Hexokinase II and reperfusion injury: TAT-HK2 peptide impairs vascular function in Langendorff-perfused rat hearts.

RATIONALE: Mitochondrial-bound hexokinase II (HK2) was recently proposed to play a crucial role in the normal functioning of the beating heart and to be necessary to maintain mitochondrial membrane potential. However, our own studies confirmed that mitochondria from ischemic rat hearts were HK2-depleted, yet showed no indication of depolarization and responded normally to ADP. OBJECTIVE: To establish whether the human TAT-HK2 peptide used to dissociate mitochondrial-bound HKII in the Langendorff-perfused heart may exert its effects indirectly by impairing coronary function. METHODS AND RESULTS: Ischemic preconditioning was blocked in rat hearts perfused with 2.5 µmol/L TAT-HK2 before ischemia or at the onset of reperfusion. However, TAT-HK2 also decreased the phosphocreatine:ATP ratio that correlated with reduced rate pressure product and increased diastolic pressure. These effects were preceded by increased aortic pressure (Langendorff constant flow) or decreased coronary flow (Langendorff constant pressure), which was also observed, albeit less pronounced, at 200 nmol/L TAT-HK2 and was prevented by coperfusion with the NO-donor diethylamine NONOate. Mitochondria from TAT-HK2-perfused hearts showed no loss of bound HK2, unlike mitochondria from ischemic hearts where the expected loss was prevented by ischemic preconditioning. CONCLUSIONS: In the perfused rat heart, TAT-HK2 should be used with caution and careful attention to dosage because some of its effects may be mediated by vasoconstriction of the coronary vasculature rather than dissociation of HK2 from myocyte mitochondria.

Pathophysiological consequences of TAT-HKII peptide administration are independent of impaired vascular function and ensuing ischemia.

RATIONALE: We have shown that partial dissociation of hexokinase II (HKII) from mitochondria in the intact heart using low-dose transactivating transcriptional factor (TAT)-HKII (200 nmol/L) prevents the cardioprotective effects of ischemic preconditioning, whereas high-dose TAT-HKII (10 µmol/L) administration results in rapid myocardial dysfunction, mitochondrial depolarization, and disintegration. In this issue of Circulation Research, Pasdois et al argue that the deleterious effects of TAT-HKII administration on cardiac function are likely because of vasoconstriction and ensuing ischemia. OBJECTIVE: To investigate whether altered vascular function and ensuing ischemia recapitulate the deleterious effects of TAT-HKII in intact myocardium. METHODS AND RESULTS: Using a variety of complementary techniques, including mitochondrial membrane potential (ΔΨm) imaging, high-resolution optical action potential mapping, analysis of lactate production, nicotinamide adenine dinucleotide epifluorescence, lactate dehydrogenase release, and electron microscopy, we provide direct evidence that refutes the notion that acute myocardial dysfunction by high-dose TAT-HKII peptide administration is a consequence of impaired vascular function. Moreover, we demonstrate that low-dose TAT-HKII treatment, which abrogates the protective effects of ischemic preconditioning, is not associated with ischemia or ischemic injury. CONCLUSIONS: Our findings challenge the notion that the effects of TAT-HKII are attributable to impaired vascular function and ensuing ischemia, thereby lending further credence to the role of mitochondria-bound HKII as a critical regulator of cardiac function, ischemia-reperfusion injury, and cardioprotection by ischemic preconditioning.

Rehidratación oral con bebidas refrescantes. Riesgo de yatrogenia / Oral rehydration with commercial beverages: risk of iatrogenic complications

Objetivo: Con la finalidad de comparar las recomendaciones de la ESPGHAN para la solución de rehidratación oral para Europa con la composición de bebidas refrescantes: españolas, se ha medido su concentración de glucosa, sodio, potasio y su osmolaridad. Material y métodos: Sesenta y una bebidas refrescantes comercializadas en España se han clasificado en 7 grupos. La concentración de sodio y potasio se ha determinado por potenciometría con electrodo selectivo. La glucosa se ha analizado por el método de la hexocinasa y la osmolaridad por osmometría basada en el punto de congelación. Resultados: De los refrescos analizados, las bebidas isotónicas son las que más sodio contienen (valor medio 17,5; valor máximo de 33 mmol/L para Isostar©), pero muy inferiores a los 60 mmol/L recomendados para la solución de rehidratación oral. Sólo los zumos de frutas contienen cifras aceptables de potasio, aunque insuficiente sodio y excesiva osmolaridad. Tanto las gaseosas como las colas light prácticamente no contienen glucosa. La relación glucosa/sodio es excesiva en todos los grupos de bebidas excepto en las colas light, por contener escasa glucosa. La osmolaridad es inaceptable en todos los grupos de bebidas (en 5 por exceso y en 2 por defecto). Los riesgos del empleo de bebidas refrescantes corno solución de rehidratación oral son la falta de reposición electrolítica (de sodio fundamentalmente) y la persistencia de la diarrea tanto por la excesiva carga osmolar como por la falta de reversión de la bomba de sodio acopiada a la glucosa. Conclusiones: El uso de refrescos como solución de rehidratación oral es inadecuado en el tratamiento de la diarrea aguda del niño por: insuficiente glucosa, sodio y osmolaridad (colas light y gaseosas), y excesivas osmolaridad y relación glucosa/sodio, con sodio insuficiente (colas, zumos, bebidas isotónicas, tés y otros) (AU)