比1组大鼠的肝组织病理损害重、肝功能差，L—Arg组病理损害较I／R组明显减轻、肝功能改善。结论NO对大鼠肝I／R损伤具有保护作用．不同亚型NOS的变化参与其中。     

Leukocyte depleting filter attenuates myocardial injury during elective coronary artery bypass surgery

BACKGROUND: Ischemia-reperfusion injury secondary to leukocyte activation has been widely recognized as one of the most relevant mechanism leading to postoperative organ dysfunction occurring after a period of ischemia. The aim of the present study was to evaluate in a prospective, randomized study, the value of leukocyte depleting filter in patients undergoing elective coronary artery bypass surgery. METHODS: Twenty patients scheduled for elective on-pump coronary artery bypass surgery were randomized to undergo cardiopulmonary bypass either with a leukocyte depleting filter incorporated in the extracorporeal circulation arterial line or without a filter. RESULTS: The main finding of this study was the significantly lower postoperative concentrations of cardiac troponin I in the leukocyte filter group (Tests of between-subjects effects: p = 0.024). There were also slightly better cardiac indices in the leukocyte filter group. A larger amount of blood units was infused intra- and postoperatively in patients undergoing cardiopulmonary bypass with leukocyte filtration (median, 600 [IQR, 0-1200] vs. 0 [IQR, 0-600], p = 0.08). Two patients in the leukocyte filter group underwent reoperation for bleeding but none in the control group (p = 0.48). Intra-and postoperative platelet count was lower in the leukocyte filter group (Tests of between-subjects effects: p = 0.08). Despite a significant increased concentration of C-reactive protein on the first postoperative day in the control group (p = 0.029), repeated-measures analysis failed to show any significant increase during the study period (p = 0.33). CONCLUSIONS: The results of this study suggest a myocardial protective effect of leukocyte filter in the setting of elective coronary artery bypass surgery.     

Impact of nitric oxide synthase 3 on myocardial dysfunction in sepsis

Septic shock is a complex syndrome that claims over 200,000 lives per year in the United States. While majority of the late mortality of sepsis appears to be due to multi-system organ failure, early death has been attributed either to distributive shock or to a cardiogenic form of septic shock. Overproduction of nitric oxide (NO), presumably by NO synthase 2 (NOS 2), has been implicated in the pathogenesis of cardiovascular dysfunction of sepsis. However, in clinical trials, NOS inhibitors that are not isoform-specific increased mortality in septic patients due to cardiac dysfunction, suggesting salutary effects of NOS 1 and/or NOS 3. Recently, we found that cardiomyocyte-specific overexpression of NOS 3 prevents lipopolysaccharide (LPS)-induced myocardial dysfunction and mortality in mice. Myocardial mechanical efficiency was markedly impaired in wild-type and NOS 3-deficient mice but not in mice with the NOS 3 transgene after LPS challenge. Improved myocardial function by excess NO during endotoxemia was associated with decreased myocardial oxidative stress, increased myofilament sensitivity to calcium, and increased phospholamban (PLB) phosphorylation. These results suggest that increased myocardial NO levels attenuate endotoxin-induced ROS production and increase total sarcoplasmic reticulum Ca2+ load and myofilament sensitivity to Ca2+ thereby reducing myocardial dysfunction and mortality in murine models of septic shock.     

Correlation between myocardial ischemia and changes in arterial resistance during coronary artery bypass surgery.

The arterial resistometer provides continuous on-line monitoring of changes in arterial resistance. Resistance index (Ri), which bears a direct relationship to systemic vascular resistance (SVR), is defined by the equation Ri = P'/(dP'/dt), where dP'/dt is the peak dP/dt of the arterial waveform, and P' is the pressure at dP'/dt. In 42 patients with unstable angina, changes in Ri were studied at six periods during aortocoronary bypass surgery before tracheal intubation, during tracheal intubation, leg elevation, presternotomy, sternotomy, and dissection of the internal mammary artery. Thirty-four episodes of ischemia (0.1 mV ST segment changes) were observed in 26 patients. All ischemic episodes were associated with increased Ri (mean increase, 102 +/- 52%). Elevation of the pulmonary capillary wedge pressure correlated with ischemia during the preintubation, intubation, and sternotomy periods, but not in the remaining periods. Changes in arterial pressure and heart rate were not good predictors of ischemia. The prevalence of ST segment changes increased markedly during all periods of anesthesia with increase in Ri (P less than 0.05). Ninety-one percent of ST segment changes were associated with a 25% increase from the baseline Ri. Raising the cutoff point to a greater than or equal to 75% increase in Ri improved the specificity of Ri in ischemia detection from 61% to 92%. An increase of greater than or equal to 75% in Ri occurred in only 8% of cases without ST segment changes. It was found that an increase in Ri as depicted by the arterial resistometer was the best hemodynamic correlate of myocardial ischemia.