Pharmacological Modulation of the Ca2+/cAMP/Adenosine Signaling in Cardiac Cells as a New Cardioprotective Strategy to Reduce Severe Arrhythmias in Myocardial Infarction

Figures

• 

  Figure 1. (Blue) ECG recording of control rats submitted to cardiac ischemia and reperfusion (CIR) protocol; (Yellow) ECG recording of rats treated with nifedipine or/and verapamil before of CIR; (Purple) ECG recording of rats treated with probenecid and nifedipine before of CIR; (Red) ECG recording of rats treated with probenecid and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) before of CIR.

• 

  Figure 2. Incidence of (A) ventricular arrhythmias (AV), (B) atrioventricular block (AVB), and (C) lethality (LET) in the CIR, NIF1 + CIR, NIF10 + CIR, NIF30 + CIR, VER1 + CIR, PROB + CIR, and DPCPX + CIR groups. The incidences of VA, AVB and LET were significantly reduced in all groups of animals treated with NIF (1, 10 and 30 mg/kg or VER 1 mg/kg) pre-CIR, when compared with vehicle-treated CIR animals. Groups were compared using Fisher’s exact test (* p < 0.05).

• 

  Figure 3. Incidence of (A) ventricular arrhythmias (AV), (B) atrioventricular block (AVB) and (C) lethality (LET) in the CIR, NIF10 + CIR, PROB + NIF10 + CIR, DPCPX + NIF10 + CIR, VER1 + CIR, PROB + VER1 + CIR, and DPCPX + VER1 + CIR groups. Pretreatment with either PROB or DPCPX 4 min before administration of NIF or VER was able to abolish the cardioprotective effects of NIF and VER in rats subjected to CIR. Groups were compared using Fisher’s exact test (* p < 0.05).

• 

  Figure 4. Histograms representing the serum concentrations of total CK (A) and CK-MB (B) in the CIR, NIF + CIR, NIF10 + CIR, NIF30 + CIR, DPCPX + NIF10 + CIR, VER 1 + CIR, and DPCPX + VER1 + CIR groups. Results were expressed as mean ± standard error of mean, and one-way analysis of variance (ANOVA) was applied, followed by Tukey’s post-test. There was no statistical difference between the different groups.

• 

  Figure 5. Theoretical model of cardioprotective response stimulated by pharmacological modulation of the Ca2+/cAMP/ADO signaling in cardiac cells. The membrane depolarization of cardiac cells generates the (1) Na+ influx via voltage-operated Na+ channels (VOC Na+) that induces (2) opening of the L-type Ca2+ channels (LTCC) containing dihydropyridine receptors (DHPR) located in the T-tubules and depolarization of the sarcolemma that lead to Ca2+ influx that (3) stimulates the release of Ca2+ from sarcoplasmic reticulum (SR) mediated by activation by Ca2+ of the R2-type ryanodine receptors (RYR2); this Ca2+ released from SR (4) binds to troponin C and (5) activates the contractile machinery generating contraction of cardiac cells. At the same time, (6) the Ca2+ concentration in the cytosol is restored by Ca2+ sequestration by SR via SERCA; Ca2+ influx via LTCC also (7) inhibits the isoforms 5 and 6 of adenylyl cyclase (AC), producing reduction in the intracellular production of cAMP and phosphorylation of RYR2 by cAMP-dependent kinases (PKA), and then reducing cardiac contraction frequency and strength; in addition (8), efflux of cAMP through membrane transporters MRP4 and (9) extracellular…