Role of calcium and other ions in reperfusion injury

Abstract

Calcium-related mechanisms may play a role in several aspects of reperfusion injury. One proposal is that internal cytosolic calcium concentration is elevated early in the reperfusion period and that excess oscillations of calcium can very significantly contribute to reperfusion ventricular arrhythmias. Alternate hypotheses, such as those involving free radicals and the local tissue renin-angiotensin system, can be married to the existing hypothesis. Furthermore, the hypothesis allows for a role of the sodium-calcium exchange system and the proton-sodium exchanger. The hypothesis also provides an explanation for "stunning," as it is proposed that early excessive cytosolic calcium damages the organelles regulating the contractile cycle, which subsequently develops into imperfect functioning of the contractile apparatus. Calcium antagonist drugs given during the ischemic period may lessen reperfusion injury by decreasing the severity of ischemic damage. When given at the time of reperfusion, results are complex and to some extent conflicting. The biggest challenge is to understand how relatively low doses of calcium antagonists given after the onset of reperfusion help to decrease delayed reperfusion "stunning." A logical but untested proposal is that calcium antagonists help to prevent delayed contraction-band necrosis, one of the causes of delayed no-reflow.

Activation of α1B-adrenoceptors alleviates ischemia/reperfusion injury by limitation of mitochondrial Ca2+ overload in cardiomyocytes

“…Maintained mitochondrial Ca 2+ homeostasis is suggested to improve ATP synthesis and maintain constant volume of the mitochondrial matrix [44]. These effects would preserve mitochondrial function of providing adequate ATP supply to cytosolic ATPase, which is essential to support the action of ATP-dependent ion pumps/exchangers and receptors, such as Na + /K + and Ca 2+ pumps [45], Na + /Ca 2+ exchangers and ryanodine receptors, to maintain cytosolic Ca 2+ homeostasis [19,46]. Thus limitation of [Ca 2+ ] m overload during I/R may represent a potential therapeutic target.…”

Role of Protein Kinase C in Mitochondrial K ATP Channel–Mediated Protection Against Ca 2+ Overload Injury in Rat Myocardium

“…High-energy production is essential to support the action of ATP-dependent ion pumps, such as Na ϩ /K ϩ and Ca 2ϩ pumps, 21 to maintain membrane intactness and calcium ion gradients across various cell membranes, including the sarcolemma, sarcoplasmic reticulum, and mitochondria. 22 Xu and colleagues. 23 proposed that glycolytically derived ATP is functionally coupled to Ca 2ϩ transport by cardiac sarcoplasmic reticulum.…”

Design, Synthesis, and Structure-Activity Relationships of 3,4-Dihydropyridopyrimidin-2(1H)-one Derivatives as a Novel Class of Sodium/Calcium Exchanger Inhibitor

“…Nonetheless, it has been suggested that sometimes early restitution of blood flow after a period of hypoxia results in the deteriorous effects called reperfusion injury. 2,3) Intracellular Ca 2ϩ overload via activation of the Na ϩ /Ca 2ϩ exchanger after ischemic reperfusion has been indicated as a potential cause of this, which induces post-ischemic cardiac injury. 1,[3][4][5][6][7][8][9] Thus, inhibition of the Na ϩ /Ca 2ϩ exchanger, which would lead to prevention of Ca 2ϩ overload, could become a new approach for the treatment of ischemic reperfusion injury.…”

“…As a peptidic inhibitor, Val-Met-Arg-Phe-NH 2 (1) with IC 50 value of 1.5 mM has been reported, which is a non-selective inhibitor. 10) As a non-peptidic inhibitor, aroylguanidine derivative (2) 11) with IC 50 value of 3.4 mM has been reported which is a modified amiloride derivative as is dimethylamiloride (3). 12) Furthermore, KB-R7943 (4), 13,14) SEA0400 (5), 15,16) benzyloxyphenyl derivative (6) 17) and SN-6 (7) 18) have been reported.…”