n-(1-3-benzodioxol-5-ylmethyl)-2-6-dichlorobenzamide and Heart-Arrest

Survival after sudden cardiac arrest is limited by postarrest myocardial dysfunction, but understanding of this phenomenon is constrained by a lack of data from a physiological model of disease. In this study, we established an in vivo model of cardiac arrest and resuscitation, characterized the biology of the associated myocardial dysfunction, and tested novel therapeutic strategies.. We developed rodent models of in vivo postarrest myocardial dysfunction using extracorporeal membrane oxygenation resuscitation followed by invasive hemodynamics measurement. In postarrest isolated cardiomyocytes, we assessed mechanical load and Ca(2) (+)-induced Ca(2+) release (CICR) simultaneously using the microcarbon fiber technique and observed reduced function and myofilament calcium sensitivity. We used a novel fiberoptic catheter imaging system and a genetically encoded calcium sensor, GCaMP6f, to image CICR in vivo.. We found potentiation of CICR in isolated cells from this extracorporeal membrane oxygenation model and in cells isolated from an ischemia/reperfusion Langendorff model perfused with oxygenated blood from an arrested animal but not when reperfused in saline. We established that CICR potentiation begins in vivo. The augmented CICR observed after arrest was mediated by the activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Increased phosphorylation of CaMKII, phospholamban, and ryanodine receptor 2 was detected in the postarrest period. Exogenous adrenergic activation in vivo recapitulated Ca(2+) potentiation but was associated with lesser CaMKII activation. Because oxidative stress and aldehydic adduct formation were high after arrest, we tested a small-molecule activator of aldehyde dehydrogenase type 2, Alda-1, which reduced oxidative stress, restored calcium and CaMKII homeostasis, and improved cardiac function and postarrest outcome in vivo.. Cardiac arrest and reperfusion lead to CaMKII activation and calcium long-term potentiation, which support cardiomyocyte contractility in the face of impaired postarrest myofilament calcium sensitivity. Alda-1 mitigates these effects, normalizes calcium cycling, and improves outcome.

Topics: Aldehyde Dehydrogenase; Animals; Benzamides; Benzodioxoles; Calcium; Calcium Signaling; Calcium-Binding Proteins; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cardiomyopathies; Heart Arrest; Long-Term Potentiation; Myocytes, Cardiac; Sarcoplasmic Reticulum

Ischemia/reperfusion damage is common during open-heart surgery. Activation of aldehyde dehydrogenase-2 can significantly reduce ischemia/reperfusion damage. We hypothesized that adding aldehyde dehydrogenase-2 agonist to regular cardioplegia solution would further ameliorate ischemia/reperfusion damage. Alda-1 was used as an aldehyde dehydrogenase-2 agonist. Cardioprotection by histidine-tryptophan-ketoglutarate solution with and without Alda-1 was compared using an ex vivo perfused rat heart model of ischemia/reperfusion. Three groups of ex vivo rat hearts endured different treatments with variant ischemia or an ischemia/reperfusion time course: sham, no ischemia/reperfusion; histidine-tryptophan-ketoglutarate; and histidine-tryptophan-ketoglutarate plus Alda-1. Aldehyde dehydrogenase-2 expressions and activities, oxidative parameters (including 4-hydroxy-2-nonenal-His adducts, malondialdehyde levels, and glutathione/oxidized glutathione ratios), myocardial protein carbonyl levels, coronary effluents creatine kinase isoenzyme MB levels, and heart function parameters were measured and compared. Alda-1 significantly elevated myocardium aldehyde dehydrogenase-2 activity (P < .01). Increased aldehyde dehydrogenase-2 activity in turn attenuated ischemia/reperfusion-induced elevation in cardiac aldehydes, creatine kinase isoenzyme MB leakage, and protein carbonyl formation (P < .01). The Alda-1 group also obtained higher glutathione/oxidized glutathione ratios (P < .01). Aldehyde dehydrogenase-2 activation alleviated ischemia/reperfusion-induced cardiomyocyte contractile function impairment as evidenced by improved maximal velocity of pressure development and decline, left ventricular developed pressure, and heart rate (P < .01). Alda-1 supplementation can significantly improve the cardioprotection effect of cardioplegia solution, possibly through activation of aldehyde dehydrogenase-2, to remove toxic aldehydes. This may aid in the identification of novel cardioplegia solutions.

Topics: Aldehyde Dehydrogenase; Aldehyde Dehydrogenase, Mitochondrial; Animals; Benzamides; Benzodioxoles; Cardioplegic Solutions; Cardiotonic Agents; Enzyme Activation; Heart Arrest; Heart Arrest, Induced; Male; Mitochondrial Proteins; Myocardial Reperfusion Injury; Rats; Rats, Wistar; Up-Regulation