cAMP signaling affects age-associated deterioration of pacemaker beating interval dynamics

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Aging Research

Background:

• Sinoatrial node (SAN) function, including beating interval variability (BIV) and average beating interval (BI), relies on a coupled-clock system involving cAMP signaling.
• Aged SAN tissue exhibits reduced responsiveness to submaximal stimulation of beta-adrenergic receptors (β-AR) and phosphodiesterase inhibition (PDEI), while maximal responses remain unchanged.

Purpose of the Study:

• To investigate if age-associated dysfunction in cAMP signaling contributes to the altered responsiveness of BI and BIV in aged SAN.
• To correlate cAMP levels with BI and BIV in adult and aged mouse SAN under various stimulation conditions.

Main Methods:

• Measurement of cAMP levels and average BI in adult and aged C57/BL6 mouse SAN tissue.
• Application of β-AR stimulation and PDEI at both submaximal (X₅₀) and maximal (X_max) levels.
• Correlation analysis of cAMP levels with BI and BIV parameters.

Main Results:

• Aged SAN tissue showed reduced cAMP levels and average BI at X₅₀, but not at X_max, compared to adult SAN.
• Significant correlations were observed between cAMP levels and average BI in both age groups.
• Correlations between BIV parameters and cAMP levels, evident in adult SAN, were diminished in aged SAN at X₅₀ due to lower cAMP.

Conclusions:

• cAMP levels generated by coupled-clock mechanisms are intrinsically linked to average BI in the SAN.
• The observed age-related reduction in cAMP levels at X₅₀ is the underlying cause for the diminished responsiveness of BI and BIV to β-AR stimulation and PDEI.