Upregulation of antioxidant nuclear factor erythroid 2-related factor 2 and its dependent genes associated with enhancing renal ischemic preconditioning renoprotection using levosimendan and cilostazol in an ischemia/reperfusion rat model

IntroductionIschemic preconditioning (Ipre) provides protection against renal ischemia-reperfusion (I/R) injury with its associated remote organ damage. This study examined the enhancing protective effect of Ipre with levosimendan or cilostazol in I/R-induced kidney and lung injury in a rat model.Material and methodsRats were divided into: sham-operated, I/R control, Ipre control, I/R + cilostazol or levosimendan and Ipre + cilostazol or levosimendan. Drugs were given 30 min before left renal I/R or 4 cycles of Ipre just before renal ischemia.ResultsThe Ipre combined with the implemented drugs enhanced physiological antioxidant defense genes including renal nuclear factor erythroid 2-related factor 2 (Nrf2) and its dependent genes heme oxygenase-1 (HO-1) and NADPH-quinone oxidoreductase-1 (NQO-1) and improved malondialdehyde and superoxide dismutase renal tissue levels. The combined effect improved I/R consequences for blood urea, creatinine, and creatinine clearance and improved blood oxygenation and metabolic acidosis. Moreover, the combination improved the renal soluble intercellular adhesion molecule (ICAM), tumor necrosis factor α (TNF-α) and interlukin-6 (IL-6) with histopathological improvement of tubular necrosis with a decrease in the apoptotic marker caspase-3 and an increase in the anti-apoptotic Bcl-2 expression.ConclusionsCilostazol or levosimendan potentiates the renoprotective effect of Ipre against renal I/R injury, associated with upregulation of antioxidant genes Nrf2, HO-1, and NOQ-1 expression.     

达格列净联合左西孟旦治疗慢性心力衰竭患者伴心律失常的疗效及安全性分析

目的 探讨达格列净联合左西孟旦治疗慢性心力衰竭（CHF）伴心律失常的疗效及安全性。方法选取2021年3月—2023年3月滕州市中心人民医院收治的192例CHF伴心律失常患者,采用随机数字表法分为对照组和研究组,每组96例（研究组最终脱落3例,对照组脱落2例）。对照组给予左西孟旦注射液,研究组在对照组的基础上给予达格列净片。两组持续治疗1个月后观察疗效。比较两组临床疗效、室性心律失常、心功能、心肌损伤指标及药物不良反应发生情况,对比两组治疗后30 d内因心力衰竭再住院情况。结果 研究组总有效率高于对照组（P <0.05）。研究组治疗前后室性早搏、成对室性早搏、短阵室速发作次数的差值高于对照组（P <0.05）。研究组治疗前后左心室射血分数、左室舒张末期内径、左心室收缩末期内径的差值高于对照组（P <0.05）。研究组治疗前后N末端脑钠肽前体、心肌肌钙蛋白Ⅰ的差值高于对照组（P <0.05）。两组总药物不良反应发生率、治疗后30 d内因心力衰竭再住院率比较,差异均无统计学意义（P>0.05）。结论 达格列净联合左西孟旦治疗CHF伴心律失常患者可增强临床疗效,减...     

Troponin component of cardiotonic effects of levosimendan on isolated myocardium from patients with chronic heart failure

Experiments on isolated myocardial preparations from patients with coronary heart disease showed that inotropic effects of levosimendan in a dose of 0.73 μmol/liter were primarily due to activation of cAMP-dependent systems of regulation of cell metabolism. Increased affinity of troponin C for Ca²⁺ impaired muscle relaxation in patients with chronic heart failure. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 128, No. 10, pp. 457–458, October, 1999     

Exploring the role of prophylactic levosimendan in coronary surgery

Background:The role of prophylactic levosimendan in coronary surgery has not been established conclusively. Methods:Postoperative outcomes of 139 patients (mean age, 68.2±9.6 years) having preoperative left ventricular ejection fraction (LVEF) ≤40% and undergoing isolated coronary surgery (2013-2017) were reviewed retrospectively. In 42 (30.2%) patients (L-group), an intravenous infusion of levosimendan was started 24 hours before operation. The remaining 97 (69.8%) patients were the control group (C-group). A comparison between the two groups regarding outcome of surgery was performed also after propensity matching. Results:Although the risk profile in L-patients was higher than in C-patients (median European System for Cardiac Operative Risk Evaluation II, 10.5% vs. 6.5%, P=0.013) due to higher prevalence of New York Heart Association class III-IV, LVEF ≤30%, and preoperative intra-aortic balloon pump, in-hospital mortality was equivalent (4.8% vs. 3.1%, P=0.48). However, low cardiac output, multiple blood transfusion, and any major complication early after surgery were more frequent in L-patients. After one-to-one propensity matching, which resulted in 15 pairs with similar baseline characteristics the use of levosimendan was associated with a trend towards an increased blood use (P=0.077), a higher frequency of any major complication (P=0.053), and lower peak serum levels of cardiac troponin I (P=0.088). No intergroup differences concerning mid-term survival or outcomes were found even for matched patients. Conclusions:When compared with traditional inotropes alone, prophylactic use of levosimendan showed clear benefits/drawbacks neither concerning immediate nor mid-term outcomes after coronary surgery. There could be any advantage in terms of myocardial preservation.     

