ISO-treated Rats Research Articles

Formononetin attenuates isoproterenol‐induced cardiac toxicity in rats owing to its antioxidant, anti‐inflammatory and anti‐apoptotic activity

IntroductionA high rate of mortality and morbidity is associated with myocardial infarction (MI), indicating a need to hunt for newer treatment modalities. Formononetin (FMN) is a dietary flavonoid with remarkable antioxidant and anti‐apoptotic properties. Therefore, the aim of this study was to evaluate the ability of FMN in attenuating isoproterenol (ISO) induced oxidative stress and myocardial infarction.MethodsA total of 48 Male Wistar rats were administered either FMN (5, 10 or 20 mg/kg/day, i.p.) or vehicle for 15 days along with subcutaneous ISO, 85 mg/kg for 2 consecutive days i.e. 13th and 14th days. On the 15th day, rats were anaesthetized followed by cannulation of right coronary artery to record hemodynamic parameters. Blood sample was collected and heart was excised to evaluate for biochemical, histopathological, ultrastructural and immuohistochemical studies.ResultsISO‐treated rats demonstrated disturbed hemodynamic. There was also a significant decrease in antioxidant enzyme levels and increase in the level, of malondialdehyde, serum TNF‐α and IL‐6. The cardiac injury markers like creatine kinase‐MB and lactate dehydrogenase were increased in the serum. Additionally, immunohistochemistry displayed an increased Bax/Bcl‐2 ratio in the myocardium. Histopathological and ultrastructural studies support the protective effect of FMN in ISO‐induced myocardial infarcted rats.ConclusionFMN alleviates myocardial damage in ISO induced cardiac injury by preserving hemodynamic and biochemical function and reducing inflammation due to its anti‐apoptotic, anti‐inflammatory and antioxidant activities.Support or Funding InformationThe Project has been funded by the AIIMS, DelhiThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

HYDROALCOHOLIC EXTRACT OF MATRICARIA CHAMOMILLA LINN. AMELIORATES LIPIDS, LIPOPROTEINS, AND PARAOXONASE IN ISOPROTERENOL-INDUCED MYOCARDIAL INFARCTION IN WISTAR RATS

Objective: The objective of this study was to evaluate the effect of the hydroalcoholic extract of Matricaria Chamomilla Linn. (CHAE) on lipids, lipoproteins, and antioxidants activity in isoproterenol (ISO)-induced myocardial infarcted rats.
 Methods: ISO (85 mg/kg, s.c.)-induced myocardial infarction for 2 consecutive days at an interval of 24 h. Rats were pretreated with CHAE (100 and 200 mg/kg, oral) for a period of 20 days and ISO was injected on 21 and 22 days at 24 h intervals and after 24 h, blood was collected through retro-orbital plexus for the estimation of lipids, lipoproteins, and antioxidants assay.
 Results: In the present study, ISO caused a significant increase in the concentration of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), very LDL-C, and lipid peroxidation whereas a significant decrease in the concentration of high-density lipoprotein-C. ISO administration also significantly decreased the activities of paraoxonase (PON) enzyme. Oral pre-treatment of CHAE at doses of 100 and 200 mg/kg body weight (bw) for 20 days challenged with a concurrent injection of ISO (85 mg/kg bw) on 21 and 22 days significantly attenuated these alterations and restored the levels of lipids and lipoproteins. In addition, CHAE significantly elevated the serum antioxidants enzyme PON and catalase (CAT).
 Conclusion: The report revealed that pre-treatment with CHAE ameliorated lipid and lipoprotein and increased the antioxidant PON and CAT activity and decreased LPO level in ISO-treated male albino Wistar rats.

Protective effect of ginsenoside Rd against isoproterenolinduced myocardial infarction in Wistar rats

