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1.
Med Princ Pract ; 32(2): 152-154, 2023.
Article in English | MEDLINE | ID: mdl-37080188
2.
J. physiol. biochem ; 70(1): 151-162, mar. 2014.
Article in English | IBECS | ID: ibc-121614

ABSTRACT

The role of pacing postconditioning (PPC) in the heart protection against ischemia-reperfusion injury is not completely understood. The aim of this study was to investigated if 17-Beta-estradiol (estrogen, E2), endogenous atrial natriuretic peptide (ANP), endogenous brain natriuretic peptide (BNP), and tumor necrosis factor-alpha (TNF-Alpha) are involved in PPC-mediated protection. Langendorff perfused female Wistar rat hearts were used for this study. Hearts challenged with regional ischemia for 30 min subjected to no further treatment served as a control. The PPC protocol was 3 cycles of 30 s pacing alternated between the right atrium and left ventricle (LV). Protection was assessed by recovery of LV contractility and coronary vascular-hemodynamics. Ischemia induced a significant (P < 0.05) deterioration in the heart function compared with baseline data. PPC alone or in combination with short-term E2 treatment (E2 infusion at the beginning of reperfusion) significantly (P < 0.05) improved the heart functions. Short-term E2 treatment post-ischemically afforded protection similar to that of PPC. However, long-term E2 substitution for 6 weeks completely attenuated the protective effects of PPC. Although no changes were noted in endogenous ANP levels, PPC significantly increased BNP expression level and decreased TNF-Alpha in the cardiomyocyte lysate and coronary effluent compared to ischemia and controls. Our data suggested a protective role for short-term E2 treatment similar to that of PPC mediated by a pathway recruiting BNP and downregulating TNF-Alpha. Our study further suggested a bad influence for long-term E2 substitution on the heart as it completely abrogated the protective effects of PPC


Subject(s)
Animals , Rats , Estradiol/pharmacokinetics , Reperfusion Injury/drug therapy , Cardiotonic Agents/pharmacokinetics , Ischemic Postconditioning , Protective Agents/pharmacokinetics , Disease Models, Animal
3.
J Physiol Biochem ; 70(1): 151-62, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24037795

ABSTRACT

The role of pacing postconditioning (PPC) in the heart protection against ischemia-reperfusion injury is not completely understood. The aim of this study was to investigated if 17-ß-estradiol (estrogen, E2), endogenous atrial natriuretic peptide (ANP), endogenous brain natriuretic peptide (BNP), and tumor necrosis factor-alpha (TNF-α) are involved in PPC-mediated protection. Langendorff perfused female Wistar rat hearts were used for this study. Hearts challenged with regional ischemia for 30 min subjected to no further treatment served as a control. The PPC protocol was 3 cycles of 30 s pacing alternated between the right atrium and left ventricle (LV). Protection was assessed by recovery of LV contractility and coronary vascular-hemodynamics. Ischemia induced a significant (P < 0.05) deterioration in the heart function compared with baseline data. PPC alone or in combination with short-term E2 treatment (E2 infusion at the beginning of reperfusion) significantly (P < 0.05) improved the heart functions. Short-term E2 treatment post-ischemically afforded protection similar to that of PPC. However, long-term E2 substitution for 6 weeks completely attenuated the protective effects of PPC. Although no changes were noted in endogenous ANP levels, PPC significantly increased BNP expression level and decreased TNF-α in the cardiomyocyte lysate and coronary effluent compared to ischemia and controls. Our data suggested a protective role for short-term E2 treatment similar to that of PPC mediated by a pathway recruiting BNP and downregulating TNF-α. Our study further suggested a bad influence for long-term E2 substitution on the heart as it completely abrogated the protective effects of PPC.


