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Commentary

Intestinal Ischemia-Reperfusion Injury and Calcium Channel Blockers: Getting to the Core of the Problem

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Calcium (Ca2+) has an essential role in numerous cellular processes such as cell growth and differentiation, membrane excitability, exocytosis, and apoptosis. Its intracellular concentration is tightly regulated and maintained around 100 nM (ie. 10 000 times lower than in the extracellular compartment). Small, localized increases in cytosolic Ca2+ are able to quickly activate proteases, lipases, endonucleases or ion channels. Cytosolic Ca2+ overload is a key pathophysiological mechanism developing during ischemia. The source of this Ca2+ is unclear and may be either the extracellular space, the sarco(endo)plasmic reticulum or the mitochondria. This lack of certainty concerning the source of the Ca2+ has significant therapeutic relevance as, depending on the cellular compartment, the Ca2+ inflow occurs through different channels or exchange systems. Calcium is central to several injurious processes by acting as a secondary messenger, binding to, and activating various cytoplasmic proteins [Citation1]. Among many interactions, Ca2+ binds to calmodulin and subsequently activates nitric oxide synthase to produce nitric oxide. Nitric oxide may later react with the free oxygen radicals generated upon reoxygenation to form peroxynitrite, a highly toxic molecule able to damage both DNA and proteins. The further interplay between cytosolic Ca2+ and mitochondria leading to the opening of the mitochondrial permeability transition pore (mPTP) and cytochrome C release or calpain activation results in additional cell injury and subsequent apoptosis or necrosis [Citation1].

Different types of Ca2+ channel blockers such as verapamil, diltiazem or nifedipine have been shown to alleviate experimental ischemia-reperfusion injury in different organs including the intestine [Citation2,Citation3]. Most of these drugs act through voltage-dependent Ca2+ channels or receptor-operated Ca2+ channels, which are located on the plasma membrane. Hence, it is reasonable to assume that these drugs modulate the inflow of extracellular Ca2+.

Several studies have pointed out the sarco(endo)plasmic reticulum and its Ca2+-release channels (ryanodine receptor, RyR) as a primary source of Ca2+ overload during ischemia-reperfusion [Citation1,Citation4]. The only drug blocking this channel currently in use is dantrolene, a highly lipophilic hydantoin derivative ryanodine receptor antagonist clinically used to treat malignant hyperthermia, ecstasy intoxication, spasticity and heat stroke [Citation1]. The site of action of dantrolene is the sarcoplasmic reticulum ryanodine receptor Ca2+ channel, where it inhibits the depolarization-induced release of Ca2+ from the sarcoplasmic reticulum into the cytoplasm, interfering with excitation-contraction coupling. Dantrolene has been found to reduce spontaneous Ca2+ release from the sarcoplasmic reticulum of heart failure-derived cardiomyocytes [Citation5] and improve the functional recovery of young hearts following hypothermic heart preservation when using dantrolene-supplemented preservation solution [Citation6]. Common side effects of dantrolene administration are drowsiness, headaches, anorexia, diarrhea, nausea and vomiting [Citation1].

In spite of the theoretical benefits and potential, evidence of dantrolene’s protective effect against ischemia-reperfusion injury is limited [Citation1,Citation7]. In this issue, Prieto-Moure et al. contribute to the limited evidence and report that dantrolene administration, alone or in combination with allopurinol alleviates the effect of ischemia-reperfusion on tissue injury and lipoperoxydation in a model of intestinal ischemia-reperfusion in rats [Citation8]. Dantrolene alone improved morphology and reduced oxidative stress. These effects were potentiated by its combination with allopurinol, a compound known to provide antioxidant protection. Interestingly, many effects were irrespective of the timing of these pharmacologic interventions, i.e. before or after the ischemic injury.

Although the study is fairly limited with respect to the methods used and the parameters studied, its design allows some speculations around the protective mechanisms, particularly on the antioxidant defense mechanisms. The authors took a risky bet by choosing a model of intestinal ischemia as the postischemic oxidative stress is particularly intense in the intestine but succeeded in showing a difference between treated groups and controls. Many other aspects that may have been influenced by dantrolene such as cytochrome C leak, the modulation of apoptosis or the activation of nitric oxide synthase were left unexplored. Further studies in other organs developing milder oxidative stress and less dramatic tissue injury and loss may reveal further protective mechanisms and increase the knowledge around dantrolene [Citation7,Citation9]. The ultimate step would be testing dantrolene as either as part of a donor pretreatment strategy before organ transplantation or as an additive in the preservation solution before transplantation as both these strategies have been previously shown to alleviate reperfusion injury and improve organ morphology and function [Citation6,Citation10].

As a final remark, we caution that lowering intracellular Ca2+ concentrations may prove a double-edged sword, as many enzymes, repair processes and important antioxidant mechanisms including superoxide dismutase and catalase are also Ca2+ dependent.

Disclosure statement

No potential conflict of interest was reported by the author(s).

References

  • Inan S, Wei H. The cytoprotective effects of dantrolene: a ryanodine receptor antagonist. Anesth Analg. 2010;111(6):1400–1410. doi:10.1213/ANE.0b013e3181f7181c.
  • Mustafa NA, Yandi M, Turgutalp H, et al. Role of diltiazem in ischemia-reperfusion injury of the intestine. Eur Surg Res. 1994;26(6):335–341. doi:10.1159/000129354.
  • Kimura M, Kataoka M, Kuwabara Y, et al. Beneficial effects of verapamil on intestinal ischemia and reperfusion injury: pretreatment versus postischemic treatment. Eur Surg Res. 1998;30(3):191–197. doi:10.1159/000008576.
  • Khalaf A, Babiker F. Discrepancy in calcium release from the sarcoplasmic reticulum and intracellular acidic stores for the protection of the heart against ischemia/reperfusion injury. J Physiol Biochem. 2016;72(3):495–508. doi:10.1007/s13105-016-0498-0.
  • Hartmann N, Pabel S, Herting J, et al. Antiarrhythmic effects of dantrolene in human diseased cardiomyocytes. Heart Rhythm. 2017;14(3):412–419. doi:10.1016/j.hrthm.2016.09.014.
  • Villanueva JE, Gao L, Chew HC, et al. Functional recovery after dantrolene-supplementation of cold stored hearts using an ex vivo isolated working rat heart model. PLoS One. 2018;13(10):e0205850. doi:10.1371/journal.pone.0205850.
  • Boys JA, Toledo AH, Anaya-Prado R, et al. Effects of dantrolene on ischemia-reperfusion injury in animal models: a review of outcomes in heart, brain, liver, and kidney. J Investig Med. 2010;58(7):875–882. doi:10.2310/JIM.0b013e3181e5d719.
  • Prieto-Moure B, Cejalvo-Lapeña D, Belda-Antoli M, et al. Combination therapy of allopurinol and dantrolene and its role in the prevention of experimental ischemia reperfusion injury of the small intestine. J Invest Surg. 2021;34(7):800–807. doi:10.1080/08941939.2019.1696904.
  • Tsaroucha AK, Valsami G, Kostomitsopoulos N, et al. Silibinin Effect on Fas/FasL, HMGB1, and CD45 expressions in a rat model subjected to liver ischemia-reperfusion injury. J Invest Surg. 2018;31(6):491–502. doi:10.1080/08941939.2017.1360416.
  • Oltean M, Pullerits R, Zhu C, et al. Donor pretreatment with FK506 reduces reperfusion injury and accelerates intestinal graft recovery in rats. Surgery. 2007;141(5):667–677. doi:10.1016/j.surg.2006.11.005.

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