Levosimendan: first in a new class of inodilator for acute and chronic severe heart failure

Heart failure is the most common malignant disease in the developed world. Levosimendan (Simdax®) is a novel intravenous agent that exerts inotropic effects through sensitization of myofilaments to calcium and vasodilator effects by opening ATP-dependent potassium channels on vascular smooth muscle. Infusion of levosimendan increases cardiac output due to an increase in stroke volume and heart rate, with a fall in pulmonary capillary wedge pressure. It has an active metabolite with a half-life of about 80 h, therefore infusions of 6 to 24 h result in hemodynamic effects that persist for 7 to 10 days. Preliminary observations suggest that a single infusion of levosimendan lasting 6 to 24 h in patients with severe heart failure due to left ventricular systolic dysfunction results in hemodynamic changes, symptomatic benefit and a reduction in morbidity and mortality over the following 2 to 4 weeks compared with placebo in one study and with dobutamine in another. Long-term follow-up suggests no loss of this early benefit over 6 months. Levosimendan is licensed for the treatment of decompensated heart failure in many countries but not in North America. Further large trials are being conducted comparing levosimendan with placebo and with dobutamine in patients with severe heart failure and left ventricular systolic dysfunction. If these studies confirm the benefits of levosimendan, then it may become routine therapy for the management of severe heart failure.     

钙增敏剂左西孟旦的研究新进展

钙增敏剂左西孟旦为新一代强心药物,具有独特的双重作用机制,用于心力衰竭的治疗,安全有效,其合成方法简便易行,具有广泛的市场前景。     

钙增敏剂左西孟旦的研究新进展

钙增敏剂左西孟旦为新一代强心药物,具有独特的双重作用机制,用于心力衰竭的治疗,安全有效,其合成方法简便易行,具有广泛的市场前景。     

Effects of levosimendan on indocyanine green plasma disappearance rate and the gastric mucosal-arterial pCO2 gradient in abdominal aortic aneurysm surgery

Background: Levosimendan has a dual mechanism of action: it improves myocardial contractility and causes vasodilatation without increasing myocardial oxygen demand. In a laboratory setting, it selectively increases gastric mucosal oxygenation in particular and splanchnic perfusion in general. The aim of our study was to describe the effects of levosimendan on systemic and splanchnic circulation during and after abdominal aortic surgery. Methods: Twenty abdominal aortic aneurysm surgery patients were randomized to receive either levosimendan (n=10) or placebo (n=10) in a double‐blinded manner. Both the mode of anaesthesia and the surgical procedures were performed according to the local guidelines. Automatic gas tonometry was used to measure the gastric mucosal partial pressure of carbon dioxide. Systemic indocyanine green clearance plasma disappearance rate (ICG‐PDR) was used to estimate the total splanchnic blood flow. Results: The immediate post‐operative recovery was uneventful in the two groups with a comparable, overnight length of stay in the intensive care unit. Cumulative doses of additional vasoactive drugs were comparable between the groups, with a tendency towards a higher cumulative dose of noradrenaline in the levosimendan group. After aortic clamping, the cardiac index was higher [4(3.8–4.7) l/min/m² vs. 2.6(2.3–3.6) l/min/m²; P<0.05] and the gastric mucosal–arterial pCO₂ gradient was lower in levosimendan‐treated patients [0.9(0.6–1.2) kPa vs. 1.7(1.2–2.1) kPa; (P<0.05)]. However, the total splanchnic blood flow, estimated by ICG‐PDR, was comparable [29(21–29)% vs. 20(19–25)%; NS]. Organ dysfunction scores (sequential organ dysfunction assessment) were similar between the groups on the fifth post‐operative day. Conclusion: Levosimendan favours gastric perfusion but appears not to have a major effect on total splanchnic perfusion in patients undergoing an elective aortic aneurysm operation.