Post Sham Research Articles

Role of low-density lipoprotein electronegativity and sexual dimorphism in contributing early ventricular tachyarrhythmias following ST-elevation myocardial infarction.

Early ventricular tachycardia/fibrillation (VT/VF) in patients with ST-elevation myocardial infarction (STEMI) has higher morbidity and mortality. This study examines gender-differentiated risk factors and underlying mechanisms for early onset VT/VF in STEMI. We analyzed data from 2,964 consecutive STEMI patients between January 1, 2008 and December 31, 2021. Early VT/VF was defined as occurrence of spontaneous VT/VF of ≥30 s or requirement of immediate cardioversion/defibrillation within the first 48 h after symptoms. An ex vivo ischemic-reperfusion experiments were conducted in 8-week-old ApoE-/- mice fed a high-fat diet to explore the underlying mechanisms of early VT/VF. In 255 of out 2,964 STEMI patients who experienced early VT/VF, the age was younger (58.6 ± 13.8 vs. 61.0 ± 13.0 years old, P = 0.008) with a male predominance. The plasma levels of L5, the most electronegative subclass of low-density lipoprotein, was higher in early VT/VF patients compared to those without early VT/VF (n = 21, L5: 14.1 ± 22.6% vs. n = 46, L5: 4.3 ± 9.9%, P = 0.016). In the experimental setup, all male mice (n = 4) developed VT/VF post sham operation, whereas no such incidence was observed in the female mice (n = 3). Significantly, male mice exhibited considerably slower cardiac conduction velocity as compared to their female counterparts in whole heart preparations (25.01 ± 0.93 cm/s vs.42.32 ± 5.70 cm/s, P < 0.001), despite analogous action potential durations. Furthermore, isolated ventricular myocytes from male mice showed a distinctly lower sodium current density (-29.20 ± 3.04 pA/pF, n = 6) in comparison to female mice (-114.05 ± 6.41 pA/pF, n = 6, P < 0.001). This decreased sodium current density was paralleled by a reduced membrane expression of Nav1.5 protein (0.38 ± 0.06 vs. 0.89 ± 0.09 A.U., P < 0.001) and increased cytosolic Nav1.5 levels (0.59 ± 0.06 vs. 0.29 ± 0.04 A.U., P = 0.001) in male mice. Furthermore, it was observed that the overall expressions of sorting nexin 27 (SNX27) and vacuolar protein sorting 26 (VPS26) were significantly diminished in male mice as compared to female littermates (0.91 ± 0.15 vs. 1.70 ± 0.28, P = 0.02 and 0.74 ± 0.09 vs. 1.57 ± 0.13, P < 0.01, respectively). Our findings reveal that male STEMI patients with early VT/VF are associated with elevated L5 levels. The gender-based discrepancy in early VT/VF predisposition might be due to compromised sodium channel trafficking, possibly linked with increased LDL electronegativity.

Gemfibrozil Improves Microcirculatory Oxygenation of Colon and Liver without Affecting Mitochondrial Function in a Model of Abdominal Sepsis in Rats.

Recent studies observed, despite an anti-hyperlipidaemic effect, a positive impact of fibrates on septic conditions. This study evaluates the effects of gemfibrozil on microcirculatory variables, mitochondrial function, and lipid peroxidation levels with regard to its potential role as an indicator for oxidative stress in the colon and liver under control and septic conditions and dependencies on PPARα-mediated mechanisms of action. With the approval of the local ethics committee, 120 Wistar rats were randomly divided into 12 groups. Sham and septic animals were treated with a vehicle, gemfibrozil (30 and 100 mg/kg BW), GW 6471 (1 mg/kg BW, PPARα inhibitor), or a combination of both drugs. Sepsis was induced via the colon ascendens stent peritonitis (CASP) model. Then, 24 h post sham or CASP surgery, a re-laparotomy was performed. Measures of vital parameters (heart rate (HR), mean arterial pressure (MAP), and microcirculation (µHbO2)) were recorded for 90 min. Mitochondrial respirometry and assessment of lipid peroxidation via a malondialdehyde (MDA) assay were performed on colon and liver tissues. In the untreated sham animals, microcirculation remained stable, while pre-treatment with gemfibrozil showed significant decreases in the microcirculatory oxygenation of the colon. In the CASP animals, µHbO2 levels in the colon and the liver were significantly decreased 90 min after laparotomy. Pre-treatment with gemfibrozil prevented the microcirculatory aberrations in both organs. Gemfibrozil did not affect mitochondrial function and lipid peroxidation levels in the sham or CASP animals. Gemfibrozil treatment influences microcirculation depending on the underlying condition. Gemfibrozil prevents sepsis-induced microcirculatory aberrances in the colon and liver PPARα-independently. In non-septic animals, gemfibrozil impairs the microcirculatory variables in the colon without affecting those in the liver.

