Moderation of myocardial ischemia reperfusion injury by calcium channel and calmodulin receptor inhibition

Abstract

Intracellular Ca2+ accumulation is implicated in the pathogenesis of myocardial reperfusion injury. To study approaches designed to modify Ca2+ uptake during coronary revascularization after acute infarction, a pig heart surgical infarct model (left anterior descending artery occlusion for 60 min) was subjected to 60 min hypothermic potassium cardioplegic arrest, followed by 60 min of global reperfusion. Four groups of six hearts each were studied in a randomized manner, i.e., cardioplegia alone (control), cardioplegia + 10 microM diltiazem (Ca2+ slow channel blocker), cardioplegia + 10 microM trifluoperazine (TFP), (a Ca(2+)-calmodulin antagonist), and cardioplegia+diltiazem (10 microM) + TFP (10 microM). Left ventricular contractility (global and segmental), metabolism (coronary blood flow and O2 consumption), and creatine kinase generation were measured during reperfusion. Both the Ca2+ channel blocker, diltiazem, and the calmodulin antagonist, TFP, improved myocardial global and regional function as well as myocardial metabolism. While diltiazem better restored global and regional contractility, trifluoperazine had a greater effect on coronary blood flow and myocardial oxygen consumption. Enzyme release and lipid peroxidation were equally moderated by both drugs. From this study it can be concluded that Ca2+ influx does play a role in ischemic and reperfusion injury. The mechanisms of its effect are complex, but can be successfully antagonized by Ca2+ blockers as well as by calmodulin antagonists, with improved myocardial preservation.

Therapeutic Effects of Astragaloside IV on Myocardial Injuries: Multi-Target Identification and Network Analysis

“…CN activity in the heart is increased upon ischemia [49]. Consistently, inhibiting CALM could alleviate myocardial ischemia reperfusion injury [44]. These facts suggest important roles of JNK, CN and CALM in the therapeutic action of AGS-IV against myocardial ischemia.…”

“…In fact, these pathways have been reported as suitable target pathways for cardiovascular disease therapies [42], [43]. We constructed a myocardial ischemia associated pathway (Figure 4D) by integrating pathways reported to be involved in the process of myocardial ischemia injury, including the calcium signaling, MAPK, JAK-STAT and NF-KB pathway [44]–[47]. Four targets for approved CVD drugs, ACE, EGFR, CALM and NOS3, are linked with this pathway.…”

“…JNK kinase activity is activated by ischemia/reperfusion [47]. Ca 2+ influx accumulation is implicated in the pathogenesis of ischemic and reperfusion injury [44]. CN is a calcium-dependent protein phosphatase that is activated by binding of Ca 2+ and CALM to the regulatory and catalytic subunits, respectively [48].…”

Oxymatrine, the Main Alkaloid Component ofSophoraRoots, Protects Heart against Arrhythmias in Rats

“…Coronary artery occlusion-induced myocardial ischemia commonly causes ischemic arrhythmias which are the main mortality factor for patients with coronary heart diseases. Calcium, potassium, and sodium channels are totally involved in the initiation and development of ischemic arrhythmias [17,18]. Many studies also showed that calcium and sodium currents were markedly upregulated in heart infarction [19,20].…”

Initial Reperfusion with Magnesium after Cardioplegic Arrest Attenuates Myocardial Reperfusion Injury*

“…Thus, Ca 2+ channel blockers such as verapamil or nifedipine have been shown to reduce ischemia-reperfusion injury when administered before, but not after cardioplegic arrest [6,7]. In previous studies by our group, initial reperfusion with 2,3-butanedione monoxime (BDM), a negative inotropic and vasodilating agent, improved myocardial recovery after cardioplegic arrest [8,9].…”