Home About us Contact
|
Home About us Contact | ||
|
|
||
Min Reperfusion (min + reperfusion)
Selected AbstractsCardioprotection of bradykinin at reperfusion involves transactivation of the epidermal growth factor receptor via matrix metalloproteinase-8ACTA PHYSIOLOGICA, Issue 4 2009C. Methner Abstract Aim:, The endogenous autacoid bradykinin (BK) reportedly reduces myocardial infarct size when given exogenously at reperfusion. Muscarinic and opioid G-protein-coupled receptors are equally protective and have been shown to couple through a matrix metalloproteinase (MMP)-dependent transactivation of the epidermal growth factor receptor (EGFR). Here we test whether BK protects the rat heart through the EGFR by an MMP-dependent pathway. Methods:, Infarct size was measured in isolated perfused rat hearts undergoing 30 min regional ischaemia followed by 120 min reperfusion. In additional studies HL-1 cardiomyocytes were loaded with tetramethylrhodamine ethyl to measure their mitochondrial membrane potential (,m). Adding the calcium ionophore calcimycin, causes ,m-collapse presumably due to calcium-induced mitochondrial permeability transition. Results:, As expected, BK (100 nmol L,1) started 5 min prior to reperfusion reduced infarct size from 38.9 ± 2.0% of the ischaemic zone in control hearts to 22.2 ± 3.3% (P < 0.001). Co-infusing the EGFR inhibitor AG1478, the broad-spectrum MMP-inhibitor GM6001, or a highly selective MMP-8 inhibitor abolished BK's protection, thus suggesting an MMP-8-dependent EGFR transactivation in the signalling. Eighty minutes of exposure to calcimycin reduced the mean cell fluorescence to 37.4 ± 1.8% of untreated cells while BK could partly preserve the fluorescence and, hence, protect the cells (50.5 ± 2.3%, P < 0.001). The BK-induced mitochondrial protection could again be blocked by AG1478, GM6001 and MMP-8 inhibitor. Finally, Western blotting revealed that BK's protection was correlated with increased phosphorylation of EGFR and its downstream target Akt. Conclusion:, These results indicate that BK at reperfusion triggers its protective signalling pathway through MMP-8-dependent transactivation of the EGFR. [source] Glutathione deficiency intensifies ischaemia-reperfusion induced cardiac dysfunction and oxidative stressACTA PHYSIOLOGICA, Issue 1 2001S. Leichtweis The efficacy of glutathione (GSH) in protecting ischaemia-reperfusion (I-R) induced cardiac dysfunction and myocardial oxidative stress was studied in open-chest, stunned rat heart model. Female Sprague,Dawley rats were randomly divided into three experimental groups: (1) GSH-depletion, by injection of buthionine sulphoxamine (BSO, 4 mmol kg,1, i.p.) 24 h prior to I-R, (2) BSO injection (4 mmol kg,1, i.p.) in conjunction with acivicin (AT125, 0.05 mmol kg,1, i.v.) infusion 1 h prior to I-R, and (3) control (C), receiving saline treatment. Each group was further divided into I-R, with surgical occlusion of the main left coronary artery (LCA) for 30 min followed by 20 min reperfusion, and sham. Myocardial GSH content and GSH : glutathione disulphide (GSSG) ratio were decreased by ,50% (P < 0.01) in both BSO and BSO + AT125 vs. C. Ischaemia-reperfusion suppressed GSH in both left and right ventricles of C (P < 0.01) and left ventricles of BSO and BSO + AT125 (P < 0.05). Contractility (+dP/dt and ,dP/dt) in C heart decreased 55% (P < 0.01) after I and recovered 90% after I-R, whereas ±dP/dt in BSO decreased 57% (P < 0.01) with ischaemia and recovered 76 and 84% (P < 0.05), respectively, after I-R. For BSO + AT125, ±dP/dt were 64 and 76% (P < 0.01) lower after ischaemia, and recovered only 67 and 61% (P < 0.01) after I-R. Left ventricular systolic pressure in C, BSO and BSO + AT125 reached 95 (P > 0.05) 87 and 82% (P < 0.05) of their respective sham values after I-R. Rate-pressure double product was 11% (P > 0.05) and 25% (P < 0.05) lower in BSO and BSO + AT125, compared with Saline, respectively. BSO and BSO + AT125 rats demonstrated significantly lower liver GSH and heart Mn superoxide dismutase activity than C rats after I-R. These data indicate that GSH depletion by inhibition of its synthesis and transport can exacerbate cardiac dysfunction inflicted by in vivo I-R. Part of the aetiology may involve impaired myocardial