ISOMETRIC HAND GRIP EXERCISE: CAN IT BE AN ALTERNATIVE TO CONVENTIONALAEROBIC EXERCISE TO REDUCE BLOOD PRESSURE?

INTRODUCTION :Isometric hand grip exercise (IHG) is a form of static resistance exercise. Such exercises are characterized by a change in muscle tension while the muscle length remains constant. Aerobic isotonic exercise has plethora of proved benets over blood pressure but needs dedicated time and willingness to perform it. In comparison to Aerobic isotonic exercise, Isometric hand grip exercise is a simple form of exercise which needs little adjustment in daily routine.OBJECTIVE:To determine the immediate effect of graded isometric hand grip exercise on Systolic and Diastolic blood pressure.MATERIALS AND METHODS:Present study was conducted on 82 healthy adults aged between 18 to 25 years including both sexes. Subjects having any form of hypertension, other cardio-vascular co-morbidities and any diseases involving wrist joint and palmar diseases are excluded from this study. Systolic and Diastolic Blood pressure is measured single handedly at resting condition, after 30% Maximum voluntary contractions (MVC), after high load contractions, Post sham, and 1 hour post sham.CONCLUSION:It is revealed that after 30% MVC and post high load ,SBP and DBP is signicantly increased compared to resting condition but after post sham, SBP and DBP is signicantly decreased in both sexes.There is no signicant change found in 1 hour post sham condition.

Anodal transcranial direct current stimulation increases corticospinal excitability, while performance is unchanged.

Anodal transcranial direct current stimulation (a-tDCS) has been shown to improve bicycle time to fatigue (TTF) tasks at 70–80% of VO2max and downregulate rate of perceived exertion (RPE). This study aimed to investigate the effect of a-tDCS on a RPE-clamp test, a 250-kJ time trial (TT) and motor evoked potentials (MEP). Twenty participants volunteered for three trials; control, sham stimulation and a-tDCS. Transcranial magnetic stimulation was used to determine the corticospinal excitability for 12 participants pre and post sham stimulation and a-tDCS. The a-tDCS protocol consisted of 13 minutes of stimulation (2 mA) with the anode placed above the Cz. The RPE-clamp test consisted of 5 minutes ergometer bicycling at an RPE of 13 on the Borg scale, and the TT consisted of a 250 kJ (∼10 km) long bicycle ergometer test. During each test, power output, heart rate and oxygen consumption was measured, while RPE was evaluated. MEPs increased significantly by 36% (±36%) post a-tDCS, with 8.8% (±31%) post sham stimulation (p = 0.037). No significant changes were found for any parameter at the RPE-clamp or TT. The lack of improvement may be due to RPE being more controlled by afferent feedback during TT tests than during TTF tests. Based on the results of the present study, it is concluded that a-tDCS applied over Cz, does not enhance self-paced cycling performance.

A receptor-binding radiopharmaceutical for imaging of traumatic brain injury in a rodent model: [99mTc]Tc-tilmanocept

