Tanzila Khatun

Significant reversal of cardiac upregulated endothelin-1 system in a rat model of sepsis by landiolol hydrochloride.

AIMS Landiolol hydrochloride, an ultra-short-acting highly cardio-selective β-1 blocker, has become useful for various medical problems. Recent studies have demonstrated that co-treatment with landiolol protects against acute lung injury and cardiac dysfunction in rats of lipopolysaccharide (LPS)-induced systemic inflammation, and was also associated with a significant reduction in serum levels of the inflammation mediator HMGB-1 and histological lung damage. Endothelin (ET)-1, a potent vasoconstrictor, has been implicated in pathogenesis of sepsis and sepsis-induced multiple organ dysfunction syndrome. Here, we investigated whether landiolol hydrochloride can play important roles in ameliorating LPS-induced alterations in cardiac ET system of septic rats. MAIN METHODS Eight-week-old male Wistar rats were administered LPS only for 3 h and the rest were treated with LPS as well as with landiolol non-stop for 3 h. KEY FINDINGS At 3 h after LPS (only) administration, circulatory tumor necrosis factor (TNF)-α level, blood lactate concentration and percentage of fractional shortening of heart were significantly increased. In addition, LPS induced a significant expression of various components of cardiac ET-1 system compared to control. Finally, treatment of LPS-administered rats with landiolol for 3 h normalized LPS-induced blood lactate levels and cardiac functional compensatory events, without altering levels of plasma TNF-α and ET-1. Most strikingly, landiolol treatment significantly normalized various components of cardiac ET-1 signaling system in septic rat. SIGNIFICANCE Taken together, these data led us to conclude that landiolol may be cardio-protective in septic rats by normalizing the expression of cardiac vasoactive peptide such as ET, without altering the circulatory levels of inflammatory cytokines.

Potential amelioration of upregulated renal HIF-1alpha–endothelin-1 system by landiolol hydrochloride in a rat model of endotoxemia

AIMS Endothelin (ET)-1 is the best known potent vasoconstrictor and has been implicated in pathogenesis of sepsis-associated acute kidney injury (AKI) in human or lipopolysaccharide (LPS)-induced AKI in animal models. We have previously shown that ET-1 is highly up-regulated in renal tissues and in plasma after LPS administration. Here, we investigated whether landiolol hydrochloride, an ultra-short-acting beta-blocker, can play an important role in ameliorating levels of LPS-induced up-regulation of renal HIF-1α-ET-1 system and inflammatory cytokines in a rat model of endotoxemia. MAIN METHODS Male Wistar rats at 8 weeks of age were either administered with: a) lipopolysaccharide (LPS) only for three hours (3 h) or b) LPS, followed by continuous administration of landiolol for 3 h; c) third group was only treated with vehicle. KEY FINDINGS At 3 h after LPS administration there was: a) minimal injury in kidney tissues; b) circulatory levels of creatinine, blood urea nitrogen and NGAL increased and c) expression of inflammatory cytokines, such as TNF-α, IL-6 and iNOS increased at the level of both circulatory and renal tissues. In addition, LPS significantly induced renal expression of ET-1 and HIF-1α compared to control. Finally, treatment of LPS-administered rats with landiolol for 3 h normalized elevated serum markers of renal injury and up-regulated levels of renal HIF-1α-ET-1 system with normalization of TNF-α. SIGNIFICANCE Taken together, these data led us to conclude that landiolol ameliorates the up-regulation of HIF-1α-ET-1 system in minimally morphologically-injured kidney and normalizes biomarkers of renal injury in early hours of endotoxemia of a rat model.

Landiolol Hydrochloride Ameliorates Liver Injury in a Rat Sepsis Model byDown Regulating Hepatic TNF-a

Aims: The effects of a beta blocker, especially an ultra-short acting selective beta blocker, such as landiolol hydrochloride on the organ protection in sepsis are unclear. The present study aimed to investigate whether acute (early hours) liver injury in a rat model of sepsis induced by lipopolysaccharide (LPS) administration: a) can be corrected by administering landiolol and b) whether landiolol’s effects on liver injury is accomplished by diminishing the elevated expression of inflammatory cytokine, such as tumor necrosis factor (TNF)-α and a vaso constrictor peptide, such as endothelin (ET)-1. Methods: Eight (8)-week-old male Wistar rats were administered for three hours with either LPS (n=12), or continuously with LPS plus landiolol (n=11). Control rats were treated with saline only in a similar manner as the treatment group during the relevant time points (n=13). Results: Following LPS administration, blood gas and hemodynamic parameters were significantly altered compared to control rats at 3 h. Also, At 3 h after LPS administration, circulatory levels of ALT, AST, TNF-α and ET-1 were significantly increased. In addition, at 3 h after LPS administration significant features of hepatic injuries at morphological levels were also evident. Co-treatment of rats with LPS and landiolol ameliorated hepatic injury at 3 h post-treatment, as well as reversed elevated circulatory levels of factors associated with liver injury back to normal levels, such as AST and ALT, and local hepatic levels of TNF-α. Conclusion: Based on the current findings, it can be stated that landiolol may exert protective effects on liver injury in septic rats by normalizing local expression levels of inflammatory cytokine, such as TNF-α.