antioxidant defenses and whole-body GSH homeostasis. [source] Thaliporphine protects ischemic and ischemic-reperfused rat hearts via an NO-dependent mechanismDRUG DEVELOPMENT RESEARCH, Issue 3 2001Li-Man Hung Abstract In ischemia or ischemia-reperfusion (I/R), nitric oxide (NO) can potentially exert several beneficial effects. Thaliporphine, a natural alkaloid with Ca2+ channel-activating and Na+/K+ channel-blocking activities, increased NO levels and exerted cardioprotective action in ischemic or I/R rats. The role of NO in the cardioprotective actions of thaliporphine was assessed. The severity of rhythm disturbances and mortality in anesthetized rats with either coronary artery occlusion for 30 min, or 5 min followed by 30-min reperfusion, were monitored and compared in thaliporphine- vs. placebo-treated groups. Thaliporphine treatment significantly increased NO and decreased lactate dehydrogenase (LDH) levels in the blood during the end period of ischemia or I/R. These changes in NO and LDH levels by thaliporphine were associated with a reduction in the incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) during ischemic or I/R period. The mortality of animals was also completely prevented by 1 × 10,8 moles/kg of thaliporphine. In animals subjected to 4 h of left coronary artery occlusion, 1 × 10,7 moles/kg of thaliporphine dramatic reduced cardiac infarct zone from 46 ± 6% to 7.1 ± 1.9%. Inhibition of NO synthesis with 3.7 × 10,6 moles/kg of N, -nitro-L-arginine methyl ester (L-NAME) abolished the beneficial effects of thaliporphine during 30 min or 4 h myocardial ischemia. However, the antiarrhythmic activity and mortality reduction efficacy of thaliporphine during reperfusion after 5 min of ischemia was only partially antagonized by L-NAME. These results showed that thaliporphine efficiently exerted the cardioprotections either in acute or prolonged coronary artery occlusion or occlusion-reperfusion situations. The fact that thaliporphine induced cardioprotective effects were abrogated by L-NAME indicates that NO is an important mediator for the cardioprotective effects of thaliporphine in acute or prolonged ischemia, whereas antioxidant activities may contribute to the protection of I/R injury. Drug Dev. Res. 52:446,453, 2001. © 2001 Wiley-Liss, Inc. [source] Cardiac and coronary function in the Langendorff-perfused mouse heart modelEXPERIMENTAL PHYSIOLOGY, Issue 1 2009Melissa E. Reichelt The Langendorff mouse heart model is widely employed in studies of myocardial function and responses to injury (e.g. ischaemia). Nonetheless, marked variability exists in its preparation and functional properties. We examined the impact of early growth (8, 16, 20 and 24 weeks), sex, perfusion fluid [Ca2+] and pacing rate on contractile function and responses to 20 min ischaemia followed by 45 min reperfusion. We also assessed the impact of strain, and tested the utility of the model in studying coronary function. Under normoxic conditions, hearts from 8-week-old male C57BL/6 mice (2 mm free perfusate [Ca2+], 420 beats min,1) exhibited 145 ± 2 mmHg left ventricular developed pressure (LVDP). Force development declined by ,15% (126 ± 5 mmHg) with a reduction in free [Ca2+] to 1.35 mm, and by 25% (108 ± 3 mmHg) with increased pacing to 600 beats min,1. While elevated heart rate failed to modify ischaemic outcome, the lower [Ca2+] significantly improved contractile recovery (by >30%). We detected minimal sex-dependent differences in normoxic function between 8 and 24 weeks, although age modified contractile function in males (increased LVDP at 24 versus 8 weeks) but not females. Both male and female hearts exhibited age-related reductions in ischaemic tolerance, with a significant decline in recovery evident at 16 weeks in males and later, at 20,24 weeks, in females (versus recoveries in hearts at 8 weeks). Strain also modified tolerance to ischaemia, with similar responses in hearts from C57BL/6, 129/sv, Quackenbush Swiss and FVBN mice, but substantially greater tolerance in BALB/c hearts. In terms of vascular function, baseline coronary flow (20,25 ml min,1 g,1) was 50,60% of maximally dilated flows, and coronary reactive and functional hyperaemic responses were pronounced (up to 4-fold elevations in flow