The Antiadrenergic Actions of Adenosine in the Heart

Summary

Adenosine serves an important antiadrenergic function in the heart. Recent studies have been undertaken to investigate the mechanism(s) by which adenosine functions and the importance of adenosine as a negative-feedback modulator of β-adrenoceptor-mediated contractile and glycogenolytic responses in the normoxic contracting myocardium. In ventricular membranes, an analogue of adenosine, phenylisopropyladenosine (PIA) at a concentration of 10⁻⁸ M inhibits isoproterenol-sensitive adenylate cyclase activity. This inhibition is prevented by isobutylme-thylxanthine. Utilizing these membranes PIA reduces the affinity of β-adrenoceptors for isoproterenol in [¹²⁵I]cyanopindolol competitive binding studies. This suggests that adenosine is most likely capable of modifying the formation of the high-affinity state of the β-adrenoceptor which in turn may reduce the degree of coupling to adenylate cyclase. Administration of adenosine deaminase (ADA) to isolated perfused hearts potentiates the isoproterenol-elicited augmentation of contractility. Such results indicate that ADA deaminates interstitial adenosine which is suspected to be involved in modulating the β-adrenoceptor-induced contractile responses. Interstitial adenosine levels were estimated by collecting epicardial surface transudates and determining the adenosine present by a HPLC fluorometric technique. The adenosine concentration was always at least two-fold greater in the transudates as compared to its concentration in coronary effluents. Overall, interstitial adenosine appears to serve an important physiological function as a negative-feedback modulator of β-adrenoceptor-mediated contractile and metabolic responses in the heart by attenuating the activation of the β-adrenoceptor-adenylate cyclase complex.