IntroductionBlood-brain barrier (BBB) disruption and subsequent neuro-inflammation occur following traumatic brain injury (TBI), resulting in a spectrum of human nervous system disorders. [99mTc]Tc-tilmanocept is a receptor-binding radiopharmaceutical FDA-approved for sentinel lymph node mapping. We hypothesize that after an intravenous (i.v.) injection, [99mTc]Tc-tilmanocept, will traverse a disrupted BBB and bind to CD206-bearing microglial cells. MethodsAge-matched mice were divided into three groups: 5-days post TBI (n = 4), and 5-days post sham (n = 4), and naïve controls (n = 4). IRDye800CW-labeled [99mTc]Tc-tilmanocept (0.15 nmol per gram body weight) and FITC-labeled bovine serum albumin (FITC-BSA) were injected (i.v.) into each mouse. Mice were imaged with a high-resolution gamma camera for 45 min. Immediately after imaging, the brains were perfused with fixative, excised, imaged with a fluorescence scanner, assayed for radioactivity, and prepared for histology. ResultsIn vivo nuclear imaging, ex vivo fluorescence imaging, ex vivo gamma well counting, and histo-microscopy demonstrated enhanced tilmanocept uptake in the TBI region. The normalized [99mTc]Tc-tilmanocept uptake value from nuclear imaging and the maximum pixel intensity from fluorescence imaging of the TBI group (1.12 ± 0.12 and 2288 ± 278 a.u., respectively) were significantly (P < 0.04) higher than the sham group (0.64 ± 0.28 and 1708 ± 101 a.u., respectively) and the naive group (0.76 ± 0.24 and 1643 ± 391 a.u., respectively). The mean [99mTc]Tc-tilmanocept scaled uptake in the TBI brains (0.058 ± 0.013%/g) was significantly (P < 0.010) higher than the scaled brain uptake of the sham group (0.031 ± 0.011%/g) and higher (P = 0.04) than the uptake of the naïve group (0.020 ± 0.002%/g). Fluorescence microscopy demonstrated increased uptake of the IRDye800CW-tilmanocept and FITC-BSA in the TBI brain regions. Conclusion[99mTc]Tc-tilmanocept traverses disrupted blood-brain barrier and localizes within the injured region. Advances in knowledge and implications for patient care[99mTc]Tc-tilmanocept could serve as an imaging biomarker for TBI-associated neuroinflammation and any disease process that involves a disruption of the blood-brain barrier.

P230 Localizing the effects of anodal tDCS: A TMS-EEG study

Introduction In the last decade, transcranial direct current stimulation (tDCS) has been increasingly used in experimental and clinical settings. Nevertheless, its neurophysiological underpinnings still remain unclear. Moreover, under debate is how and to what extent these effect spread through brain pathways. Objectives In this study, we explored local and global cortical excitability and time–frequency modulation after active and sham tDCS by means of an integrated Transcranial Magnetic Stimulation and Electroencephalography (TMS-EEG) system. Materials and methods Fourteen healthy subjects took part in the experiment. Single pulse TMS was delivered over the left posterior parietal cortex (PPC), before, and after 15 min of anodal tDCS over the right PPC. 180 trials was delivered in each session, while EEG was concurrently recorded from 60 channels. Six subjects performed an additional session receiving sham tDCS. For each session, indexes of global and local cerebral excitability were obtained, computed as global and local mean field power (GMFP and LMFP) on mean TMS-evoked potentials (TEPs). LMFP were computed in six clusters of electrodes placed over the left and right frontal, parietal and temporal regions. Additionally, source analysis was performed computing Significant Current Density both globally and locally on Brodmann areas 6, 7 and 21. Moreover, we computed and index for Current Spread, to estimate where the current peak occurred in the pre and post stimulation conditions. Finally, time–frequency analyses were run to investigate how the natural frequencies of the stimulated area were affected by tDCS. Results Concerning results recorded at the sensor level, GMFP increased, compared to baseline, after active tDCS, while no difference was found between pre and post sham tDCS. LMFP increased after the end of stimulation in parietal and frontal clusters bilaterally, while no difference was found in the temporal clusters. Source modeling confirmed GMFP and LMFP results. Frontal and parietal regions (namely BA 6 and 7) increased in cortical current density after real tDCS. Conclusion Anodal tDCS induces a widespread increase of cortical excitability, both during and after the end of the stimulation, modulating a fronto-parietal network, likely following structural connections.

Burn injury induces histopathological changes and cell proliferation in liver of rats.

To investigate effects of severe burn injury (BI) in rat liver through the histopathological and inflammatory markers analysis. Forty-two male Wistar rats were distributed into two groups, control (C) and subjected to scald BI (SBI). The animals were euthanized one, four and 14 d post sham or 45% of the total body surface BI. Liver fragments were submitted to histopathological, morphoquantitative (hepatocyte area and cell density), ciclooxigenase-2 (COX-2) immunoexpression, and gene expression [real-time polymerase chain reaction for tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS) and caspase-3] methods. Histopathological findings showed inflammatory process in all periods investigated and hepatocyte degeneration added to increased amount of connective tissue 14 d post injury. Hepatocyte area, the density of binucleated hepatocytes and density of sinusoidal cells of SBI groups were increased when compared with control. COX-2 immunoexpression was stronger in SBI groups. No differences were found in TNF-α, iNOS and caspase-3 gene expression. BI induces histopathological changes, upregulation of COX-2 immunoexpression, and cell proliferation in liver of rats.

