1. Cardioprotective effects of intracoronary administration of 4-chlorodiazepam in small and large animal models of ischemia-reperfusion
- Author
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Konstantinos Malliaras, Stella Vakrou, Chris J. Kapelios, Michalis Tsamatsoulis, Maria Anastasiou-Nana, Lambros Katsaros, Vasilis Sousonis, Stefania Sventzouri, Nicholas Michelinakis, and Despoina Perrea
- Subjects
Male ,0301 basic medicine ,Cardiac function curve ,medicine.medical_specialty ,Cardiotonic Agents ,Swine ,Ischemia ,Hemodynamics ,Myocardial Reperfusion Injury ,030204 cardiovascular system & hematology ,Random Allocation ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Translocator protein ,Animals ,Infusions, Intra-Arterial ,cardiovascular diseases ,Myocardial infarction ,Rats, Wistar ,Hypolipidemic Agents ,Benzodiazepinones ,biology ,business.industry ,medicine.disease ,Coronary Vessels ,Rats ,Disease Models, Animal ,Treatment Outcome ,030104 developmental biology ,No reflow phenomenon ,cardiovascular system ,Cardiology ,biology.protein ,Cardiology and Cardiovascular Medicine ,business ,Ligation ,Reperfusion injury - Abstract
Background The Translocator Protein (TSPO) of the mitochondrial membrane has been recognized as a potential therapeutic target for mitigation of myocardial ischemia-reperfusion injury. Administration of 4-chlorodiazepam (4-CLD), a TSPO ligand, has been shown to confer acute cardioprotective effects in small animals; however, long-term studies and studies in clinically-relevant large animal models are lacking. In the present study we investigated a potential cardioprotective effect of intracoronary administration of 4-CLD in small and large animal models of ischemia-reperfusion. Methods Acute myocardial infarction was induced in 38 Wistar rats and 29 farm pigs by ligation of the left anterior descending coronary artery, followed by reperfusion. Animals were randomized to undergo intracoronary infusion of 2μM 4-CLD or vehicle just prior (pigs) or immediately after (rats) reperfusion. Infarcted rats were euthanized either after 1h of reperfusion (for histological assessment of the "no reflow" area) or after 60days (for serial evaluation of cardiac function and structure by echocardiography and assessment of infarct size). Infarcted pigs were euthanized after 2h of reperfusion for histological assessment of infarct size and "no reflow" area. Results In infarcted rats, intracoronary infusion of 4-CLD resulted in acute reduction of the "no reflow" area and conferred durable long-term structural and functional benefits (reduction in infarct size, attenuation of adverse remodeling, improvement in global systolic function). In infarcted pigs, intracoronary infusion of 4-CLD was well-tolerated from a hemodynamic standpoint and resulted in acute reduction in infarct size, reduction in "no reflow" area and more rapid resolution of ST-segment elevation. Conclusions In a rat model of myocardial infarction, intracoronary administration of 4-CLD attenuated the "no reflow" phenomenon and produced long-term structural and functional benefits. In a porcine model of myocardial infarction intracoronary administration of 4-CLD did not raise safety concerns and conferred acute cardioprotective effects.
- Published
- 2016