Purpose: To investigate the protective effect of ginsenoside Rd (GRd) against isoproterenol (ISO)- induced myocardial infarction in a rat model.Methods: Forty healthy male rats were equally divided into four groups (10/group). Rats in the control group received only saline, whereas rats in GRd group were intraperitoneally (i.p.) injected GRd at a dose of 50 mg/kg body weight (b.wt.) for 14 days. The other two groups were ISO-treated rats. One group (MI model) received ISO at a dose of 80 mg/kg b.wt i.p. for 2 days, while the other group (GRd + ISO group) was pretreated with GRd at a dose of 50 mg/kg for 14 days prior i.p. administration of the same dose of ISO.Results: Treatment with GRd (for 14 days) prior to ISO exposure resulted in significant increase in the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) as well as significant decreases in heart-to-body weight ratio, infarct size, inflammatory markers {tumour nectosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB), interleukin 1 beta (IL-1β) and interleukin 6 (IL-6)}, relative to ISO-treated rats (p > 0.05). In addition, prior exposure to ISO led to significant elevation in malondialdehyde (MDA), cardiac troponin T (cTnT), creatine kinase (CPK), lactate dehydrogenase (LDH) and apoptotic markers (caspase-3 and caspase-9). However, pre-treatment with GRd reversed the ISO-induced histopathological changes (necrosis/oedema and altered cardiac fibres) in cardiac tissue.Conclusion: These results demonstrate that GRd ameliorates ISO-induced cardiotoxicity in rats via upregulation of the activities of antioxidants, and suppression of inflammatory and apoptotic biomarkers. Thus, GRd has cardio-protective properties.Keywords: Ginsenoside Rd, Myocardial infarction, Apoptosis, Inflammation, Antioxidants

Resveratrol protects against isoproterenol induced myocardial infarction in rats through VEGF-B/AMPK/eNOS/NO signalling pathway

According to our previous results, resveratrol (RSV, 3, 5, 4-trihydroxystilbene), a naturally polyphenolic phytoalexin, could attenuate myocardial ischemia/reperfusion injury through up-regulation of vascular endothelial growth factor B (VEGF-B) in isolated rat heart or H9c2 cells. However, the molecular mechanism remains unclear. In this study, we investigated the protective effect of RSV on myocardial infarction (MI) in rats and further explored the underlying signal pathway after VEGF-B. Rats received RSV or normal saline by intragastric administration for 7 consecutive days and followed by subcutaneously isoproterenol (ISO) or normal saline injections for another 2 days. We found that RSV pretreatment prevented the unfavourable changes in HW/BW, HW/TL, infarct size, and cell apoptosis in ISO-treated rats. Moreover, superoxide and malondialdehyde (MDA) production were significantly reduced and superoxide dismutase (SOD) was increased by RSV in ISO-treated rats. Furthermore, it showed that RSV pretreatment increased VEGF-B, p-eNOS and p-AMPK expression, and NO production in ISO-treated rats. Using Neonatal Rat Ventricular Myocytes (NRVM), we found that VEGF-B siRNA could abolish the cardio-protective effect of RSV. The enhanced ratios of eNOS phosphorylation to eNOS expression induced by RSV were markedly reversed by VEGF-B siRNA in NRVM also. Meantime, we found that the effect of VEGF-B knock-down on eNOS activation was rescued by AMPK activator AICAR. L-NAME, a NOS inhibitor, could inhibit RSV enhanced eNOS phosphorylation but had no effect on VEGF-B expression in NRVM or in rats. Collectively, our results indicate that RSV exerts cardio-protection from ISO-induced myocardial infarction through VEGF-B/AMPK/eNOS/NO signalling pathway.

Angiotensin (1-7) and Apelin co-therapy: New strategy for heart failure treatment of rats.

Objective:Isoproterenol (ISO)–induced heart failure is a standardized model for the study of beneficial effects of various drugs. Both apelin and angiotensin 1–7 have a cardiac protective effect. We assumed that co–therapy with apelin and angiotensin 1–7 [Ang (1–7)] may have synergistic cardioprotective effects against isoproterenol-induced heart failure.Methods:The rats were randomly assigned to one of eight groups, 7 animals in each, as follows: (1) Control I (saline; IP injection), (2) Control II (saline; via mini-osmotic pump), (3) ISO (5 mg/kg; IP), (4) Apelin (20 μg/kg; IP), (5) Ang (1–7) (30 μg/kg/day; via mini-osmotic pump), (6) Apelin+ISO, (7) Ang (1–7)+ISO, and (8) Apelin+Ang (1–7)+ISO. Rat myocardial injury was induced by intraperitoneal injection of 5 mg/kg of ISO for 10 days. Apelin and Ang (1–7) were administered 30 minutes before the ISO injection.Results:A decrease in the systolic blood pressure [SBP (p<0.001)], diastolic blood pressure [DBP (p=0.024)], left ventricular systolic pressure [LVSP (p<0.001)], left ventricular contractility [dP/dt max. (p<0.001)], relaxation [dP/dt min. (p<0.001)], and an increase in left ventricular end-diastolic pressure [LVEDP, (p<0.001)] were observed in ISO-treated rats. Plasma LDH and myocardial and plasma MDA were higher in the ISO heart than in controls (p<0.001). Histopathological examination of the cardiac tissue showed myocardial fibrosis and leukocyte infiltration in ISO-treated rats as compared to control. Co-therapy with apelin and Ang (1–7) was more effective than either agent used alone in restoring these parameters to that of control rats.Conclusion:The results of this study showed that the combination of apelin and Ang (1–7) had a more cardioprotective effect than either used alone against ISO-induced heart failure, and co–therapy may be a useful treatment option for myocardial injuries and heart failure.

