zoniporide and Reperfusion-Injury

Primary neuroprotective properties of new inhibitor of Na⁺/⁺ exchanger (compound RU-1355) were established on the model of 60-min focal ischemia of the left middle cerebral artery followed by 24-h reperfusion in rats. Compound RU-1355 significantly (by 34%) decreased neurological symptoms, reduced (1.67 times) the growth of neuron-specific enolase level in serum, decreased (2.3 times) the size of the necrotic zone, and reduced by 59% (p <0.05) the degree of cerebral edema According to the results of morphometric, immunoassay, and neurological assessments of brain damage, compound RU-1355 is superior on ave- rage by 43.5% (p < 0.05) in comparison to selective NHE1 inhibitor zoniporide.

Topics: Animals; Animals, Outbred Strains; Benzimidazoles; Brain; Brain Edema; Brain Ischemia; Cerebral Arteries; Cerebrovascular Disorders; Female; Gene Expression; Guanidines; Neuroprotective Agents; Phosphopyruvate Hydratase; Psychomotor Performance; Pyrazoles; Rats; Reperfusion Injury; Sodium-Hydrogen Exchanger 1

Ischemia-reperfusion injury plays an important role in the development of primary allograft failure after heart transplantation. Inhibition of the Na+/H+ exchanger is one of the most promising therapeutic strategies for treating ischemia-reperfusion injury. Here we have characterized the cardioprotective efficacy of zoniporide and the underlying mechanisms in a model of myocardial preservation using rat isolated working hearts.. Rat isolated hearts subjected to 6 h hypothermic (1-4°C) storage followed by 45 min reperfusion at 37°C were treated with zoniporide at different concentrations and timing. Recovery of cardiac function, levels of total and phosphorylated protein kinase B, extracellular signal-regulated kinase 1/2, glycogen synthase kinase-3β and STAT3 as well as cleaved caspase 3 were measured at the end of reperfusion. Lactate dehydrogenase release into coronary effluent before and post-storage was also measured.. Zoniporide concentration-dependently improved recovery of cardiac function after reperfusion. The functional recovery induced by zoniporide was accompanied by up-regulation of p-extracellular signal-regulated kinase 1/2 and p-STAT3, and by reduction in lactate dehydrogenase release and cleaved caspase 3. There were no significant differences in any of the above indices when zoniporide was administered before, during or after ischemia. The STAT3 inhibitor, stattic, abolished zoniporide-induced improvements in functional recovery and up-regulation of p-STAT3 after reperfusion.. Zoniporide is a potent cardioprotective agent and activation of STAT3 plays a critical role in the cardioprotective action of zoniporide. This agent shows promise as a supplement to storage solutions to improve preservation of donor hearts.

Topics: Animals; Cardiotonic Agents; Cardiovascular Physiological Phenomena; Caspase 3; Cyclic S-Oxides; Disease Models, Animal; Dose-Response Relationship, Drug; Guanidines; Heart; Heart Transplantation; L-Lactate Dehydrogenase; Male; Mitogen-Activated Protein Kinase 3; Myocardium; Naloxone; Narcotic Antagonists; Pyrazoles; Rats; Rats, Wistar; Reperfusion Injury; STAT3 Transcription Factor

Intracellular Na(+) concentration ([Na(+)](i)) rises in the heart during ischemia, and on reperfusion, there is a transient rise followed by a return toward control. These changes in [Na(+)](i) contribute to ischemic and reperfusion damage through their effects on Ca(2+) overload. Part of the rise of [Na(+)](i) during ischemia may be caused by increased activity of the cardiac Na(+)/H(+) exchanger (NHE1), activated by the ischemic rise in [H(+)](i). In support of this view, NHE1 inhibitors reduce the [Na(+)](i) rise during ischemia. Another possibility is that the rise of [Na(+)](i) during ischemia is caused by Na(+) influx through channels. We have reexamined these issues by use of two different NHE1 inhibitors, amiloride, and zoniporide, in addition to tetrodotoxin (TTX), which blocks voltage-sensitive Na(+) channels. All three drugs produced cardioprotection after ischemia, but amiloride (100 microM) and TTX (300 nM) prevented the rise in [Na(+)](i) during ischemia, whereas zoniporide (100 nM) did not. Both amiloride and zoniporide prevented the rise of [Na(+)](i) on reperfusion, whereas TTX was without effect. In an attempt to explain these differences, we measured the ability of the three drugs to block Na(+) currents. At the concentrations used, TTX reduced the transient Na(+) current (I (Na)) by 11 +/- 2% while amiloride and zoniporide were without effect. In contrast, TTX largely eliminated the persistent Na(+) current (I (Na,P)) and amiloride was equally effective, whereas zoniporide had a substantially smaller effect reducing I (Na,P) to 41 +/- 8%. These results suggest that part of the effect of NHE1 inhibitors on the [Na(+)](i) during ischemia is by blockade of I (Na,P). The fact that a low concentration of TTX eliminated the rise of [Na(+)](i) during ischemia suggests that I (Na,P) is a major source of Na(+) influx in this model of ischemia.

Topics: Amiloride; Anesthetics, Local; Animals; Cardiotonic Agents; Cell Separation; Female; Guanidines; In Vitro Techniques; Intracellular Space; Myocardium; Patch-Clamp Techniques; Pyrazoles; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sodium; Sodium Channel Blockers; Sodium-Hydrogen Exchanger 1; Sodium-Hydrogen Exchangers; Tetrodotoxin