HYPEROXIC PRECONDITIONING FAILS TO CONFER ADDITIONAL PROTECTION AGAINST ISCHEMIA-REPERFUSION INJURY IN ACUTE DIABETIC RAT HEART

Experimental studies show that detrimental effects of ischemia-reperfusion (I/R) injury can be attenuated by hyperoxic preconditioning in normal hearts, however, there are few studies about hyperoxia effects in diseased myocardium. The present study was designed to assess the cardioprotective effects of hyperoxia pretreatment (≥ 95 % O2) in acute diabetic rat hearts. Normal and one week acute diabetic rats were either exposed to 60 (H60) and 180 (H180) min of hyperoxia or exposed to normal atmospheric air (21 % O2). Then hearts were isolated immediately and subjected to 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size, cardiomyocyte apoptosis, enzymes release and ischemia induced arrhythmias were determined. Heart of diabetic control rats had less infarct size and decreased LDH and CK-MB release compared to normal hearts. 60 and 180 min of hyperoxia reduced myocardial infarct size and enzymes release in normal hearts. 180 min of hyperoxia also decreased cardiomyocytes apoptosis in normal state. On the other hand, protective values of hyperoxia were not significantly different in diabetic hearts. Moreover, hyperoxia reduced severity of ventricular arrhythmias in normal rat hearts whereas; it did not confer any additional antiarrhythmic protection in diabetic hearts. These findings suggest that diabetic hearts are less susceptible to ischemia-induced arrhythmias and infarction. Hyperoxia greatly protects rat hearts against I/R injury in normal hearts, however, it could not provide added cardioprotective effects in acute phase of diabetes

Involvement of neuronal pathways in the protective effects of hindlimb perconditioning during renal ischemia

Remote ischemic perconditioning (RPEC) is a therapeutic intervention that has been demonstrated to reduce renal ischemia/reperfusion (I/R) injury. However, the underlying renal protective mechanism remains unclear. The present study hypothesized that RPEC may utilize neural pathways to transfer the protective signal from the perconditioned hindlimb to the kidney. Following a right nephrectomy, rats were randomly allocated into five groups (n=6). The sham group underwent the surgical protocol only. In all other groups, the left renal pedicle was clamped for 45 min and reperfused for 24 h. The I/R control group then underwent 45 min ischemia and 24 h reperfusion (I/R) with no more intervention but the I/R‑NR control group underwent the ischemia and reperfusion followed by left femoral nerve (FN) and sciatic nerve (SN) resection. The RPEC group underwent ischemia and reperfusion followed by four cycles of 5 min occlusions of the left femoral artery and 5 min reperfusion. Finally, the RPEC‑NR group underwent ischemia and reperfusion followed by left FN and SN resection. Following 24 h, renal functional indices, plasma blood urea nitrogen (BUN) and creatinine (Cr) levels, urinary N‑acetyl‑β‑glucosaminidase (NAG) release and histopathological changes were assessed. Compared with the sham group, ischemia and reperfusion in the sham and I/R control groups resulted in renal dysfunction, indicated by significantly increased levels of BUN and Cr. This was accompanied by increased urinary NAG activity and morphological damage observed in control groups. In the RPEC group, renal histology and function were significantly improved compared with the control groups. However, FN and SN resection eliminated the protection of the kidney, which was induced by RPEC. In conclusion, remote hindlimb ischemic perconditioning reduced renal I/R injury in the rat kidney in a manner that potentially involves a neural pathway

Cardiotoxic and Arrhythmogenic Effects of Hemiscorpius lepturus Scorpion Venom in Rats

Background: Envenomation by Hemiscorpius lepturus is not painful and the clinical manifestations include bloody urine due to hemoglobinuria or hematuria, dermonecrotic reactions,cardiac arrhythmia and in minority of cases acute renal failure which may lead to death following disseminated intravascular coagulation in infants. Cardiac effects of envenomation by H. lepturus venom including inotropic, chronotropic and arrhythmogenic properties are not studied as now in rat hearts with Langendorff apparatus. Methods: Rat hearts were allowed to equilibrate in its buffer and cardiotropic plus arrhythmogenic effects induced by injection of different doses of H. lepturus venom were detected and recorded by computer acquisition based data in Langendorff apparatus. The neutralizing effects of Razi Institute antivenom and autonomic drugs were assayed in parallel studies. Results: Hemiscorpius lepturus venom (25 μg/100 l) treatment caused a negative inotropic (65.4 ± 3.2 versus 110.2 ± 3.4) and chronotropic effects (186.3 ± 4.2 versus 302 ± 6.3) in comparison to normal saline. Arrhythmogenic aspects including bradycardia, QRS widening and ST depression were induced by venom injection. Pre venom treatment (20 min) of Razi Institute antivenom (10 μl) neutralized cardiotropic effects but post venom injection (15 min later) had no therapeutic role. Pre (10 min before) and post (15 min after) injection of adrenaline (10 μl) neneutralized cardiotropic effects while pre venom injection (20 min) of propanolol (10 μl) had aggravating effects. Conclusion: Our study paves the way for further in vivo investigation of cardiovascular effects of this venom for finding suitable treatments instead of its ordinary antivenom medication in cardiogenic shock induced by the veno