Decalepis hamiltonii and its bioactive compounds protects isoproterenol-induced myocardial oxidative stress in rats

Background: Decalepis hamiltonii (Dh), a climbing shrub belonging to the family Apocynaceae, is consumed for its health-promoting properties. Objective: The present study was designed to evaluate the cardioprotective potential of Dh extract and its bioactive compounds on region-specific responses against isoproterenol (ISO)-induced myocardial injury in male Wistar rats. Materials and Methods: Rats were orally supplemented with ellagic acid (50 mg/kg body weight [BW]), 4-hydroxy isophthalic acid (30 mg/kg BW), and Dh extract (100 mg/kg BW) for 30 days, and they were subsequently administered (intraperitoneally) with ISO (150 mg/kg BW) for the last 2 days. Results: ISO-treated rats showed a significant increase in serum lipid profile, markers of cardiac damage, and decreased antioxidant status. Supplemented groups showed improved lipid profile, reduced serum marker enzymes, and enhanced antioxidant status in ISO-administered rats. Histopathological studies further confirmed the protective effect of Dh extract against ISO-induced myocardial infarction (MI). Conclusion: Our results demonstrated that Dh extract and its compounds efficiently ameliorated ISO-induced MI in rats.

Protocatechuic aldehyde protects against isoproterenol-induced cardiac hypertrophy via inhibition of the JAK2/STAT3 signaling pathway.

Protocatechuic aldehyde (PCA) is a natural compound found in the Chinese herb Salvia miltiorrhiza. It has been shown to possess multiple biological activities and to protect the cardiovascular system against oxidative stress, inflammation, and atherosclerosis. However, the potential effects of PCA on cardiac hypertrophy remain to be investigated. In this study, we showed that isoproterenol treatment (ISO, 10μM for 24h) induced significant hypertrophy in cultured neonatal rat cardiomyocytes, as manifested by enlargement of cell surface area (1.74-fold greater than that of the control, p < 0.05) and upregulation of hypertrophic gene markers (2.44- to 2.75-fold increase in ANF and β-MHC protein expression, p < 0.05). These ISO-induced hypertrophic responses were attenuated by PCA (50-200μM, p < 0.05). Furthermore, intragastric administration of PCA (10-100mg/kg/day) ameliorated cardiac hypertrophy in ISO-treated rats (1.5mg/kg/day, s.c., for 7days). PCA inhibited the abnormal changes in echocardiographic parameters and suppressed ISO-induced increase in cardiomyocyte cross-sectional area and collagen content (p < 0.05). It also ameliorated ISO-mediated elevation of HW/BW, LVW/BW, and HW/TL ratios (p < 0.05). Mechanistically, ISO facilitated JAK2 and STAT3 phosphorylation, increased STAT3 nuclear translocation, and enhanced STAT3 transcriptional activity. All these changes were attenuated by PCA. Taken together, these findings showed that PCA could protect against cardiac hypertrophy induced by ISO possibly via inhibition of the JAK2/STAT3 signaling pathway, suggesting the potential of PCA as a therapeutic candidate for hypertrophy-associated heart diseases.

Paradoxical effects of atorvastatin in isoproterenol-induced cardiotoxicity in rats: Role of oxidative stress and inflammation

Atorvastatin (ATV) was previously shown to improve oxidative stress, inflammation and endothelial dysfunction in several experimental and clinical studies yet other studies have reported a pro-oxidant and damaging effect upon ATV administration. The present study was directed to investigate the effect of ATV pre- and post-treatment in isoproterenol (ISO)-induced cardiotoxicity in rats. Myocardial damage was induced by ISO (5 mg/kg/day, s.c.) for 1 week. ATV (10 mg/kg/day, p.o.) was given for 2 weeks starting 1 week before or after ISO administration. ISO-treated rats showed significant alterations in electrocardiographic recordings, serum creatine kinase-MB (CK-MB) level as well as oxidative stress and inflammatory biomarkers. Moreover, ISO administration resulted in endothelial dysfunction and significant histopathological damage. Pre-treatment with ATV aggravated ISO-induced cardiotoxicity. On the other hand, ATV post-treatment succeeded to significantly improve oxidative stress and inflammatory biomarkers, endothelial dysfunction and myocardial degeneration. These results suggest that ATV might produce a synergistic pro-oxidant effect if given before or along with another pro-oxidant (ISO). Thus, caution should be applied upon the use of statin as a prophylactic therapy for primary cardiovascular disease prevention.