Subject(s)
Cardiotonic Agents/therapeutic use , Estradiol/therapeutic use , Ischemic Postconditioning , Myocardial Reperfusion Injury/prevention & control , Animals , Cardiac Pacing, Artificial , Cardiotonic Agents/pharmacology , Coronary Vessels/physiopathology , Drug Evaluation, Preclinical , Estradiol/pharmacology , Female , Gene Expression , Heart/drug effects , Heart/physiopathology , In Vitro Techniques , Male , Myocardial Contraction , Natriuretic Peptide, Brain/genetics , Natriuretic Peptide, Brain/metabolism , Rats , Rats, Wistar , Sex Characteristics , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
4.
Mol Cell Biochem ; 373(1-2): 259-64, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23124851

ABSTRACT

Diabetes is associated with increased incidence of cardiovascular disease. Mechanisms that contribute to development of diabetic cardiopathy are not well understood. Phosphatidylinositol 3-kinase (PI3K) is a family of protein kinases that play an important role in regulation of cardiac function. It has been shown that inhibition of certain PI3K enzymes may produce cardiovascular protection. The aim of the present study was to determine whether chronic treatment with LY294002, an inhibitor of PI3K, can attenuate diabetes-induced cardiac dysfunction in isolated hearts obtained from normotensive and hypertensive rats. Recovery of cardiac function after 40 min of global ischemia and 30 min of reperfusion, measured as left ventricular developed pressure, left ventricular end-diastolic pressure, coronary flow and coronary vascular resistance, was worse in hearts obtained from diabetic and/or hypertensive animals compared to their respective controls. Treatment with LY294002 (1.2 mg/kg/day) for 4 weeks significantly prevented diabetes-induced cardiac dysfunction in both normotensive and hypertensive rats. Treatment with LY294002 did not significantly alter blood pressure or blood glucose levels. These results suggest that inhibition of PI3K signaling pathways can prevent ischemia/reperfusion-induced cardiac dysfunction in normotensive and hypertensive rats without correcting hyperglycemia or high blood pressure.


Subject(s)
Cardiotonic Agents/administration & dosage , Chromones/administration & dosage , Diabetes Mellitus, Experimental/physiopathology , Hypertension/physiopathology , Morpholines/administration & dosage , Phosphoinositide-3 Kinase Inhibitors , Ventricular Dysfunction, Left/prevention & control , Animals , Coronary Vessels/physiopathology , Diabetes Mellitus, Experimental/complications , Hypertension/complications , In Vitro Techniques , Male , Myocardial Contraction/drug effects , Myocardial Reperfusion Injury/etiology , Myocardial Reperfusion Injury/physiopathology , Myocardial Reperfusion Injury/prevention & control , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Regional Blood Flow , Signal Transduction , Vascular Resistance/drug effects , Ventricular Dysfunction, Left/etiology , Ventricular Dysfunction, Left/physiopathology , Ventricular Pressure/drug effects
5.
Exp Clin Cardiol ; 17(3): 95-100, 2012 Sep.
Article in English | MEDLINE | ID: mdl-23620695

ABSTRACT

BACKGROUND: The protective effects of 17-beta estradiol (E2) on cardiac tissue during ischemia/reperfusion (I/R) injury have not yet been fully elucidated. OBJECTIVE: To assess the protective effects of short- and long-term E2 treatments on cardiac tissue exposed to I/R, and to assess the effects of these treatments in combination with ischemic preconditioning (IPC) on cardiac protection from I/R injury. METHODS: SPRAGUE DAWLEY RATS WERE ASSIGNED TO THE FOLLOWING TREATMENT PROTOCOLS: control (no preconditioning); IPC (isolated hearts were subjected to two cycles of 5 min global ischemia followed by 10 min of reperfusion); E2 preconditioning (E2PC; isolated hearts were subjected to E2 pharmacological perfusion for 15 min); short-term in vivo E2 pretreatment for 3 h; long-term in vivo E2 pretreatment or withdrawal (ovariectomy followed by a six-week treatment with E2 or a placebo); combined IPC and E2PC; combined IPC and short- or long-term E2 pretreatments or withdrawal. All hearts were isolated and stabilized for at least 30 min before being subjected to 40 min of global ischemia followed by 30 min of reperfusion; left ventricular function and vascular hemodynamics were then assessed. RESULTS: IPC, E2PC and short-term E2 pretreatment led to the recovery of left ventricle function and vascular hemodynamics. Long-term E2 and placebo treatments did not result in any protection compared with untreated controls. The combination of E2PC or short-term E2 treatments with IPC did not block the IPC protection or result in any additional protection to the heart. Long-term E2 treatment blocked IPC protection; however, placebo treatment did not. CONCLUSIONS: Short-term treatment with E2 protected the heart against I/R injury through a pathway involving the regulation of tumour necrosis factor-alpha. The combination of short-term E2 treatment with IPC did not provide additional protection to the heart. Short-term E2 treatment may be a suitable alternative for classical estrogen replacement therapy.