Efficacy of cathodal transcranial direct current stimulation in drug-resistant epilepsy: a proof of principle.

It has been proved that Transcranial DCS (tDCS) can modulate cortical excitability, enhancing or decreasing, respectively by anodal or cathodal polarity. The short-term and lasting alterations induced by tDCS are strictly related to the charge density, duration of stimulation and the depth of neuron below the skull. Epilepsy represents a pathophysiological model of unbalanced relation between cortical excitation and inhibition. In this line, tDCS can be exploited to counterbalance the neuronal hyper-excitation through electric neural modulation. This paper aims at providing the efficacy of cathodal tDCS in reducing seizures' frequency in drug-resistant focal epilepsy. The study was single blind and sham-controlled with an observation period of one month during which the patients or the caregivers provided a detailed seizures' calendar (frequency as n°/week; basal, post sham and post tDCS). Patients received sham or real tDCS treatment on the 8th and 22th days. Two patients affected by focal resistant epilepsy were enrolled. They both underwent a consistent reduction of the seizures'frequency: about 70 % for Patient 1 and about 50% for Patient 2. This study represents the proof that cathodal tDCS may be efficient in reducing seizures'frequency in focal resistant epilepsy.

P 206. Monitoring short term effects of repetitive transcranial magnetic stimulation (TMS) by TMS-evoked potentials in children

Repetitive transcranial magnetic stimulation (rTMS) allows non-invasive stimulation of the human brain. However, no suitable marker has yet been established to monitor the immediate rTMS effects on cortical areas in children. TMS-evoked EEG potentials (TEPs) could present a well-suited marker for real-time monitoring. Monitoring is particularly important in children where only few data about rTMS effects and safety are currently available. In a single-blind sham-controlled study, 25 school-aged children with ADHD received subthreshold 1 Hz-rTMS to the primary motor cortex. The TMS-evoked N100 was measured by 64-channel-EEG pre, during and post rTMS, and compared to sham stimulation as an intraindividual control condition. TMS-evoked N100 amplitude decr eased during 1 Hz-rTMS and, at the group level, reached a stable plateau after approximately 500 pulses. N100 amplitude to supra-threshold single pulses post rTMS confirmed the amplitude reduction in comparison to the pre-rTMS level while sham stimulation had no influence. EEG source analysis indicated that the TMS-evoked N100 change reflected rTMS effects in the stimulated motor cortex. Amplitude changes in TMS-evoked N100 and MEPs (pre versus post 1 Hz-rTMS) correlated significantly, but this correlation was also found for pre versus post sham stimulation. The TMS-evoked N100 represents a promising candidate marker to monitor rTMS effects on cortical excitability in children with ADHD. TMS-evoked N100 can be employed to monitor real-time effects of TMS for subthreshold intensities. Though TMS-evoked N100 was a more sensitive parameter for rTMS-specific changes than MEPs in our sample, further studies are necessary to demonstrate whether clinical rTMS effects can be predicted from rTMS-induced changes in TMS-evoked N100 amplitude and to clarify the relationship between rTMS-induced changes in TMS-evoked N100 and MEP amplitudes. The TMS-evoked N100 amplitude reduction after 1 Hz-rTMS could either reflect a globally decreased cortical response to the TMS pulse or a specific decrease in inhibition.

Are media warnings about the adverse health effects of modern life self-fulfilling? An experimental study on idiopathic environmental intolerance attributed to electromagnetic fields (IEI-EMF)

ObjectiveMedically unsubstantiated ‘intolerances’ to foods, chemicals and environmental toxins are common and are frequently discussed in the media. Idiopathic environmental intolerance attributed to electromagnetic fields (IEI-EMF) is one such condition and is characterized by symptoms that are attributed to exposure to electromagnetic fields (EMF). In this experiment, we tested whether media reports promote the development of this condition. MethodsParticipants (N=147) were randomly assigned to watch a television report about the adverse health effects of WiFi (n=76) or a control film (n=71). After watching their film, participants received a sham exposure to a WiFi signal (15min). The principal outcome measure was symptom reports following the sham exposure. Secondary outcomes included worries about the health effects of EMF, attributing symptoms to the sham exposure and increases in perceived sensitivity to EMF. Results82 (54%) of the 147 participants reported symptoms which they attributed to the sham exposure. The experimental film increased: EMF related worries (β=0.19; P=.019); post sham exposure symptoms among participants with high pre-existing anxiety (β=0.22; P=.008); the likelihood of symptoms being attributed to the sham exposure among people with high anxiety (β=.31; P=.001); and the likelihood of people who attributed their symptoms to the sham exposure believing themselves to be sensitive to EMF (β=0.16; P=.049). ConclusionMedia reports about the adverse effects of supposedly hazardous substances can increase the likelihood of experiencing symptoms following sham exposure and developing an apparent sensitivity to it. Greater engagement between journalists and scientists is required to counter these negative effects.