Sacubitril and valsartan protect from experimental myocardial infarction by ameliorating oxidative damage in Wistar rats

ABSTRACTBackground: Sacubitril (SAC), a neprilysin inhibitor prevent degradation of neprilysin and activate cGMP signaling pathways leading to rise in blood volume concurrent to blood pressure by means of vasoactive peptides, adrenomedullin, and bradykinin.Objective: The aim of this study was to evaluate the anti-ischemic effects of SAC through inhibiting neprilysin in isoproterenol (ISO) induced myocardial infarction (MI) in Wistar albino rats. ISO (85 mg/kg) was injected subcutaneously at the end of 14 days pre-treatment with SAC and valsartan (VAL).Result: Biochemical investigation revealed that SAC along with VAL significantly prevented the antioxidant enzymes (SOD, Catalase, GR, GPx, GST, and GSH) degradation and malondialdehyde (MDA) induced by ISO intoxication in Wistar rats. Along with this, cardiac biomarkers (LDH, CK-MB, ALT, AST, and ALP) were also significantly ameliorated by SACand VAL in ISO-treated rats. Concurrently, decreased infarction area (IA)and marked reduction in myofibril damage by SACand VAL further supported its protective benefits in MI.Conclusion: Taken together, the results suggest that inhibition of enzyme neprilysin alleviated the ISO induces myocardial damage mediated by its strong antioxidant potential.

Catalpol pretreatment attenuates cardiac dysfunction following myocardial infarction in rats.

Objective:To investigate the effects and mechanisms of catalpol on cardiac function in rats with isoproterenol (ISO)-induced myocardial infarction (MI).Methods:Adult male Wistar rats were divided into four groups: control group, ISO group, catalpol (L, low dose) group, and catalpol (H, high dose) group. Isoproterenol (85 mg/kg) was injected subcutaneously for 2 consecutive days to induce experimental MI. At the end of experiment, the effects of catalpol on cardiac function; apelin levels; apoptosis index; apelin, APJ, Bcl-2, and Bax protein expression; and caspase-3/9 activities were investigated.Results:The rats in the ISO group showed lower left ventricular maximum rate of positive or negative pressure development (±LVdp/dtmax) and left ventricular end-systolic pressure (LVSP) and higher left ventricular end-diastolic pressure (LVEDP) than those in the control group, suggesting severe cardiac dysfunction. Interestingly, catalpol administration significantly ameliorated the ISO-induced cardiac dysfunction. The groups administered low and high dosages catalpol (5 and 10 mg/kg/day, respectively) showed higher ±LVdp/dtmax and LVSP and lower LVEDP than the group administered ISO alone. Catalpol markedly upregulated apelin levels in the plasma and myocardium. Further, catalpol increased the apelin and APJ expression levels in the myocardium of the ISO-treated rats. In addition, catalpol pretreatment inhibited cardiomyocyte apoptosis as indicated by a decrease in the TUNEL-positive cell percentage, alterations in the Bax and Bcl-2 expression levels, and a decline in caspase-3 and caspase-9 activities.Conclusion:Our results revealed that catalpol can improve cardiac function. Its protective effects may be linked to the enhancement of myocardium contractility, regulation of the apelin/APJ pathway, and inhibition of cardiomyocyte apoptosis.

