sabiporide and Reperfusion-Injury

The present study investigated the protective effects of a novel NHE1 selective inhibitor, sabiporide, in a porcine model of asphyxia-induced cardiac arrest. Asphyxial cardiac arrest was induced by endotracheal tube clamping (ETC). The animals remained untreated for 3 min after loss of aortic pulsations (LOAP), and followed by chest compression and defibrillation. Sixteen of eighteen pigs had return of spontaneous circulation (ROSC), and were randomly assigned to two study groups. Group 1: vehicle control. Group 2: 3mg/kg sabiporide was given at 15 min after ROSC. Post-arrest myocardial dysfunction was present in both groups, and progressed over hours. Animals treated with sabiporide had less wall motion abnormality and higher left ventricular ejection fraction than control animals (33% in control group vs. 47% in sabiporide group). Sabopiride treatment also significantly improved post-arrest arterial blood pressure by 25% and cardiac stroke volume by 44%, and improved mixed-venous blood oxygen saturation by 38% and oxygen delivery by 118%. Furthermore, compared to the control group, the sabiporide group also had higher blood flows in the brain, heart, kidney, liver and spleen at 30 min after ROSC. There was no significant blood flow difference in distal ileum mucosa between control and sabiporide groups. In addition, sabiporide treatment significantly reduced cardiac myeloperoxidase (MPO) activity by 53% and cardiac troponin I by 51%, and reduced the plasma level of TNF-α by 52% and IL-6 by 41%. This study shows that post-arrest pharmacological conditioning with sabiporide affords protection from whole body ischemia-reperfusion injury in this model of asphyxia-induced cardiac arrest and resuscitation.

Topics: Animals; Asphyxia; Blood Circulation; Blood Pressure; Cardiotonic Agents; Cation Transport Proteins; Guanidines; Heart Arrest, Induced; Interleukin-6; Models, Animal; Myocardial Stunning; Myocardium; Oxygen; Oxygen Consumption; Peroxidase; Reperfusion Injury; Sodium-Hydrogen Exchanger 1; Sodium-Hydrogen Exchangers; Stroke Volume; Swine; Troponin I; Tumor Necrosis Factor-alpha

Sabiporide, a new benzoguanidine, was characterized on fibroblasts stably expressing the Na(+)/H(+) exchanger isoforms NHE-1, NHE-2 and NHE-3. 22Na(+) uptake experiments show that this compound possesses a K(i) of 5+/-1.2 x 10(-8) M for NHE-1, and discriminates efficiently between the NHE-1, -2 and -3 isoforms (K(i) for NHE-2: 3+/-0.9 x 10(-6) M, and K(i)>1 mM for NHE-3). Similar K(i) values are obtained on rat cardiomyocytes and human platelets expressing NHE-1 (K(i)'s of 7+/-1 x 10(-9) and 2.7+/-0.4 x 10(-8) M respectively). Interestingly, when compared with amiloride and cariporide, sabiporide inhibition persists even after this molecule had been rinsed out (half time of 7 h for sabiporide, and of 1 and 2.5 min for amiloride and cariporide, respectively), the decay of all these molecules exhibiting a complex multiexponential behavior. Thus, sabiporide, which possesses remarkable cardioprotective properties, is a specific NHE-1 inhibitor possessing unique binding kinetics.

Topics: Animals; Cardiotonic Agents; Cell Line; Cricetinae; Dose-Response Relationship, Drug; Female; Guanidines; Humans; Male; Myocytes, Cardiac; Protein Isoforms; Rabbits; Rats; Rats, Wistar; Reperfusion Injury; Sodium-Hydrogen Exchangers