7.
Exp Clin Cardiol ; 16(2): e5-e10, 2011.
Article in English | MEDLINE | ID: mdl-21747660

ABSTRACT

BACKGROUND: Tumour necrosis factor-alpha (TNF-α) has been reported to play an important role in ischemia reperfusion injury and ischemic preconditioning (IPC). However, its role is not completely understood. Recently, normothermic IPC (NIPC), hyperthermic IPC (HIPC), preconditioning (PC) with 17-beta estradiol (estrogen, E2) and E2 pretreatment were proven to be effective in reducing ischemia reperfusion injury. OBJECTIVES: To investigate the detrimental effects of TNF-α on the heart, and the protective effects of NIPC, HIPC, E2 PC and pretreatment on TNF-α-induced injury. METHODS: A Langendorff-perfused rat heart model was used for the present study. Hearts isolated from male rats were studied under eight different conditions (n=5 each): negative control; control treated with TNF-α without any further treatment; NIPC (preconditioned at 37°C); HIPC (preconditioned at 42°C); E2 PC; E2 pretreatment; normal, untreated hearts plus E2; or pretreated hearts perfused for 60 min with TNF-α and an E2-containing buffer. RESULTS: TNF-α treatment resulted in deterioration of heart function. HIPC offered better protection by significantly increasing left ventricular developed pressure (Pmax) and coronary flow (P<0.01), and by decreasing left ventricular end-diastolic pressure (P<0.01). NIPC or pretreatment of the hearts with E2 normalized left ventricular end-diastolic pressure, coronary flow and coronary vascular resistance (P<0.001); however, it did not normalize Pmax. The combination of E2 and HIPC did not show any synergetic protection; however, the addition of HIPC normalized Pmax (P<0.001). CONCLUSIONS: TNF-α treatment resulted in deterioration of heart hemodynamics, which were reversed by HIPC, E2 PC and pretreatment. The combination of these treatments did not add to the previously observed protection compared with when they were used individually.

8.
Exp Clin Cardiol ; 12(1): 11-6, 2007.
Article in English | MEDLINE | ID: mdl-18650974

ABSTRACT

BACKGROUND: Myocardial ischemic preconditioning (PC) is a protective intervention that aims to reduce the deleterious effects of ischemia-reperfusion injury. OBJECTIVES: : To assess the comparative efficacy of ischemic PC induced at hypothermic, normothermic and hyperthermic temperatures on the postischemic recovery of left ventricular contractile and coronary vascular functions in the aortic perfused rat heart model. METHODS: An isolated aorta-perfused (Langendorff) rat heart model was used. Hearts were studied in eight different groups (n=5 each). Unprotected ischemia for 60 min served as control. For the remaining seven groups, ischemia was preceded by PC at 10 degrees C, 20 degrees C, 30 degrees C, 34 degrees C, 37 degrees C, 40 degrees C and 42 degrees C achieved by two episodes of 5 min ischemia at the designated PC temperature and 10 min of reperfusion, respectively. The postischemic recovery in contractile (maximum developed pressure and left ventricular end-diastolic pressure) and coronary vascular functions (coronary flow and coronary vascular resistance) was assessed at the end of 30 min reperfusion. RESULTS: Hyperthermic PC provided optimal preservation and resulted in a 25% increase in the myocardial and 15% increase in the coronary vascular tolerance to ischemia. Normothermic PC resulted in a 21% increase in myocardial and 14% increase in coronary vascular tolerance to ischemia. Hypothermic PC was comparatively less effective and resulted in 11% increase in myocardial and 15% increase in the coronary vascular tolerance to ischemia. The temperature-dependence of PC may be summarized as: PC-42 degrees C > PC-40 degrees C > PC-37 degrees C > PC-34 degrees C > PC-30 degrees C > PC-20 degrees C > PC-10 degrees C. CONCLUSIONS: The results of the present study indicate that the extent of reversibility of the ischemic damage depends on the PC temperature and that optimal preservation occurred at the ideal PC temperature between 40 degrees C and 42 degrees C.