Inhibition of NADPH oxidase by apocynin promotes myocardial antioxidant response and prevents isoproterenol-induced myocardial oxidative stress in rats

Preventive and/or therapeutic interventions for ischemic heart disease have gained considerable attention worldwide. We investigated the mechanism(s) underlying cardioprotection of apocynin (APO) and whether it attenuates isoproterenol (ISO)-induced myocardial damage in vivo. Thirty-two male Wistar Albino rats were randomised into four groups (n = 8 for each group): Group I (Control); Group II (ISO), ISO was given intraperitoneally (ip) (150 mg/kg/d) daily for 2 consecutive days; Group III (APO + ISO), APO was applied ip 20 mg/kg 30 min before the first ISO administration and continued for the next 2 d after the second ISO administration; Group IV (ISO + APO), after the ISO treatment on days 1 and 2, 20 mg/kg APO was given ip on days 3 and 4. Cardioprotective effects of APO were evaluated by biochemical values, histopathological observations and the antiapoptotic relative proteins. Mean blood pressure, heart rate, and electrocardiography (ECG) were also monitored. Malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), total oxidant status (TOS), total antioxidant capacity (TAC), oxidative stress index (OSI), caspase-3 and connexin 43 levels were determined. Major ECG changes were observed in the ISO-treated rats. MDA, TOS, OSI and creatine kinase levels decreased and SOD, CAT, GSH and TAC levels increased, indicating that APO reduced cardiac injury and oxidative stress compared with controls. APO also decreased the number of cardiomyocytes with pyknotic nuclei, inflammatory cell infiltration, intracytoplasmic vacuolisation and myofibrils. APO provides preventive and therapeutic effects on ISO-induced myocardial injury in rats by inhibiting reactive oxygen species production, blocking inflammation and enhancing antioxidant status.

MiR-30e Attenuates Isoproterenol-induced Cardiac Fibrosis Through Suppressing Snai1/TGF-β Signaling

Background:MicroRNAs are a class of small RNA molecules that inhibit protein expression through either degradation of messenger RNA or interference with protein translation. Our previous work suggested an involvement of miR-30e in myocardial fibrosis; however, the exact role of miR-30e in the pathogenesis of cardiac fibrosis and the underlying mechanisms are not known.Methods:Male Sprague Dawley rats were treated with isoproterenol (ISO) to induce cardiac remodeling and fibrosis and treated with either miR-30e agomir (AG) or antagomir and respective controls. The expression of miR-30e was evaluated by reverse transcription and quantitative polymerase chain reaction. Myocardial fibrosis was assessed by Masson's trichrome staining, and the level of oxidative stress and the expression of Snai1 and transforming growth factor-beta (TGF-β) were detected using Western blots.Results:A significant downregulation of miR-30e was found in the hearts of ISO-treated rats with cardiac fibrosis compared with nontreated controls. In vivo administration of miR-30e AG increased the survival of ISO-treated rats compared with AG-negative control administration, which was associated with reduced oxidative stress. We further identified Snai1 as a novel miR-30e target. Snai1 expression was significantly increased in hearts from ISO-treated rats, which coincided with decreased miR-30e expression and increased TGF-β expression. An miR-30e putative target sequence was identified in the 3′-untranslated region (UTR) Snai1. In a reporter assay, miR-30e greatly suppressed the activity of wild-type 3′-UTR–fused luciferase reporter, but showed no significant effect with the mutated 3′-UTR–fused reporter.Conclusion:MiR-30e attenuated ISO-induced cardiac dysfunction and cardiac fibrosis in a rat cardiac remodeling model. Mechanistically, miR-30e suppressed Snai1/TGF-β pathway which was involved in ISO-induced cardiac remodeling.

Coenzyme Q10 prevents oxidative stress and fibrosis in isoprenaline induced cardiac remodeling in aged rats

BackgroundThe objective of the present study aimed to investigate the effect of CoQ10 treatment on isoprenaline (ISO)-induced cardiac remodeling in rats.MethodsRats were divided into three groups namely Control group, ISO treated group and CoQ10 + ISO treated group, each consisting of 6 rats. The cardiac specific CK-MB, AST, ALT activity and other oxidative stress parameters were estimated in heart and kidneys. Additionally histological examination was also performed to visualize the inflammatory cells infiltration and fibrosis in both tissues.ResultsAdministration of ISO resulted in an increase in the heart-to-body weight (HW/BW) ratio and an also increased the serum CK-MB, AST and ALT enzyme activity. Serum levels of lipid peroxidation products, and oxidative stress markers showed significant increase in ISO-treated rats. Histopathological examination of heart tissue revealed focal areas of endocardium degeneration, mononuclear cells infiltration, fibrous tissue deposition, and increased thickness of the myocardium of left ventricle. Similar degeneration was also found in kidneys. Treatment with CoQ10 (100 mg/kg) significantly improved the oxidative stresses in ISO treated rats. Moreover, CoQ10 treatment prevented inflammatory cells infiltration and reduced fibrosis in ISO administered rats.ConclusionIn conclusion, our study provides evidence that CoQ10 may prevent the development of cardiac remodeling, and fibrosis in ISO administered rats.