Silymarin Administration Attenuates Cirrhotic-induced Cardiac Abnormality in the Rats: A Possible Role of β1-adrenergic Receptors and L-type Voltage-Dependent Calcium Channels

Background: Cirrhotic cardiomyopathy is a well-recognized cardiac dysfunction in cirrhotic patients. Studies have confirmed the protective effects of silymarin in different types of cardiac injury. This study aimed to examine the effectiveness and molecular mechanism of silymarin against myocardial dysfunction and hypertrophy in a rat model of cirrhosis. Methods: The experiment was performed at Alborz University of Medical Sciences (Karaj, Iran) during 2020-2021. Thirty-two male Wistar rats were randomly divided into four groups of Sham-operated (control group for surgical procedures), Bile Duct Ligated (BDL), and two Silymarin extract (SE)-treated groups of 300 and 600 mg/Kg/day. After 28 days, serum levels of AST, ALT, GGT, and ALP, liver histopathological status, as well as cardiac mechanical function, were assessed. Cardiac β1-adrenergic receptors (β1-AR), L-type voltage-dependent calcium channels (L-VDCC), and GATA4 mRNA expression were also determined using real-time RT-PCR. Data analysis was performed using the one-way ANOVA followed by Duncan’s multiple range test. Histological data has been analyzed with Kruskal-Wallis nonparametric test. The analysis was performed at P≤0.05. Results: BDL was associated with a significant elevation in serum AST, ALT, GGT, and ALP, development of necrosis and fibrosis of the liver texture, increased Heart Weight and Heart Weight to Body Weight ratio, enhanced cardiac mechanical function as well as a significant up-regulation of ventricular β1-AR and L-VDCC. Administration of SE600, but not SE300, significantly reduced the serum levels of the enzymes and alleviated signs of liver necrosis and fibrosis. Cirrhotic-induced cardiac dysfunction was also restored by SE600, but not by the lower dose. In addition, cardiac expression of the β1-AR and L-VDCC was down-regulated toward normal values by either higher or lower doses of the SE. Conclusion: Silymarin treatment in higher dose attenuated cirrhosis-associated cardiac remodeling and reduced cardiac mechanical dysfunctions

Delayed Effects of Remote Limb Ischemic Preconditioning on Maximum Oxygen Consumption, Lactate Release and Pulmonary Function Tests in Athletes and non-Athletes

Background: Remote Ischemic Preconditioning (RIPC) improves exercise performance, and since this phenomenon has two phases, the aim of the current study was to investigate the delayed effects of remote ischemic preconditioning on cardiopulmonary function in athletes and non-athletes. Materials and Methods: 25 male and female students were studied in two main athletes and non-athletes groups. RIPC was induced by using 3 cycles of alternative 5 minutes ischemia and 5 minutes reperfusion at arms of participants. Cardiopulmonary tests were measured before, after and 24 hours after inducing remote ischemic preconditioning. Maximum oxygen consumption (VO2max) estimated by using queen steps test. Results: Analysis of data demonstrated that delayed RIPC in non-athletes group caused significant improvement in Forced Expiratory Volume in one second (FEV1) and Maximum Voluntary Ventilation (MVV) and noticeable improvement in some other parameters of pulmonary function tests. Moreover, it decreased systolic blood pressure and heart rate and decreased lactate release in both groups especially athletes group but it had no significant effect on VO2max of both groups. Conclusion: Delayed RIPC improves cardiovascular function of athletes and pulmonary function of non-athletes subjects. Thus, it can be considered as a good replacement for doping to improve sports performance of subjects in sports tournaments

The cardiotoxicity of crude tentacle-only extract from the Persian Gulf jellyfish “Cassiopea sp.” in isolated rat heart

