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

by Selleckchem | Dec 18 2023

Acute myocardial infarction (AMI) is the main cause of morbidity and mortality worldwide and is characterized by severe and fatal arrhythmias induced by cardiac ischemia/reperfusion (CIR). However, the molecular mechanisms involved in these arrhythmias are still little understood. To investigate the cardioprotective role of the cardiac Ca2+/cAMP/adenosine signaling pathway in AMI, L-type Ca2+ channels (LTCC) were blocked with either nifedipine (NIF) or verapamil (VER), with or without A1-adenosine (ADO), receptors (A1R), antagonist (DPCPX), or cAMP efflux blocker probenecid (PROB), and the incidence of ventricular arrhythmias (VA), atrioventricular block (AVB), and lethality (LET) induced by CIR in rats was evaluated. VA, AVB and LET incidences were evaluated by ECG analysis and compared between control (CIR group) and intravenously treated 5 min before CIR with NIF 1, 10, and 30 mg/kg and VER 1 mg/kg in the presence or absence of PROB 100 mg/kg or DPCPX 100 µg/kg. The serum levels of cardiac injury biomarkers total creatine kinase (CK) and CK-MB were quantified. Both NIF and VER treatment were able to attenuate cardiac arrhythmias caused by CIR; however, these antiarrhythmic effects were abolished by pretreatment with PROB and DPCPX. The total serum CK and CK-MB were similar in all groups. These results indicate that the pharmacological modulation of Ca2+/cAMP/ADO in cardiac cells by means of attenuation of Ca2+ influx via LTCC and the activation of A1R by endogenous ADO could be a promising therapeutic strategy to reduce the incidence of severe and fatal arrhythmias caused by AMI in humans.

Comments:

The study you described investigates the role of the cardiac Ca2+/cAMP/adenosine signaling pathway in acute myocardial infarction (AMI) and the associated arrhythmias induced by cardiac ischemia/reperfusion (CIR). The researchers used L-type Ca2+ channel blockers (nifedipine and verapamil) in combination with adenosine receptor antagonists (DPCPX) and a cAMP efflux blocker (probenecid) to evaluate their effects on ventricular arrhythmias (VA), atrioventricular block (AVB), and lethality (LET) in rats subjected to CIR.

Here's a summary of the findings:

1. **L-type Ca2+ Channel Blockers (Nifedipine and Verapamil):**
- Both nifedipine and verapamil were able to attenuate cardiac arrhythmias induced by CIR.

2. **Role of Ca2+/cAMP/Adenosine Signaling Pathway:**
- The antiarrhythmic effects of nifedipine and verapamil were abolished when pretreated with probenecid (a cAMP efflux blocker) and DPCPX (an adenosine receptor antagonist).

3. **Cardiac Injury Biomarkers:**
- The study measured cardiac injury biomarkers, specifically total creatine kinase (CK) and CK-MB, in the serum.
- Serum levels of total CK and CK-MB were similar in all groups, indicating that the treatments did not significantly impact these markers of cardiac injury.

4. **Therapeutic Implications:**
- The findings suggest that modulating the Ca2+/cAMP/adenosine pathway in cardiac cells by attenuating Ca2+ influx via L-type Ca2+ channels and activating A1 adenosine receptors could be a promising therapeutic strategy.
- This modulation could potentially reduce the incidence of severe and fatal arrhythmias caused by AMI in humans.

In summary, the study indicates that targeting the Ca2+/cAMP/adenosine signaling pathway through the inhibition of L-type Ca2+ channels and activation of adenosine receptors might offer a valuable approach for preventing life-threatening arrhythmias associated with acute myocardial infarction. Further research and clinical studies would be necessary to validate these findings and explore the practical applications of this therapeutic strategy in human patients.