Inhibition of poly(ADP-ribose) polymerase may have preventive potential for varicocoele-associated testicular damage in rats.

Varicocele is ordinarily accompanied by testicular damage and male infertility. Several theories have been proposed to explain the detrimental effect of varicocele on testis tissue, including the possible effects of oxidative stress. The poly(ADP-ribose) polymerase (PARP) pathway has been established as a major downstream intracellular pathway of oxidative stress. Recently we have reported that PARP pathway has been activated in varicocele-induced rat testicular damage model. The aim of the present study was to investigate the possible protective effect of PARP inhibition in varicocele-associated testicular damage. Fifty male Wistar rats were divided into five groups: control, sham, varicocele-induced, varicocele-induced 1,5-isoquinolinediol (ISO, a PARP inhibitor)-treated, and ISO treated groups. The ISO-treated rats received intraperitoneal injections of 3mg/kg ISO daily for 13weeks. After 13weeks of varicocele induction, body and testes weights were investigated in all groups. Histopathology of testes were evaluated by light microscopy. Expressions of PAR, p53 and cytochrome c were detected by immunohistochemistry and cleaved PARP-1, PAR, p53 and cytochrome c by western blot. The degree of apoptosis was determined by TUNEL. Light microscopy revealed testicular damage comprising various degrees of seminiferous tubule degeneration in varicocele-induced rats and their testes weights decreased significantly, whereas ISO administration prevented it. Expressions of cleaved PARP-1, PAR, cytochrome c, and p53 increased significantly in varicocele-induced rats, whereas the level of these molecules were similar to controls in varicocele-induced rats treated with ISO. In conclusion, increased PARP activation in testes seems to be related with testicular damage and apoptosis associated with varicocele and pharmacological inhibition of this pathway might be an effective intervention to prevent varicocele-induced testicular injury.

CARDIOPROTECTIVE EFFICACY OF TAURINE ON LIPID-METABOLISM OF ISOPROTERENOL-INDUCED MYOCARDIAL INFARCTION

&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;The present study aimed to evaluate the effect of pre-treatment with taurine on rats in which MI had been induced using isoproterenol (ISO).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Rats were randomly allocated into three groups&lt;strong&gt;;&lt;/strong&gt; the 1st group is the normal control (C) one, the 2nd is the isoproterenol cardiotoxic (ISO) one and the 3rd group is the taurine pretreated (T-ISO) one.&lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The activities of the cardiac biomarker enzymes, AST, LDH, CK and CK-MB were elevated in the ISO-treated group. The membrane-bound Na&lt;sup&gt;+&lt;/sup&gt;-K&lt;sup&gt;+ &lt;/sup&gt;and Ca&lt;sup&gt;2+ &lt;/sup&gt;ATPase enzyme activities were decreased in the ISO-treated group. The lipid profile either in sera or cardiac tissues was increased in ISO-treated rats except for HDL-cholesterol and phospholipids. The cholesterol ester synthetase (CES) activity was elevated, while lecithin: Cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL) activities were decreased in the myocardial infarcted rats. In addition, the high level of the troponins I and T was an indication of cardiac necrosis. Pre-treatment with Taurine, however, ameliorated all of these changes, in addition to its effect in improving the oxidation process, as measured by lipid peroxidation and the antioxidant enzymes, superoxide dismutase and peroxidase enzymes.&lt;strong&gt; &lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Taurine showed amelioration effects on the changes in lipid profile, oxidative stress and myocardial infarction biomarkers and therefore, can be protected against cardiotoxicity.&lt;/p&gt;

Abstract 11921: Altered Cardiomyocyte Functional Response to Vasopressin in Heart Failure