9.
Pharmacol Res ; 52(5): 401-12, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16027001

ABSTRACT

The purpose of this study was to examine the effect of inhibition of Ras-GTPase mediated signalling on the development of hypertension and end-organ damage in spontaneously hypertensive rats chronically treated with nitric oxide synthesis inhibitor L-NAME (SHR-L-NAME). Administration of L-NAME in drinking water (80 mg/L) for 3 weeks significantly elevated mean arterial blood pressure (MABP) (223+/-4 mmHg) as compared to that of SHR controls (165+/-3 mmHg). The administration of Ras-GTPase inhibitor FPTIII (232 ng/min) to SHR-L-NAME during the last 6 days significantly attenuated high blood pressure (192+/-4 mmHg). Morphological studies of the kidneys and hearts showed that treatment with FPTIII minimized the extensive arterial fibrinoid necrosis, arterial thrombosis, narrowing of arterial lumen with marked arterial hyperplastic arterial changes that were observed in vehicle treated SHR-L-NAME. L-NAME-induced increase in urine volume and protein was also significantly lower in FPTIII-treated animals. The impaired vascular responsiveness to isoprenaline in the perfused mesenteric vascular bed of SHR-L-NAME-treated animals was significantly attenuated by FPTIII treatment. In isolated perfused hearts, recovery of left ventricular function from a 40 min of global ischemia was significantly better in FPTIII-treated SHR-L-NAME. Treatment with FPTIII also significantly reduced expression of cardiac sodium-hydrogen exchanger-1 (NHE-1) which was elevated in SHR-L-NAME. These data indicate that inhibition of Ras-GTPase-mediated signalling can attenuate end-organ damage during severe hypertension and endothelial dysfunction.


Subject(s)
Hypertension/etiology , NG-Nitroarginine Methyl Ester/pharmacology , Signal Transduction/physiology , ras Proteins/physiology , Animals , Blood Pressure/drug effects , Collagen Type III/metabolism , Hypertension/pathology , Hypertension/physiopathology , Isoproterenol/pharmacology , Kidney/pathology , Myocardial Reperfusion Injury/physiopathology , Myocardium/pathology , Organophosphonates/pharmacology , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Sodium-Hydrogen Exchangers/analysis , Ventricular Function, Left , ras Proteins/antagonists & inhibitors
10.
Mol Cell Biochem ; 268(1-2): 175-83, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15724451

