Blocking Na+/H+exchange reduces [Na+]iand [Ca2+]iload after ischemia and improves function in intact hearts

An, Jianzhong; Varadarajan, Srinivasan G.; Camara, Amadou K.S.; Chen, Qun; Novalija, Enis; Gross, Garrett J.; Stowe, David F.

doi:10.1152/ajpheart.2001.281.6.h2398

Cited by 79 publications

(81 citation statements)

References 45 publications

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“…Protective effects of NHE inhibitors by posttreatment have been shown in previous studies in cardiac ischemic model [2,19]. Our results suggest that the effect of sabiporide may be involved in the reperfusion period, and similar results have been previously shown [2].…”

Section: Fig 2 Effect Of Sabiporide On Intracellular Casupporting

confidence: 91%

Effects of sabiporide, a specific Na+/H+ exchanger inhibitor, on neuronal cell death and brain ischemia

et al. 2005

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Section: Fig 2 Effect Of Sabiporide On Intracellular Casupporting

confidence: 91%

Effects of sabiporide, a specific Na+/H+ exchanger inhibitor, on neuronal cell death and brain ischemia

et al. 2005

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“…Prior approval was obtained from the Medical College of Wisconsin animal studies committee. The preparation has been described in detail previously (2,3,25,28,39). Guinea pigs (n ϭ 56) were prepared by the Langendorff method and perfused via the aortic root at 55 mmHg with a 37°C oxygenated, modified Krebs-Ringer (KR) solution as described previously (2,3,32,35,52).…”

Section: Methodsmentioning

confidence: 99%

“…If F values (P Ͻ 0.05) were significant, post hoc comparisons of means compared with the baseline control period (at 15 min) (Student's t-test with Duncan's adjustment for multiplicity) were used to differentiate treatment groups. The incidence of VF versus sinus rhythm was determined by 2 -analysis, and differences in VF duration were determined by unpaired t-tests. Differences among means were considered statistically significant when P Յ 0.05.…”

Section: Methodsmentioning

confidence: 99%

Anesthetic preconditioning: triggering role of reactive oxygen and nitrogen species in isolated hearts

Novalija¹,

Varadarajan²,

Camara³

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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We postulated that anesthetic preconditioning (APC) is triggered by reactive oxygen/ nitrogen species (ROS/RNS). We used the isolated guinea pig heart perfused with L-tyrosine, which reacts with ROS and RNS to form strong oxidants, principally peroxynitrite (ONOO Ϫ ), and then forms fluorescent dityrosine. ROS scavengers superoxide dismutase, catalase, and glutathione (SCG) and NO⅐ synthesis inhibitor N G -nitro-L-arginine methyl ester (L-NAME) were given 5 min before and after sevoflurane preconditioning stimuli. Drugs were washed out before 30 min of ischemia and 120 min of reperfusion. Groups were control (nontreated ischemia control), APC (two, 2-min periods of perfusion with 0.32 Ϯ 0.02 mM of sevoflurane; separated by a 6-min period of perfusion without sevoflurane), SCG, APC ϩ SCG, L-NAME, and APC ϩ L-NAME. Effluent dityrosine at 1 min reperfusion was 56 Ϯ 6 (SE) ‡, 15 Ϯ 5, 40 Ϯ 5 ‡, 39 Ϯ 4 ‡, 35 Ϯ 4 ‡, and 33 Ϯ 5 ‡ units ( ‡P Ͻ 0.05 vs. APC), respectively; left ventricular pressure (%baseline) at 60 min of reperfusion was 30 Ϯ 5 ‡, 60 Ϯ 4, 35 Ϯ 5 ‡, 37 Ϯ 5 ‡, 44 Ϯ 4, and 47 Ϯ 4; and infarct size (%total heart weight) was 50 Ϯ 5 ‡, 19 Ϯ 2, 48 Ϯ 3 ‡, 46 Ϯ 4 ‡, 42 Ϯ 4 ‡, and 45 Ϯ 2 ‡. Thus APC is initiated by ROS as shown by improved function, reduced infarct size, and reduced dityrosine on reperfusion; protective and ROS/RNS-reducing effect of APC were attenuated when bracketed by ROS scavengers or NO⅐ inhibition. guinea pig; experimental; pathophysiology; contractile function; infarct size CARDIAC ISCHEMIC PRECONDITIONING (IPC), first described in 1986 (21), is most often assessed by observations of reduced infarct size, attenuated mechanical dysfunction, or limited ultrastructural abnormality on reperfusion after prolonged ischemia (3,5,16,25,27,28,43). Anesthetics can also precondition hearts against ischemic-reperfusion (IR) injury (3,7,14,25,28). For example, Novalija and Stowe (28) reported that anesthetic preconditioning (APC) with sevoflurane mimics IPC by improving vascular, mechanical, and metabolic function in isolated hearts.The role of reactive oxygen species (ROS) in effecting cardiac injury on aerobic reperfusion after ischemia is now well known (11, 32). The seemingly paradoxical role of ROS and reactive nitrogen species (RNS) in triggering or mediating IPC has gained increasing importance (23,33,37). Studies using inhibitors of nitric oxide (NO⅐) synthase during IR injury suggest the specific role of NO⅐ in cardioprotection is unclear (12,16,22,23,33,(42)(43)(44). However, because NO⅐ is a free radical produced constitutively and because superoxide (O 2 Ϫ ⅐) reacts faster with NO⅐ than it does with superoxide dismutase (SOD), NO⅐ is a factor that must be considered in IR injury. We showed that NO⅐ release is improved along with vascular and mechanical function after IPC and APC with sevoflurane and that these effects are blocked by ATP-sensitive K (K ATP ) channel inhibition (25,28). Peroxynitrite (ONOO Ϫ ), the product of NO⅐ and O 2 Ϫ ⅐, is released on reperfusion after ischemia (45) and ...