Background . In heart failure (HF), circulating levels of arginine vasopressin (AVP) are elevated and there is direct relationship between a rise in AVP levels and increased morbidity and mortality. Recent observations further demonstrated the increased AVP 1A receptor (V1AR) expression in failing human hearts and suggested that these alterations may alter cardiac contractile behavior in HF. However, the direct cardiac effects of V1AR in normal and HF remain undetermined. The cellular basis for AVP-associated adverse clinical consequences in HF is unclear. We assessed the hypothesis that in HF, AVP may produce negative modulation on [Ca 2+ ] i regulation and cause direct depression in cardiomyocyte contractile performance. Methods . We assessed LV myocyte functional and calcium transient ([Ca 2+ ] iT ) responses to AVP (10 -7 M) in 8 control and 12 SD rats with isoproterenol (ISO) induced HF (2 months after 170 mg/kg sq for 2 days) in the absence and presence of selective V1AR blockade ([Pmp1, Tyr (OMe) 2, Arg 8 ] AVP, 10 -6 M), or pretreatment of myocytes with G i inhibitor (PTX, 2 μg/ml, 6 hrs). Results . Compared with controls, ISO-treated rats had established HF after ISO at 2 months with significant LV dilatation and decreased ejection fraction (EF, 31% vs 61%). In normal myocytes, versus baselines, AVP superfusion caused no significant changes in myocyte contraction (dL/dt max ) (130.6 vs 136.8 μm/s), relaxation (dR/dt max ) (99.5 vs 103.5 μm/s) and [Ca 2+ ] iT (0.24 vs 0.24). In contrast, in HF, myocyte function was impaired and further depressed by AVP. Versus HF baselines, AVP resulted significantly decreases in dL/dt max (24%, 57.2 vs 75.4 μm/s) and dR/dt max (20%, 39.3 vs 49.0 μm/s) accompanied by reduced [Ca 2+ ] iT (17%, 0.14 vs 0.17). In HF myocytes, these AVP mediated effects were abolished by prior exposure of myocytes to V1AR blockade or PTX. Conclusions . HF alters AVP cardiac effects. In HF, AVP exacerbates the dysfunctional [Ca 2+ ] i homeostasis, producing decreased the peak systolic [Ca 2+ ] iT . AVP causes direct inhibitions of LV myocyte contraction and relaxation, These effects are coupled with the activation of V1AR and are likely to be mediated through the PTX-sensitive G protein pathway and may thus play an important role in promoting functional impairment in HF.

Abstract 16113: Upregulation of Cardiac β3-Adrenergic Signaling Promotes Heart Failure Progression

Background. The negative inotrope and upregulation of β 3 -adrenergic receptors (AR) in failing human and animal hearts suggest a direct and contributing role of cardiac β 3 -AR activation on heart failure (HF) progression. However, its precise role is still being debated. We hypothesize that up-regulation of β 3 -AR is detrimental and chronic β 3 -AR blockade may limit or prevent the progression of HF. Methods. We determined Left ventricular (LV) and myocyte functional response and β 1 - and β 3 -AR expressions in 3 groups of rats (6/group) for a period of 4 months: 1) Isoproterenol (ISO)-treated, 4 months after receiving ISO (170 mg/kg, sq, for 2 days); 2) ISO/β 3 -ANT, two months after receiving ISO, L-748,337, a selective β 3 -AR antagonist (β 3 -ANT) (10 -7 M/kg/day by implanted osmotic mini pump) was initiated after established HF and was given for 2 months; and 3) sham controls. Results. Compared with controls, ISO-treated rats had HF onset at one month after ISO and progressed to severe HF at 4 months. Plasma norepinephrine (NE, 1482 vs 247 pg/ml) increased 6 fold. Both stroke volume (SV) and ejection fraction (EF, 32% vs 61%) decreased more than 48%, and LV end-diastolic pressure (P ED , 15.4 vs 6.0 mmHg) doubled, parallel with 48% reductions in cell contraction (dL/dt max, 78 vs 149 μm/s) and relaxation (dR/dt max , 66 vs 128 μm/s) and a much less increase in dL/dt max (30% vs 74%) in response to superfusion of ISO (10 -8 M). These changes were associated with significantly decreased β 1 -AR mRNA (0.30 vs 0.64) and protein levels (0.36 vs 0.62), but increased β 3 -AR mRNA (1.29 vs 0.52) and protein levels (0.35 vs 0.18). Treatment with β 3 -ANT significantly decreased P ED and plasma NE (191 pg/ml). Both SV and EF (59%) increased to more than 76% from ISO-treated values. The signal ratios of β 1 -AR mRNA (0.61) and β 3 -AR mRNA (0.59) remained close to control levels. ISO-induced increase in dL/dt max (75%) was also significantly augmented. Conclusion. Chronic β 3 -ANT prevented plasma norepinephrine elevations and causes normalization of β 1 - and β 3 -AR gene expression, restores normal responsiveness of myocyte to β-AR stimulation, and leads to regression of LV and myocyte dysfunction in a rat model of progressive HF. Thus, β 3 -AR blocker may provide a new therapeutic strategy for the treatment of HF.