in hearts lacking ventricular balloons). These data indicate that attention to age (and sex) of mice will reduce variability in contractile function and ischaemic responses. Even small differences in perfusion fluid [Ca2+] also significantly modify tolerance to ischaemia (whereas modest shifts in heart rate do not impact). Ischaemic responses are additionally strain dependent, with BALB/c hearts displaying greatest intrinsic tolerance. Finally, the model is applicable to the study of vascular reactivity, providing large responses and excellent reproducibility. [source] Effects of melatonin and caffeic acid phenethyl ester on testicular injury induced by myocardial ischemia/reperfusion in ratsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2005Mukaddes E Abstract Experimental studies indicate that ischemia/reperfusion (I/R) causes remote organ injury although the molecular mechanism has not been clearly defined. In this report, the role of oxidative injury on testicular damage following myocardial I/R injury and the effects of antioxidant agents, melatonin and caffeic acid phenethyl ester (CAPE), on testicular injury were investigated. As far as we know, this is the first report demonstrating that myocardial I/R induces damage to the testes. Thirty-two male Wistar rats were randomly divided into four groups: sham operation (SO), I/R + vehicle, I/R + melatonin, and I/R + caffeic acid phenethyl ester. To produce cardiac damage, the left main coronary artery was occluded for 30 min, followed by 120 min reperfusion, in anesthetized rats. Serum nitric oxide (NO) and malondialdehyde (MDA) levels and morphological changes were examined. I/R was accompanied by a significant increase in serum MDA and NO levels, whereas, melatonin and CAPE administration significantly reduced these values. Melatonin was more efficient in reducing MDA levels than CAPE (P < 0.05). I/R induced myocardial damage, manifested as the histopathological evidence of intracellular vacuolization, interstitial edema, neutrophil infiltration and coagulative necrosis. I/R + vehicle group showed many histological alterations such as focal tubular atrophy, and degeneration and disorganization of the seminiferous epithelium in testes. The number of atrophic tubules and degenerating cells was significantly higher in I/R + vehicle group than that of SO group. Melatonin and CAPE significantly reduced the number of degenerating cells; additionally, melatonin reduced the number of atrophic tubules (P < 0.05). Our results indicate that myocardial I/R induces severe testicular damage and antioxidant agents, especially melatonin, have protective effects on testicular injury after myocardial I/R. Our data emphasize that oxygen-based reactants may play a central role in remote organ injury. [source] Post-conditioning with cyclosporine A fails to reduce the infarct size in an in vivo porcine modelACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 7 2010R. H. LIE Background: Cyclosporine A has generated intense interest in the field of cardioprotection due to its ability to protect the mitochondria at reperfusion by blocking the opening of the mitochondrial permeability transition pore. The aim of our study was to examine the cardioprotective effect of Sandimmun®, a clinically available formulation of cyclosporine A, in an in vivo large mammal model. Methods: Forty-eight pigs were randomly allocated to one of three groups: (i) Control group (Con, n=19), (ii) Cyclosporine group, (Cyclo, n=19) Sandimmun® 10 mg/kg i.v. bolus 5 min before reperfusion and (iii) Pre-conditioning group (Precon, n=10) two cycles of 10 min ischemia interspersed with 30-min reperfusion. The study was further sub-divided into a metabolic protocol, evaluating myocardial metabolism by measuring changes in the interstitial lactate concentration, and a coronary flow protocol. All animals were subjected to 40 min of left anterior descending coronary artery occlusion, followed by 180 min of reperfusion before histochemical staining and assessment of infarct size by planimetry. Results: Infarct sizes were measured as: Con 51.4 ± 16.5%, Cyclo 47.3 ± 15.7% and Precon 2.4 ± 3.6%, with no significant difference between the Con and Cyclo groups but a highly significant difference between