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“…Less cytosolic Ca 2ϩ overload could also favor postresuscitation electrical stability and myocardial function. 24 …”

Section: Mechanisms Of Protective Actionmentioning

confidence: 99%

Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation

Ayoub

Kolarova

et al. 2003

Circulation

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Background-Inhibition of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) is emerging as a promising novel strategy for ameliorating myocardial injury associated with ischemia and reperfusion. We investigated whether NHE-1 inhibition (with cariporide) could minimize mechanical and electrical myocardial abnormalities that develop during ventricular fibrillation (VF) and improve outcome using a porcine model of closed-chest resuscitation. Methods and Results-Two groups of 8 pigs each were subjected to 8 minutes of untreated VF and randomized to receive either a 3-mg/kg bolus of cariporide or 0.9% NaCl immediately before an 8-minute interval of conventional closed-chest resuscitation. Cariporide prevented progressive increases in left ventricular free-wall thickness (from 1.0Ϯ0.2 to 1.5Ϯ0.3 cm with NaCl, PϽ0.001 versus 0.9Ϯ0.1 to 1.1Ϯ0.3 cm with cariporide, PϭNS), maintained the coronary perfusion pressure above resuscitability thresholds (10Ϯ8 versus 19Ϯ3 mm Hg before attempting defibrillation, PϽ0.05), and increased resuscitability (2 of 8 versus 8 of 8, PϽ0.005). In 2 additional groups of 4 pigs each subjected to a briefer interval of untreated VF, cariporide ameliorated postresuscitation shortening of the action potential duration (APD) at 30%, 60%, and 90% repolarization (ie, APD 60 at 2 minutes after resuscitation; 75Ϯ29 versus 226Ϯ16 ms, PϽ0.05), minimized postresuscitation ventricular ectopic activity preventing recurrent VF, and lessened postresuscitation myocardial dysfunction. Conclusions-NHE-1 inhibition may represent a highly potent novel strategy for resuscitation from VF that can ameliorate myocardial manifestations of ischemic injury and improve the effectiveness and outcome of closed-chest resuscitation.

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Blocking Na⁺/H⁺exchange reduces [Na⁺]_iand [Ca²⁺]_iload after ischemia and improves function in intact hearts

Cited by 79 publications

References 45 publications

Effects of sabiporide, a specific Na+/H+ exchanger inhibitor, on neuronal cell death and brain ischemia

Effects of sabiporide, a specific Na+/H+ exchanger inhibitor, on neuronal cell death and brain ischemia

Anesthetic preconditioning: triggering role of reactive oxygen and nitrogen species in isolated hearts

Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation

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