Monitoring cortical excitability during repetitive transcranial magnetic stimulation in children with ADHD: a single-blind, sham-controlled TMS-EEG study.

BackgroundRepetitive transcranial magnetic stimulation (rTMS) allows non-invasive stimulation of the human brain. However, no suitable marker has yet been established to monitor the immediate rTMS effects on cortical areas in children.ObjectiveTMS-evoked EEG potentials (TEPs) could present a well-suited marker for real-time monitoring. Monitoring is particularly important in children where only few data about rTMS effects and safety are currently available.MethodsIn a single-blind sham-controlled study, twenty-five school-aged children with ADHD received subthreshold 1 Hz-rTMS to the primary motor cortex. The TMS-evoked N100 was measured by 64-channel-EEG pre, during and post rTMS, and compared to sham stimulation as an intraindividual control condition.ResultsTMS-evoked N100 amplitude decreased during 1 Hz-rTMS and, at the group level, reached a stable plateau after approximately 500 pulses. N100 amplitude to supra-threshold single pulses post rTMS confirmed the amplitude reduction in comparison to the pre-rTMS level while sham stimulation had no influence. EEG source analysis indicated that the TMS-evoked N100 change reflected rTMS effects in the stimulated motor cortex. Amplitude changes in TMS-evoked N100 and MEPs (pre versus post 1 Hz-rTMS) correlated significantly, but this correlation was also found for pre versus post sham stimulation.ConclusionThe TMS-evoked N100 represents a promising candidate marker to monitor rTMS effects on cortical excitability in children with ADHD. TMS-evoked N100 can be employed to monitor real-time effects of TMS for subthreshold intensities. Though TMS-evoked N100 was a more sensitive parameter for rTMS-specific changes than MEPs in our sample, further studies are necessary to demonstrate whether clinical rTMS effects can be predicted from rTMS-induced changes in TMS-evoked N100 amplitude and to clarify the relationship between rTMS-induced changes in TMS-evoked N100 and MEP amplitudes. The TMS-evoked N100 amplitude reduction after 1 Hz-rTMS could either reflect a globally decreased cortical response to the TMS pulse or a specific decrease in inhibition.

Short-term transcutaneous electrical nerve stimulation after cardiac surgery: effect on pain, pulmonary function and electrical muscle activity

This study aimed to evaluate the effectiveness of transcutaneous electrical nerve stimulation (TENS) for treatment of postoperative pain in patients who underwent cardiac surgery. In addition, we sought to determine whether TENS would be related to improved pulmonary function and muscle electrical activity in this patient population. Forty-five patients, 32 males and 13 females, aged 41-74 years were randomly allocated to receive TENS (n=23) or sham treatment (n=22) during 4 h on the third postoperative day. A 0-10 visual analogic scale was used to assess pain; lung function was evaluated by spirometry and surface electromyography (n=10 in each group) was used to quantify electrically-induced muscle activity (trapezius and pectoralis major). TENS was associated with significant reductions on spontaneous and cough-induced postoperative pain as compared to sham (P<0.05). There was also improvement in chest wall-pulmonary mechanics after TENS with proportional increases in tidal volume and vital capacity (P<0.05). In addition, electrical activity of both muscle groups was enhanced after TENS, but not post sham (P<0.05). TENS is a valuable strategy to alleviate postoperative pain following cardiac surgery with positive effects on pulmonary ventilatory function and electrical activity of thoracic and girdle muscles.