the Precon and Cyclo and Con groups (P<0.0001 for both comparisons). In the Cyclo group, the interstitial lactate concentration was significantly increased compared with the Con group at 6-min reperfusion, although significantly lower at 14 min presumably due to accelerated washout. Conclusion: In this large animal model, a 10 mg/kg bolus administration of Sandimmun® 5 min before reperfusion did not reduce the infarct size. [source] Regulatory proteins of eukaryotic initiation factor 2-alpha subunit (eIF2,) phosphatase, under ischemic reperfusion and toleranceJOURNAL OF NEUROCHEMISTRY, Issue 4 2007Lidia García-Bonilla Abstract Phosphorylation of the , subunit of eukaryotic translation initiation factor 2 (eIF2,), which is one of the substrates of protein phosphatase 1 (PP1), occurs rapidly during the first minutes of post-ischemic reperfusion after an episode of cerebral ischemia. In the present work, two experimental models of transient global ischemia and ischemic tolerance (IT) were used to study PP1 interacting/regulatory proteins following ischemic reperfusion. For that purpose we utilized PP1 purified by microcystin chromatography, as well as 2D DIGE of PP1, and PP1, immunoprecipitates. The highest levels of phosphorylated eIF2, found after 30 min reperfusion in rats without IT, correlated with increased levels in PP1 immunoprecipitates of the inhibitor DARPP32 as well as GRP78 and HSC70 proteins. After 4 h reperfusion, the levels of these proteins in PP1c complexes had returned to control values, in parallel to a significant decrease in eIF2, phosphorylated levels. IT that promoted a decrease in eIF2, phosphorylated levels after 30 min reperfusion induced the association of GADD34 with PP1c, while prevented that of DARPP32, GRP78, and HSC70. Different levels of HSC70 and DARPP32 associated with PP1, and PP1, isoforms, whereas GRP78 was only detected in PP1, immunoprecipitates. Here we suggest that PP1, through different signaling complexes with their interacting proteins, may modulate the eIF2, phosphorylation/dephosphorylation during reperfusion after a transient global ischemia in the rat brain. Of particular interest is the potential role of GADD34/PP1c complexes after tolerance acquisition. [source] Acute remote ischemic preconditioning II: The role of nitric oxideMICROSURGERY, Issue 6 2002Markus V. Küntscher M.D. The purpose of this study was to determine whether nitric oxide (NO) plays a role in the mechanism of acute "classic" as well as acute remote ischemic preconditioning (IP). Thirty-two male Wistar rats were divided into five experimental groups. The rat cremaster flap in vivo microscopy model was used for assessment of ischemia/reperfusion injury. In the control group (CG, n = 8), a 2-hr flap ischemia was induced after preparation of the cremaster muscle. The animals of group NO (n = 6) received 500 nmol/kg of the NO-donor spermine/nitric oxide complex (Sper/NO) intravenously 30 min prior to ischemia. The group LN + P (L-NAME + preclamping, n = 6) received 10 mg/kg N,-nitro-L-arginine methyl ester (L-NAME) intravenously before preclamping of the flap pedicle (10-min cycle length, 30-min reperfusion). L-NAME (10 mg/kg) was administered in group LN + T (L-NAME + tourniquet, n = 6) before ischemia of the right hindlimb was induced, using a tourniquet for 10 min after flap elevation. The limb was then reperfused for 30 min. Thereafter, flap ischemia was induced in each group as in group CG. In vivo microscopy was performed after 1 hr of flap reperfusion in each animal. Group NO demonstrated a significantly higher red blood cell velocity (RBV) in the first-order arterioles and capillaries, a higher capillary flow, and a decreased number of leukocytes adhering to the endothelium (stickers) of the postcapillary venules by comparison to all other groups (P < 0.05). The average capillary RBV and capillary flow were still higher in the CG than in the groups receiving L-NAME (P < 0.05). The data show that NO plays an important role in the mechanism of both acute "classic" as well as acute remote IP, since the administration of a NO-donor previous to ischemia simulates the effect of IP, whereas the nonspecific blocking of NO synthesis by L-NAME abolishes the protective effect of flap preconditioning. © 