Abstract 2165: Activation of A1 Adenosine Receptors Inhibits the Adrenal Aldosterone Production and Attenuates Severity of Heart Failure
Background. Aldosterone receptor antagonists exert their beneficial effects on the treatment of chronic heart failure (CHF). We demonstrated that an elevation of adenosine levels attenuates severity of CHF, however, direct effects of adenosine on aldosterone production remains unknown.
Methods and Results. The additional administration of dipyridamole (300 ng/day), an adenosine uptake inhibitor, on conventional therapy in patients with CHF increased the plasma adenosine levels (placebo, from 163±23 to 161±27 nmol/L; DIP, from 166±26 to 300±61nmol/L, P<0.05), decreased the plasma aldosterone concentrations (placebo, from 36.8±9.1 to 41.8±6.4 nmol/L; DIP, from 36.0±12.1 to 16.6±6.4 pg/mL, P<0.05), decreased the plasma BNP concentrations, and improved the severity of CHF without electrolyte disturbance. Next, we tested the effect of adenosine on aldosterone production in vitro. In human adrenocortical (H295R) cells, N6-cyclopentyladenosine (CPA), a specific A1 adenosine receptor (AR) agonist, suppressed the angiotensin II (ANGII)- or K+-induced increase in CYP11B2 mRNA expression, the enzyme responsible for aldosterone production. These effects of CPA were mediated by suppression of T-type Ca2+ currents that promote aldosterone synthesis. Furthermore, the adenosine analogue suppressed the elevation of plasma aldosterone levels and prevented cardiac remodeling in rat models of chronic inhibition of NO synthesis. Importantly, administration of CPA attenuated the ANGII-induced increase of adrenal aldosterone production in wild-type mice, but not in A1AR deficient mice.
Conclusion. We conclude that activation of A1 adenosine receptors inhibits the adrenal aldosterone production and attenuates severity of heart failure. Adenosine therapy is a promising candidate of the novel treatment of CHF without electrical disturbance.