Free radical scavenging and radioprotective activity of dehydrozingerone against whole body gamma irradiation in Swiss albino mice

Dehydrozingerone (DZ) was explored for in vitro– in vivo antioxidant potential and in vivo radioprotective activity against whole body gamma irradiation in Swiss albino mice. DZ scavenged the ABTS (2, 2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) and DPPH (1, 1-dipehnyl-2-picrylhydrazyl) free radicals at room temp. DZ reduced Fe (III) to Fe (II) at pH 7.4 and scavenged the NADH/phenazine methosulfate generated superoxide radical in cell free system. DZ also scavenged the nitric oxide radical generated by sodium nitroprusside. To evaluate the radioprotective activity, mice were exposed to whole body gamma irradiation 30 min after the drug treatment at a dose rate of 1.66 Gy/min. Pretreatment with DZ 75, 100 and 125 mg/kg, i.p. reduced the radiation induced mortality and increased the mean survival times (MSTs). An i.p. dose of DZ 100 mg/kg was found the most effective dose in preventing radiation sickness and increasing the MST. Pretreatment DZ100 mg/kg maintained the spleen index (spleen weight/body weight × 100) and stimulates the endogenous spleen colony forming units (CFU). Pretreatment with DZ100 mg/kg maintained the villus height close to normal, prevents mucosal erosion and basement membrane damage in irradiated mice jejunum. However, no significant reductions in dead, inflammatory and mitotic cells were observed in DZ pretreated mice, but there was an increased in crypt cells proliferation and regeneration. Pretreatment with DZ100 mg/kg significantly elevated the endogenous antioxidant enzymes (GSH, GST and SOD) in mice at 2, 4 and 8 h post sham irradiation. Radiation induced fall in endogenous antioxidant enzymes was significantly prevented by DZ pretreatment. Pretreatment with DZ 75 and 100 mg/kg reduced the radiation induced micronucleated polychromatic erythrocytes (MPCE) and normochromatic erythrocytes (MNCE) in mice bone marrow. DZ also maintained the polychromatic erythrocytes (PCE) and normochromatic erythrocytes (NCE) ratio ( P/ N ratio) in irradiated mice. Dose modifying factor (DMF) was calculated by using the graded radiation dose (8.0, 9.0, 9.5 and 10 Gy). DZ 100 mg/kg elevated radiation LD 50 from 9.1 to 10.0 Gy, indicating the DMF of 1.09.

Bigendothelin-1 (1-21) fragment during early sepsis modulates tau, p38-MAPK phosphorylation and nitric oxide synthase activation

Earlier we have demonstrated that inhibition of endothelin biosynthesis ameliorates endotoxemia-induced inducible nitric oxide synthase (iNOS) activation and phosphorylation of p38-mitogen activated protein kinase (pp38-MAPK). Therefore, in the present study, we tested the hypothesis that activation of endothelin (ET)-1 biosynthesis using bigET-1 during early sepsis would upregulate iNOS and affect myocardial function in the rat. Male Sprague-Dawley rats (350-400 g) were anesthetised using Nembutal (50 mg/kg, i.p.) and jugular vein, tail artery (Mean arterial pressure, MAP) and right carotid arteries (advanced to left ventricle, LV) were cannulated. The rats were randomly divided into saline-, bigET-1- and C-terminal fragment of bigET-1 (bigET-1(22-38))-treated groups. Sepsis was induced using i.p. injection of cecal inoculum obtained from a donor rat (200 mg/kg in 5 ml 5% sterile dextrose water, D5W). Sham animals received an i.p. injection of D5W (5 ml/kg). MAP and LVP were recorded and cardiodynamic parameters were calculated at 0, 2, 6, 12 and 24 h post sham or sepsis-induction. A significant elevation in LV isovolumic relaxation rate constant (tau), LV end diastolic pressure (LVEDP) and rate pressure product (RPP) was observed in vehicle-treated septic group at 24 h. BigET-1 significantly increased concentration of LV ET-1 both in sham and septic groups. BigET-1 elevated tau and LVEDP both in sham and septic animals as early as 12 h which persisted through 24 h. However, bigET-1(22-38) elevated LVEDP in septic group at 24 h but not in sham group. BigET-1 accentuated the levels of plasma nitric oxide byproduct (NOx) levels in both sham and septic animals at 6, 12 and 24 h. Sepsis increased myocardial iNOS at 24 h. BigET-1 significantly upregulated expression of myocardial iNOS and pp38-MAPK. The data suggest that increased substrate availability for ET-1 at the time of sepsis-induction contributes in diastolic dysfunction, iNOS activation and p38-MAPK phosphorylation.