2002 Wiley-Liss, Inc. MICROSURGERY 22:227-231 2002 [source] Effect of dantrolene in an in vivo and in vitro model of myocardial reperfusion injuryACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 2 2000B. Preckel Background: In skeletal muscle, dantrolene reduces free cytosolic calcium by inhibiting calcium release from the sarcoplasmic reticulum. A similar effect in ischemic-reperfused heart cells would protect myocardial tissue against reperfusion injury. We tested the hypothesis that dantrolene infusion during reperfusion protects the heart against reperfusion injury. Methods: Isovolumetric beating rat hearts were subjected to 30 min of ischemia followed by 60 min of reperfusion. Left ventricular (LV) developed pressure (LVDP) and creatine kinase release (CKR) were determined as indices of myocardial performance and cellular injury, respectively. In the treatment groups, dantrolene (25 (DAN25) or 100 (DAN100) ,mol l,1) was infused during the first 15 min of reperfusion; control hearts received the respective concentration of the vehicle (mannitol (CON25, CON100), each group n=7). To investigate the effects of dantrolene on reperfusion injury in vivo, 18 chloralose-anesthetized rabbits were subjected to 30 min occlusion and 180 min reperfusion of a major coronary artery. LV pressure (LVP), cardiac output (CO), and infarct size were determined. During the last 5 min of ischemia, nine rabbits received 10 mg kg,1 dantrolene intravenously (DAN). Another nine rabbits received the vehicle (dimethylsulfoxide) and served as controls (CON). Results: In isolated rat hearts, there was no recovery of LVDP in any group. Total CKR during 1 h of reperfusion was 845±76 (CON100) and 550±81 U g,1 dry mass (DAN100, P<0.05). In rabbits in vivo, hemodynamic baseline values were similar between groups (CON vs. DAN: LVP, 99±6 (mean±SEM) vs. 91±6mm Hg, P=0.29; CO, 252±26 vs. 275±23 ml min,1, P=0.53). During coronary artery occlusion, LVP and CO were reduced in both groups (CON: LVP, 89±3%; CO, 90±5% of baseline values) and LVP did not recover to baseline values during reperfusion (51±5% (CON) vs. 67±7% (DAN) of baseline, P=0.10). Infarct size was 41±4% of the area at risk in controls and 37±6% in dantrolene treated hearts (P=0.59). Conclusions: Dantrolene reduced CKR, indicating an attenuation of lethal cellular reperfusion injury in isolated rat hearts. However, in the rabbit in vivo, there was no effect on the extent of reperfusion injury after regional myocardial ischemia. [source] Evidence that endogenous inosine and adenosine-mediated hyperglycaemia during ischaemia,reperfusion through A3 adenosine receptorsAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2009D. Cortés Summary 1,The molecular mechanism underlying stress-induced hyperglycemia has not been comprehensively clarified. Recently, we demonstrated in ischaemia-reperfusion (I-R) stress-subjected liver that inosine and adenosine are mainly responsible for the hyperglycemia observed. 2,We aimed to advance in the knowledge of the role of inosine plus adenosine as mediators of hepatic-induced hyperglycemia detected after I-R in lower limbs. 3,Acute ischaemia was conducted in anesthetized rats by occluding downstream abdominal aorta and cava vein; then, reperfusion was allowed. Blood samples from hepatic or abdominal cava veins were taken throughout the experiments to measure glucose, inosine and adenosine. Antagonists to adenosine (AdoR) and adrenergic receptors (AdrR) were administered during ischaemia to analyze their effect on hepatic glucose release. 4,Ischaemia up to 60 min produced minor increase of glucose and nucleosides blood values, but 5 min of ischaemia followed by 2- (or 10-) min reperfusion increased glucose 23%, and those of inosine or adenosine by 100%. After 60 min of ischaemia and 10 min of reperfusion, glycemia rose 2-fold and blood inosine and adenosine, 3.3- and 2.7-fold, respectively. A linear positive correlation, r2, as high as 0.839 between glucose and either nucleoside blood values was calculated. The hyperglycemia response to I-R decreased by 0, 25, 33, 45 and 100% after selective inhibition of A2B AdoR, A2A AdoR, a1B AdrR, A1 AdoR, and A3 AdoR, respectively. 