The upside-down jellyfish produces venom with some biological activities. In the present study, direct cardiotoxicity of crude tentacle-only extract from the Persian Gulf jellyfish “Cassiopea sp.” was assessed by a Langendorff isolated perfused rat heart system. Treatments were performed with concentrations of 50, 20, 10, 5, and 2.5 μg/ml of crude tentacle-only extract (CTOE) on isolated rat hearts for 60 min. Then, the hemodynamic parameters of heart rate, left ventricular end-diastolic pressure, left ventricular systolic pressure, left ventricular developed pressure, and coronary flow were evaluated. Lactate dehydrogenase (LDH) levels as well as histopathological examinations were also investigated. Based on the ECG findings, treatments in a dose-dependent pattern changed cardiac electrical activity and decreased coronary effluent. The higher concentrations of CTOE produced severe bradycardia, atrioventricular dissociation, complete atrioventricular block, and ultimately cardiac arrest. Ventricular end-diastolic pressure was also significantly increased by high concentrations of CTOE. At high CTOE concentrations, scatter lymphocytic infiltration and wavy fibers were found in the histopathological examinations. Treatment with concentrations of 2.5–10 μg/ml caused a considerable increase in LDH levels within 30 min compared with baseline levels. In conclusion, CTOE from the Persian Gulf upside-down jellyfish had significant direct cardiotoxicity effects on isolated rat heart

Repeated Daily Normobaric Hyperoxia: A Non-Pharmacological Strategy Against Gentamicin-Induced Nephrotoxicity

Background: Gentamicin (GM) induced nephrotoxicity is one of the most common causes of acute kidney injury and limits its administration. Evidence suggests that pre-treatment with oxygen increases the activity of antioxidant enzymes and protects tissues against different kinds of damage. In this study, the effect of daily normobaric heperoxia pre-treatment on alleviating gentamicin induced nephrotoxicity was investigated. Materials and Methods: Twenty-eight male Wistar rats were randomly divided into four groups (n=7): Control (room air); Gentamicin (100 mg/kg, IP, for 9 days); Hyperoxia60 (60 min daily pretreatment with 95% oxygen and then 100 mg/kg gentamicin, IP, for 9 days) and Hyperoxia180 (180 min daily pretreatment with 95% oxygen and then 100 mg/kg gentamicin, IP, for 9 days). Then 24 h urine was collected and on day 10, the rats were sacrificed for serum, urine and renal tissue sampling. Results: Results showed that hyperoxia significantly enhanced renal antioxidative capacity and decreased serum creatinine and renal failure index. Histological examination and SPECT scan also showed that tissue damage in the hyperoxia groups was lower compared to the gentamicin group. However, hyperoxia effect on body weight, kidney-to-body weight ratio, urine volume, blood urea nitrogen and glomerular filtration was not significant. Conclusion: Although pre-treatment with hyperoxia enhances the antioxidant capacity of renal tissue and improves some of the functional and histopathological parameters of the kidney, it failed to completely restore the adverse effects of gentamicin-induced nephrotoxicity. Thus, more studies are needed to determine the clinical effect of hyperoxia on gentamicin-induced nephrotoxicity

Effects of anabolic steroid nandrolone decanoate on ischemic preconditioning in isolated heart of sedentary rats

Background: Previous studies have shown that use of supraphysiologocal doses of anabolic adrogenic steroids (AAS) associated with detrimental cardiovascular effects including ventricular hypertrophy, increased susceptibility to ischaemia/reperfusion injury, impairment of exercise-induced cardioprotection and sudden cardiac death. The aim of the present study was to evaluate the impact of 8 weeks treatment of AAS nandrolone decanoate (10 mg/kg/week), on ischemic preconditioning (IPC) phenomena in isolated hearts of sedentary rats. Materials and Methods: Three groups of animals were studied in the present study. Control ischemia/reperfusion injury group (IR), 2- Ischemic preconditioned group before main test ischemia and reperfusion (IPC+IR), and 3- Nandrolone treated ischemic preconditioned group before main test ischemia and reperfusion (Nan+IPC+IR). After two months of nandrolone and/or its solvent, the isolated Langendorff perfused rat hearts were subjected to 30 min of ischemia followed by 120 min reperfusion. The IPC was induced by three cycles of 3-min occlusion and 3-min reperfusion of the left anterior descending coronary artery (LAD) before main test ischemia. Heart rate, left ventricular developed pressure (LVDP), rate pressure product (RPP), Max dp/dt, Min dp/dt and coronary flow were recorded during experiment. Infarction size was measured after 120 min reperfusion by TTC staining. Results: Eight weeks&rsquo; nandrolone treatment decreased body weight and increased cardiac to body weight ratio in treated rats. Nandrolone increased pre-ischemic base line cardiac function parameters in the rat hearts. Cardiac function recovery parameters in different time points during reperfusion were also greater in nandrolone treated rats compared to their respective controls. IPC decreased infarct size in the rats (P<0.05). Nandrolone could not significantly change the infarct size lowering effect of IPC in the rat heart. Conclusion: The present study revealed that chronic supraphysiological doses of AAS nandrolone, could not impair cardioprotective effects of ischemic preconditioning in isolated rats heart