ABSTRACT

It is well established that brief episodes of ischemia/reperfusion (I/R) [preconditioning (PC)] protect the myocardium from the damage induced by subsequent more prolonged I/R. However, the signaling pathways activated during PC or I/R are not well characterized. In this study, the role of Ras-GTPase, tyrosine kinases (TKs), epidermal growth factor receptor (EGFR) and Ca2+/calmodulin-dependent protein kinase II (CaMK II) in mediating PC in a perfused rat heart model was investigated. A 40-min episode of global ischemia in perfused rat hearts produced significantly impaired cardiac function, measured as left ventricular developed pressure (Pmax) and left ventricular end-diastolic pressure (LVEDP), and impaired coronary hemodynamics, measured as coronary flow (CF) and coronary vascular resistance (CVR). PC significantly enhanced cardiac recovery after IR. Combination of PC and FPT III (Ras-GTPase inhibitor FPT III; 232 ng/min for 6 days) treatment did not produce any additive benefits as compared to PC alone. In contrast, PC-induced improvements in cardiac function after I/R were significantly attenuated by pretreatment with genistein (1mg/kg/day for 6 days), a broad-spectrum inhibitor of TKs, or AG1478 (1mg/kg/day for 6 days), a specific inhibitor of EGFR tyrosine kinase or KN-93 (578 ng/min for 6 days), a CaMK II inhibitor, before PC. These observations suggest that PC and FPT III pretreatment may produce cardioprotection via similar mechanisms. Present results also indicate that activation of TKs and specifically activation of EGFR-mediated TKs and CaMK II-mediated regulation of calcium homeostasis are part of the PC mechanisms that improve recovery after IR.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , ErbB Receptors/antagonists & inhibitors , Myocardial Reperfusion Injury/physiopathology , Signal Transduction/drug effects , ras Guanine Nucleotide Exchange Factors/antagonists & inhibitors , Animals , Calcium/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2 , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , ErbB Receptors/metabolism , Organ Culture Techniques , Rats , Rats, Wistar , ras Guanine Nucleotide Exchange Factors/metabolism
11.
Mol Cell Biochem ; 259(1-2): 35-42, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15124905

ABSTRACT

The signaling pathways involved in ischemic heart disease are not well characterized. In this study, the roles of Ras-GTPase, tyrosine kinases (TKs) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in global ischemia and reperfusion (I/R) in a perfused rat heart model were investigated and compared to beneficial effects produced by preconditioning (PC). A 40 min episode of global ischemia followed by a 30 min reperfusion in perfused rat hearts produced significantly impaired cardiac function, measured as left ventricular developed pressure (Pmax) and left ventricular end-diastolic pressure (LVEDP), and impaired coronary hemodynamics, measured as coronary flow (CF) and coronary vascular resistance (CVR). Hearts from male Wistar rats pre-treated with the tyrosine kinase inhibitor, genistein (1 mg/kg/day for 6 days), or the CaMKII inhibitor, KN-93 (578 ng/min for 6 days), produced detrimental effects on recovery of cardiac function and coronary hemodynamics. In contrast, pre-treatment with Ras-GTPase inhibitor FPT III (232 ng/min for 6 days) significantly enhanced cardiac recovery in terms of left ventricular contractility and coronary vascular hemodynamics. Treatment with FPT III also significantly reduced expression of the sodium-hydrogen exchanger-1 (NHE-1) which was elevated during I/R as detected by Western blotting. These data suggest that TKs and CaMKII are involved in signaling pathways leading to recovery from cardiac ischemia, whereas activation of Ras-GTPase signaling pathways are critical in the development of cardiac dysfunction due to I/R.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors , Enzyme Inhibitors/administration & dosage , Myocardial Ischemia/enzymology , Myocardium/enzymology , Protein-Tyrosine Kinases/antagonists & inhibitors , Recovery of Function/drug effects , Alkyl and Aryl Transferases/metabolism , Animals , Calcium-Calmodulin-Dependent Protein Kinase Type 2 , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Coronary Circulation/drug effects , Coronary Circulation/physiology , In Vitro Techniques , Injections, Intraperitoneal , Ischemic Preconditioning, Myocardial , Male , Myocardial Contraction/drug effects , Myocardial Contraction/physiology , Myocardial Ischemia/physiopathology , Myocardial Reperfusion , Myocardium/pathology , Protein-Tyrosine Kinases/metabolism , Rats , Rats, Wistar , Recovery of Function/physiology , Ventricular Pressure/drug effects , Ventricular Pressure/physiology
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