5,Inosine-adenosine couple through activation of hepatic A3 AdoR is the main signal for releasing glucose from liver glycogen and for promoting hyperglycemia following experimental injury of I-R from lower limbs. [source] Cardioprotection from ischemia-reperfusion injury due to Ras-GTPase inhibition is attenuated by glibenclamide in the globally ischemic heartCELL BIOCHEMISTRY AND FUNCTION, Issue 4 2007Ibrahim Al-Rashdan Abstract The present study was designed to see if acute local inhibition of Ras-GTPase before or after ischemia (during perfusion) would produce protection against ischemia and reperfusion (I/R)-induced cardiac dysfunction. The effect of glibenclamide, an inhibitor of cardiac mitochondrial ATP-sensitive potassium (mitoKATP) channels, on Ras-GTPase-mediated cardioprotection was also studied. 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). Perfusion with Ras-GTPase inhibitor FPT III before I/R [FPT(pre)], significantly enhanced cardiac recovery in terms of left ventricular contractility. Pmax was significantly higher at the end of 30,min reperfusion in FPT(pre)-treated hearts compared to pre-conditioned hearts. However, the degree of improvement in left ventricular contractility was significantly less when FPT III was given only after ischemia during reperfusion [FPT(post)]. Combination treatment with FPT III and glibenclamide before I/R resulted in significant reduction of FPT III-mediated cardioprotection. These data suggest that activation of Ras-GTPase signaling pathways during ischemia are critical in the development of left ventricular dysfunction and that opening of mitoKATP channels, at least in part, contributes to cardioprotection produced by Ras-GTPase inhibition. Copyright © 2006 John Wiley & Sons, Ltd. [source] Activation Of ,1 -Adrenoceptors Is Not Essential For The Mediation Of Ischaemic Preconditioning In Rat HeartCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2002E Vasara SUMMARY 1. The aim of the present study was to clarify the role of ,1 -adrenoceptors in the mechanism of ischaemic preconditioning (IP). 2. Rat isolated perfused hearts were either non- preconditioned, preconditioned with 5 min ischaemia or treated for 5 min with ,1 -adrenoceptor agonists (50 ,mol/L phenylephrine; 0.1, 0.5 and 1 ,mol/L methoxamine) before being subjected to 45 min of sustained ischaemia followed by 60 min reperfusion. 3. Within each of the above protocols, hearts were divided into groups to which ,1 -adrenoceptor antagonists (prazosin, 5,-methyl urapidil and chloroethylclonidine (CEC)) were administered. Functional recovery and infarct size were used as indices of the effects of ischaemia. Ischaemic contracture characteristics and maximal diastolic pressure during reflow were also assessed. 4. Blockade of ,1 -adrenoceptors with prazosin or the subtype-selective antagonists 5,-methyl urapidil and CEC did not abolish the protective effect of IP with respect to both functional recovery and infarct size reduction. 5. Protection afforded by phenylephrine was attenuated in hearts treated with prazosin or the ,1B -adrenoceptor- selective antagonist CEC, but not in those treated with the ,1A -adrenoceptor-selective antagonist 5,-methyl urapidil. 6. Treatment with low concentrations of methoxamine, considered to be ,1A -adrenoceptor selective, did not confer any protection to the ischaemic myocardium. 7. A close relationship between accelerated ischaemic contracture and enhanced cardioprotection was observed. 8. The results suggest that ,1 -adrenoceptor stimulation mimics IP, but it is not an essential component in the mechanism behind the protective effect of IP in rat heart. In addition, the present study demonstrates that stimulation of the ,1B - but not the ,1A -adrenoceptor subtype is responsible for the catecholamine-induced protection of ischaemic myocardium in rat. [source] Impaired Heart Function And Noradrenaline Release After Ischaemia In Stroke-Prone Spontaneously Hypertensive RatsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2000Hong Chen SUMMARY 1. Stroke-prone spontaneously hypertensive rats (SHRSP) are a strain of rat that exhibit severely high blood pressure and stroke attacks at an early age, but their heart function in vitro has seldom been studied in detail. Although the activity of the sympathetic nervous system is known to increase after myocardial ischaemia, there is little information about the cardiac release of noradrenaline (NA) associated with heart function after ischaemia in SHRSP. The aim of the present study was to examine heart function and cardiac NA release after ischaemia in SHRSP. 