Landiolol hydrochloride ameliorates acute lung injury in a rat model of early sepsis through the suppression of elevated levels of pulmonary endothelin-1

Among the dysfunctions and pathologies associated with sepsis, the underlying molecular mechanisms of sepsis-induced acute lung injury (ALI) are poorly understood. Endothelin (ET)-1, a potent vasoconstrictor and pro-inflammatory peptide, is known to be involved in the pathogenesis of ALI in a rat model of sepsis. Here, we investigated whether landiolol hydrochloride, an ultra-short-acting β-blocker, plays a crucial role in ameliorating and attenuating LPS-induced ALI through modulation of the ET-1 system. Male Wistar rats at 8weeks of age were administered with either saline or lipopolysaccharide (LPS) for three hours (3h) and some of the LPS-administered rats were continuously treated with landiolol for 3h. ALI was induced by LPS, including levels of both circulatory and pulmonary TNF-α and IL-6 but [PaO2] was significantly decreased. LPS also induced a significant increase in levels of pulmonary ET-1 and ET-A receptor, but levels of ET-B receptor, which has vasodilating effects, were remarkably diminished. Further, LPS administration upregulated the pulmonary expression of HIF-1α. Finally, the treatment of LPS-administered rats with landiolol for 3h ameliorated and prevented ALI, normalized the altered levels of pulmonary ET-1 and ET-A receptors. Landiolol also induced significant down-regulation of ET-B receptor in lung tissues in the early hours (phase) of sepsis. However, Landiolol treatment had no effect on the up-regulated inflammatory mediators (TNF-α, IL-6) in both plasma and lung tissues during sepsis, and expression of pulmonary HIF-1α also remained unchanged after landiolol treatment. Collectively, these data led us to conclude that landiolol may ameliorate sepsis-induced ALI via the pulmonary ET system.

Dual blockade of endothelin action exacerbates up-regulated VEGF angiogenic signaling in the heart of lipopolysaccharide-induced endotoxemic rat model

AIMS Sepsis is a cluster of heterogeneous syndromes associated with progressive endotoxemic developments, ultimately leading to damage of multiple organs, including the heart. However, the pathogenesis of sepsis-induced myocardial dysfunction is still not fully understood. The present study is the first to examine alterations in expression of key angiogenic signaling system mediated by vascular endothelial growth factor (VEGF) in septic heart and the effects of endothelin dual blocker (ETDB) on it. MAIN METHODS Normal Wistar rats were either administered with: a) vehicle only (control group), b) lipopolysaccharide only (LPS: 15 mg/kg) and then sacrificed at different time points (1 h, 3 h, 6 h and 10 h), and c) the last group was co-administered with LPS and ETDB (SB-209670, 1 mg/kg body weight) for 6 h and then sacrificed. KEY FINDINGS Administration of LPS resulted in increases in levels of: a) serum tumor necrosis factor (TNF)-α, b) serum VEGF and c) serum endothelin (ET)-1 levels accompanied by up-regulation of cardiac VEGF and its downstream angiogenic signaling molecules. While cardiac TNF-α level was unchanged among experimental groups, cardiac ET-1 level was significantly higher in LPS-administered group. SIGNIFICANCE We conclude that elevation in VEGF angiogenic signaling may be triggered by diminished oxygenation in the myocardium following LPS administration as a consequence of sepsis-induced microvascular dysfunction. Because of this cardiac dysfunction, oxygen supply may be inadequate at microregional level to support the normal heart metabolism and function. ETDB at 6 h further increased the elevated levels of VEGF angiogenic signaling in endotoxemic heart.

Assessment of circulatory and pulmonary endothelin-1 levels in a lavage-induced surfactant-depleted lung injury rabbit model with repeated open endotracheal suctioning and hyperinflation.

