Combination of Cyclosporine A and Levosimendan Induces Cardioprotection under Acute Hyperglycemia

Abstract

Prognosis of patients with myocardial infarction is detrimentally affected by comorbidities like diabetes mellitus. In the experimental setting, not only diabetes mellitus but also acute hyperglycemia is shown to hamper cardioprotective properties by multiple pharmacological agents. For Levosimendan-induced postconditioning, a strong infarct size reducing effect is demonstrated in healthy myocardium. However, acute hyperglycemia is suggested to block this protective effect. In the present study, we investigated whether (1) Levosimendan-induced postconditioning exerts a concentration-dependent effect under hyperglycemic conditions and (2) whether a combination with the mitochondrial permeability transition pore (mPTP) blocker cyclosporine A (CsA) restores the cardioprotective properties of Levosimendan under hyperglycemia. For this experimental investigation, hearts of male Wistar rats were randomized and mounted onto a Langendorff system, perfused with Krebs-Henseleit buffer with a constant pressure of 80 mmHg. All isolated hearts were subjected to 33 min of global ischemia and 60 min of reperfusion under hyperglycemic conditions. (1) Hearts were perfused with various concentrations of Levosimendan (Lev) (0.3–10 μM) for 10 min at the onset of reperfusion, in order to investigate a concentration–response relationship. In the second set of experiments (2), 0.3 μM Levosimendan was administered in combination with the mPTP blocker CsA, to elucidate the underlying mechanism of blocked cardioprotection under hyperglycemia. Infarct size was determined by tetrazolium chloride (TTC) staining. (1) Control (Con) hearts showed an infarct size of 52 ± 12%. None of the administered Levosimendan concentrations reduced the infarct size (Lev0.3: 49 ± 9%; Lev1: 57 ± 9%; Lev3: 47 ± 11%; Lev10: 50 ± 7%; all ns vs. Con). (2) Infarct size of Con and Lev0.3 hearts were 53 ± 4% and 56 ± 2%, respectively. CsA alone had no effect on infarct size (CsA: 50 ± 10%; ns vs. Con). The combination of Lev0.3 and CsA (Lev0.3 ± CsA) induced a significant infarct size reduction compared to Lev0.3 (Lev0.3+CsA: 35 ± 4%; p < 0.05 vs. Lev0.3). We demonstrated that (1) hyperglycemia blocks the infarct size reducing effects of Levosimendan-induced postconditioning and cannot be overcome by an increased concentration. (2) Furthermore, cardioprotection under hyperglycemia can be restored by combining Levosimendan and the mPTP blocker CsA.

The Coadministration of Levosimendan and Exenatide Offers a Significant Cardioprotective Effect to Isolated Rat Hearts against Ischemia/Reperfusion Injury

“…Moreover, Chen et al showed that Levosimendan is superior to epinephrine in producing higher coronary flow levels and faster recovery when reversing bupivacaine-induced asystole [ 58 ]. Finally, Torregroza et al demonstrated that cardioprotection under hyperglycemia can be restored by combining Levosimendan and Cyclosporine A (CsA) [ 59 ]. They also showed that infarct size could be reduced up to 56%.…”

“…CsA alone had no effect on infarct size. The combination of Levosimendan and CsA induced a significant infarct size reduction compared to Levosimendan alone [ 59 ]. Stroethoff et al presented a study in which Levosimendan reduced infarct size to 30 ± 5% [ 60 ].…”

Trimetazidine Attenuates Heart Failure by Improving Myocardial Metabolism via AMPK

“…The cardiomyocytes were isolated from adult C57/BL mice heart using the langendorff system as described previously ( Torregroza et al, 2021 ). Briefly, before intraperitoneal injection of 100 mg/kg pentobarbital, mice were injected with 150 units of heparin to prevent blood from clotting in the heart cavity.…”

Preclinical multi-target strategies for myocardial ischemia-reperfusion injury

“…Different experimental settings in vivo and in vitro resulted in the opposite results on whether the increase of levosimendan concentration could have a protective effect on the diabetic rats’ hearts. However, it is impractical to use levosimendan at 10-fold higher concentrations ( 104 , 105 ). Cyclosporine A, an MPTP opening inhibitor, reverses the loss of cardioprotective effects of levosimendan in diabetic rats under high glucose environments, suggesting the possibility that increased drug stimulation can change the loss of cardioprotective function.…”