2. Isolated hearts of 4- and 8-month-old SHRSP and age-matched Wistar-Kyoto (WKY) rats were perfused in a working heart preparation and were subjected to 30 min ischaemia followed by 30 min reperfusion. Heart function and coronary flow were monitored throughout the experiment. Coronary effluent was collected for determination of NA using high- performance liquid chromatography coupled with electrochemical detection. 3. Under baseline conditions, cardiac output of 4-month-old SHRSP was slightly but significantly decreased compared with that of WKY rats (P < 0.05), although coronary flow was maintained normally at this age. Eight-month-old SHRSP showed a further impairment of systolic heart function, with lower coronary flow and higher coronary vascular resistance under baseline conditions. Elevated left ventricular end-diastolic pressure was evident in SHRSP at both ages before ischaemia. Heart function was severely damaged after 30 min global ischaemia in SHRSP from both age groups. Stroke-prone spontaneously hypertensive rats also showed lower coronary flow and higher coronary vascular resistance during reperfusion. 4. Coronary NA was not detectable in WKY rats or SHRSP at 4 months of age under baseline conditions. In 8-month-old SHRSP, pre-ischaemic NA release was significantly higher than that in age-matched WKY rat controls. The concentration of NA in the coronary effluent of SHRSP during reperfusion was also significantly higher than that of WKY rats at both ages. 5. These data demonstrate that SHRSP have early impairment of both systolic and diastolic heart function compared with WKY rats. Severe damage of heart function and coronary flow after ischaemia in SHRSP was accompanied with an increased release of NA, which may play a harmful role in heart function impairment in SHRSP after ischaemia. [source] Effects Of The Na+/H+ Exchange Inhibitor Cariporide (HOE 642) On Cardiac Function And Cardiomyocyte Cell Death In Rat Ischaemic,Reperfused HeartCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2000Hajime Otani SUMMARY 1. Na+/H+ exchange has been implicated in the mechanism of reperfusion injury. We examined the effects of the cardiac-specific Na+/H+ exchange inhibitor cariporide (HOE 642) on postischaemic recovery of cardiac function and cardiomyocyte cell death (i.e. necrosis and apoptosis). 2. Rat isolated and buffer-perfused hearts were subjected to 25 min normothermic global ischaemia followed by 120 min reperfusion. Cariporide (10 ,mol/L) or its vehicle (0.01% dimethylsulphoxide) was administered for 15 min before ischaemia and for the first 30 min after reperfusion. 3. Cariporide significantly improved the recovery of isovolumic left ventricular function (heart rate, left ventricular developed pressure and left ventricular end-diastolic pressure) and coronary flow throughout reperfusion. Creatine kinase release during reperfusion was significantly less in the cariporide-treated heart. In situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL)- positive cardiomyocytes were also significantly less in the cariporide-treated heart after 120 min reperfusion. Electron microscopy showed necrotic changes without typical apoptotic features in cardiomyocytes after reperfusion. Such necrotic changes were mitigated by cariporide. Simultaneous detection of necrotic and apoptotic cardiomyocytes using propidium iodide (PI) and Annexin V revealed that cardiomyocytes in the infarct area were stained with only PI or both PI and Annexin V. Cariporide did not alter the pattern of cardiomyocyte staining with PI and Annexin V, although the number of cardiomyocytes stained with PI or PI plus Annexin V was less than that in vehicle-treated hearts. 4. These results suggest that apoptosis is not a major manifestation of cardiomyocyte cell death in the ischaemic, reperfused myocardium and a cariporide-sensitive mechanism of reperfusion injury promotes both necrotic and apoptotic processes of cell death. [source] | |||||||||||||