Paving the Route to Plasma miR-208a-3p as an Acute Cardiac Injury Biomarker: Preclinical Rat Data Supports Its Use in Drug Safety Assessment.

Drug-induced cardiac injury (DICI) detection remains a major safety issue in drug development. While circulating microRNAs (miRs) have emerged as promising translational biomarkers, novel early detection biomarkers of cardiotoxicity are needed. This work aims at evaluating whether a panel of putative cardiac injury plasma miRs could serve as early DICI biomarkers in a 4-day rat preclinical model. Out of a panel of 68 selected targets, we identified plasma miR-208a-3p as being significantly upregulated after single administration with either isoproterenol (ISO) or allylamine (AAM). This provides the first evidence of miR-208a-3p detection after AAM administration. Moreover, similarly to cardiac troponins (cTn), plasma miR-208a-3p expression profile appears to be compound-specific with most significant early changes occurring in ISO-treated rats. Overall, miR-208a-3p performance in detecting the severity of myocardial injury, as well as the magnitude of miR-208a-3p increase after ISO or AAM administration, were comparable to that of cTn. Our results highlight the importance of assessing the whole time-dependent profiles of miR expression. Hence, time course evaluation revealed plasma miR candidates whose expression was not stable across the duration of the study in the vehicle group, restricting their utility as cardiac injury-specific biomarkers. In light of these findings, miR-208a-3p has a potential to complement the existing biomarkers of cardiac injury specifically in the context of evaluating toxicity in a time-dependant manner. Assessment of miR-208a-3p in other DICI settings would strengthen its robustness as an early detection biomarker leading to a warranted extensive and rigorous validation.

Apigenin Attenuates β-Receptor-Stimulated Myocardial Injury Via Safeguarding Cardiac Functions and Escalation of Antioxidant Defence System.

Apigenin (AP) is a flavone in dietary flavonoids reported as strong antioxidant and elite modulator of PPARγ. The current study evaluated the consequence of AP in isoproterenol (ISO)-induced oxidative stress and myocardial infarction during β-adrenergic receptor stimulus in rats by persistent hemodynamic, biochemical and histopathological changes. Rats received AP (25, 50 and 75mg/kg/day) or vehicle i.p. for 14days and ISO (100mg/kg, s.c.) on 13th and 14th days for initiation of cardiotoxicity. ISO-treated rats showed evidence of significant dwindle in systolic and diastolic arterial pressures, maximal positive rate of developed left ventricular pressure. In totting up, a noteworthy diminution in activities of creatine kinase-MB isoenzyme, reduced glutathione, superoxide dismutase, catalase and level along with rise in malondialdehyde content were observed. The shielding function of AP on isoproterenol-induced myocardial damage was observed by attenuating all the endogenous parameters and the membrane-bound enzymes. It was confirmed by histopathological examinations. The effect of AP at the doses of 50 and 75mg/kg showed added apparent than at the dose of 25mg/kg. Current study thus provides confirmation for protective effects of AP on myocardium in experimentally induced myocardial infarction.

Protective effect of a polysaccharide from Salvia miltiorrhiza on isoproterenol (ISO)-induced myocardial injury in rats

In this study, we investigated the cardioprotective effect of one purified polysaccharide (SMP1) from Salvia miltiorrhiza on isoproterenol (ISO)-induced myocardial infarction (MI) in rats. ISO-treated rats showed severe myocardial damage and high lipid peroxidation level, as well as decreased endogenous myocardial antioxidant function. Pretreatment with SMP1 (100 and 400mg/kg) for 30 days significantly increased the body weight, decreased the heart weight, attenuated the serum levels of creatine kinase (CK), creatine phospokinase-MB (CK-MB), dehydrogenase (LDH), alkaline phosphate (ALP), aspartate transaminase (AST), alanine transaminase (ALT), total cholesterol, triglyceride, and LDL-cholesterol (LDL-C), along with the increased concentration of HDL-cholesterol (HDL-C). In addition, SMP1 also enhanced myocardial superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities and elevated myocardial reduced glutathione (GSH) level, along with a decrease in thiobarbituric acid reactive substances (TBARS) concentration. Collectively, our results indicated that long-term oral administration of SMP1 offered significant protection against the damage induced by ISO in rat heart through enhancement of endogenous antioxidants and antihyperlipidemic activity.