AIMS Endothelin-1 (ET-1) is a mediator of various physiological and pathological processes, including vascular inflammation, cell proliferation and vasoconstriction. Attenuation of ET action using ET-1 antagonists reduces pulmonary vascular leakage and inflammation in several models of lung injuries and experimental acute respiratory distress syndrome (ARDS). Based on these earlier reports, the current study investigates the patterns of ET-1 levels in circulation and pulmonary tissues in an experimental model of lavage-induced surfactant-depleted lung injury. Additionally, we also test the effects of open endotracheal suctioning (OES) and hyperinflation (HI) as recruitment maneuver following OES on ET-1 levels. MAIN METHODS Briefly, 24 Japanese white rabbits were anesthetized and intubated. Normal saline was instilled into the lung and washed mildly. After instillation, rabbits were ventilated at definite settings at a total duration of 3 hours. OES and HI were performed every 15 minutes from the beginning of the protocol. KEY FINDINGS Here, we show that both circulatory and pulmonary ET-1 levels increased in models with lung injury induced by saline lavage compared to healthy control group. No further aggravation in expression of pulmonary ET-1 was seen after OES and HI, although OES and HI worsened arterial hypoxygenation and severity of lung injury. In contrast, circulatory ET-1 levels significantly decreased after OES and HI but were not associated with blood pressure changes. SIGNIFICANCE We conclude that in a saline lavage-induced lung injury model, both circulatory and pulmonary ET-1 levels increased. Further, OES and HI exerted differential effects on ET-1 expression at both circulatory and pulmonary levels.

Effects of Closed Vs. Open Repeated Endotracheal Suctioning During Mechanical Ventilation on the Pulmonary and Circulatory Levels of Endothelin-1 in Lavage-Induced Rabbit ARDS Model

Background: A growing body of evidence demonstrates discretely the difference of open endotracheal suctioning (OES) and closed endotracheal suctioning (CES) on the respiratory and hemodynamic parameters in acute respiratory distress syndrome (ARDS). Endothelin-1 (ET-1), a mediator of vascular inflammation, cell proliferation, and fibrosis in addition to being a potent vasoconstrictor has been potentially implicated in the pathogenesis of ARDS. Here, we investigated the effects of repeated OES vs. CES during mechanical ventilation on circulatory and pulmonary levels of ET-1 in ARDS. Methods: Briefly, 22 Japanese White Rabbits were intubated with a 3.5-mm endotracheal tube. Normal saline was instilled into lung and washed mildly. After instillation, rabbits were ventilated at definite setting; OES and CES duration was for 6 hours and performed every 30 minutes from protocol start. Results: At circulatory level, either OES or CES did not alter plasma ET-1 level compared to the ET-1 level in ARDS before the initiation of endotracheal suctioning (OES 4.7 ± 1.3 pg/ml vs. CES 4.8 ± 1.5 pg/ml, p=0.839). In contrast, pulmonary ET-1 level was significantly higher in CES group compared to OES group after 6 hours of repeated suctioning in ARDS (OES 26.9 ± 2.2 pg/mg vs. CES 29.9 ± 3.3 pg/mg, p=0.018). This change in pulmonary ET-1 level could maintain a parallel relation with PaO2 level. Conclusion: At this moment, we cannot clarify the mechanism and effects of the observed change in ET-1 in a rabbit model of ARDS as well as its clinical impact.

Concomitant Down-Regulation of Et1-Etb System and VEGF AngiogenicSignaling in the Frontal Cortex of Endotoximic Mice: A HeightenedVulnerability to Cerebral Microcirculation in Sepsis

Aims: Sepsis is a disease that involves abnormal alterations in the microcirculation, with endothelial dysfunction playing a central role in the pathogenesis and mortality. The exact pathophysiology of brain dysfunction associated with sepsis remains poorly understood and experimental data are scarce. It is likely that cerebral microcirculatory alterations may play a potential role. Thus, the present study sought to investigate whether key angiogenic pathways are altered in the frontal cortexin a clinically-relevant animal model of endotoxemia/sepsis, and verify whether the alterations in angiogenic pathways affect the cerebral capillary density. Main methods: Male mice at 8 weeks of age were administered either with saline alone (control group) or 20 mg/kg lipopolysaccharide (LPS) (treatment group) at different time points (1, 3, 6, and 10 h). Microvascular alterations were determined by measuring levels of cerebral mRNA, protein levels of angiogenic factors, namely vascular endothelial growth factor (VEGF) and its receptors, endothelin-1 (ET-1) and their downstream molecules, and calculating microvascular density in frontal cortex. Key findings: In the frontal cortex of the endotoxemic model, the expressions of VEGF and KDR with the downstream molecule, eNOS, were diminished sharply in a time-dependent manner, implying significant alterations in the cerebral microcirculation during sepsis. Concomitantly, ET-1, which behaves as a pro-angiogenic factor under the mediation of the ET-B receptor subtype, was similarly downregulated time-dependently. Cerebral capillary density was significantly decreased at 10 hours after LPS administration (56%, p<0.05) compared to that of control brain. Significance: A recent study reported a significant decrease in cerebral capillary density in a sheep model of sepsis, which is strongly associated with the progression of cerebral pathologies. The current findings are consistent with the findings with this earlier study and provide the first likely mechanisms underlying the altered microcirculation based brain dysfunction in sepsis.