Effects of dantrolene on ischemia-reperfusion injury in animal models: a review of outcomes in heart, brain, liver, and kidney

Abstract

Background/objectives: Ischemia-reperfusion (IR) is the restoration of blood flow to a tissue that was formerly deficient of blood flow. Tissue damage after IR is considered an IR injury (IRI). During IR, there is an increased level of cytosolic calcium ([Ca(2+)]i) due to the release of calcium from mitochondrial, sarcoendoplasmic reticulum, and nuclear organelles. Dantrolene sodium (dantrolene) is a 1-[[[5-(4-nitrophenol)-2-furanyl]methylene]amino]-2, 4-imidazolidinedione sodium salt with a nonspecific mechanism, inhibiting organelle release of Ca(2+) into the cytosol. This work reviews the outcomes of administering dantrolene in brain, heart, liver, and kidney animal models of IRI.

Methods: An extensive PubMed, MEDLINE, and MEDLAR literature review during the last 30 years on the effect of dantrolene in IRI in animal models was analyzed to determine the clinical implications of this important study. Particular attention was given to dantrolene in heart, brain, liver, and kidney IRI.

Results: Heart: Nine studies of heart IRI were reviewed and include an in vivo dog model (n = 1), in vivo rabbit model (n = 1), isolated dog myocardial fibers (n = 1), and isolated rat hearts (n = 6). Four studies showed decreased infarct size and increased cardiac function after IRI. One in vivo rabbit study found no difference in infarct size or cardiac function after IRI versus controls. Dantrolene may be protective or inductive of post-IRI arrhythmias depending on preestablished myocyte cycling times. Brain: Nine studies of brain IRI were reviewed and include an in vivo dog model (n = 1), in vivo gerbil model (n = 2), and in vivo rat models (n = 6). Dantrolene shows protective decreases in apoptotic markers in 6 studies, but it shows no effect on the necrotic core and mixed effects on reduction of infarct volume. One study found increased mortality in the dantrolene group. Liver: One study of in vivo rat liver IRI found that dantrolene decreased liver function tests, tissue necrosis factor α, tissue necrosis, and increased interleukin 10. Kidney: One study of in vivo rat kidney IRI showed that dantrolene had no effect.

Conclusions: Dantrolene shows protective effects in animal models of heart, brain, and potentially liver IRI, reinforcing the importance of calcium homeostasis during IRI. Variations of dose, timing of administration, route of administration, and outcomes between studies make definitive conclusions difficult. The nonspecific mechanism of action of dantrolene may also account for the variation among studies. Lack of studies in the liver and kidney makes any consensus in these organs premature, and thus, emphasis for this review was put on studies of the heart and brain.