Hemodynamic Changes in Experimentally Envenomed Anaesthetized Rats by Intravenous Injection of Hemiscorpius lepturus Venom

Background: We investigated the hemodynamic changes (Inotropic, chronotropic and arrhythmogenic) in intrave­nously envenomed anesthetized rats with Hemiscorpius lepturus venom. The neutralizing potencies of different drugs and commercial antivenom were assessed simultaneously. Methods: Different doses of the crude venom (100, 200 and 400μg/rat) were injected during five minutes via the femoral vein and cardiovascular changes were recorded in rats in Razi Institute Corporation, Karaj, Iran in 2017. The drugs (Atropine, lidocaine, propranolol and prazosin) were injected before the venom for determination of the coun­teracting effects. Different volumes (100, 500 and 1000µl) of the antivenom were pre envenomed to neutralize cardi­ovascular changes. Results: Temporary hypertension and bradycardia with no arrhythmogenic effects were depicted within twenty minutes. There was a difference in arterial pressure between the venom (400μg/rat) and the vehicle at 8 minutes (114.68±5.1mmHg versus 70.2±4.3mmHg). Elevation of the mean arterial pressure was inhibited by propranolol (2 mg/kg) and neutralized by prazosin (1mg/kg) while lidocaine (4mg/kg) and atropine (1mg/kg) had no effects. Pre­medication with Iranian commercial antivenom (1000μl) produced surprisingly temporary hypertension compared to the vehicle (140.84±4.5 versus 84.3±3.2). It had no neutralizing properties on blood pressure variation before the venom injection. Volume-expanded hypertension phenomenon was ruled out in a parallel study. Conclusion: This venom has vasoconstrictive effects in rats probably due to the presence of norepinephrine like ma­terials in its content or liberated from adrenal gland inhibited by prazosin premedication. The neutralizing effects of antivenom on venom-induced hypertension are questionable

Saffron Protection against Bleomycin-Induced Pulmonary Fibrosis in Rats

Background: Bleomycin-induced lung fibrosis has been accepted as an animal model for fibrosis in rats. The aim of this study was to evaluate the effects of saffron aqueous extract on this disorder paving the way for more investigation in treating idiopathic pulmonary fibrosis in human. Methods: Male Wistar rats (250–300 gr) were instilled a single dose of bleomycin (5 mg/kg) via intratracheal tube (n=6) in 2015. Sham group received normal saline. Saffron aqueous extract (50 mg/kg and 100 mg/kg) were given orally in two different treated groups with bleomycin for 28 days. Lung Indices was calculated at the end of this experiment. Lung segments fixed in 10% formaldehyde were used for pathological preparation with Hematoxylin & Eosin and trichrome staining. Results: The body weight was decreased and lung Indices increased in bleomycin group (P<0.5). Bleomycin administration increased myeloperoxidase, malondialdehyde and finally TNF-α in lung tissue homogenates (P<0.05) compared with sham group. The fibrotic process and thickening of alveolar septa in treated rats with bleomycin were increased by H&E and Masson Trichrome staining. Saffron treatment (50 and 100 mg/kg) attenuated the increase in MDA (264.43±10.4 nmol/g by the higher dose versus 378.4±18.1nmol/g), MPO (0.19±0.03 and 0.13± 0.04 IU/ml versus 0.39.2±0.05 IU/ml) and TNF-α level (18.42±3.7 ng/ml and14.31±3.6 ng /ml versus 35.32±4.2) in lung homogenates compared to bleomycin group (P<0.05). It decreased collagen accumulation and alveolar destructive patterns in pulmonary fibrosis. Conclusion: This study introduces saffron as novel anti-fibrotic agent against bleomycin-induced fibrosis due to histological examinations and preventive effects on destructive enzyme release in rats