Effects of adenosine analogues on force and cAMP in the heart. Influence of adenosine deaminase

Abstract

The effects of the adenosine receptor agonists (−)-N 6-phenylisopropyladenosine (PIA) and 5′-N-ethylcarboxamideadenosine (NECA) on the force of contraction, adenylate cyclase activity and cAMP content in the presence of isoprenaline (Iso) were studied in ventricular preparations of the guinea-pig heart. Only in the presence of adenosine deaminase (ADA) and 50 nM sodium chloride, i.e. under ‘optimal’ conditions, did PIA and NECA reduce the Iso-stimulated adenylate cyclase activity in broken cell preparations, with a maximal effect of about 25%. In electrically driven (1 Hz) papillary muscles from guinea-pigs, both compounds concentration dependently reduced the Iso-stimulated force of contraction maximally by about 50% in the presence of ADA (1 μg/ml). cAMP was measured in the same preparations. Low concentrations (0.1–1 μM) of PIA reduced the cyclic AMP content while higher concentrations increased the cyclic AMP content. The negative inotropic effect of NECA was accompanied by a concentration-dependent increase in the cyclic AMP content. We conclude that the negative inotropic effect of PIA in the presence of Iso is only in part due to a decrease in the cyclic AMP content resulting from inhibition of adenylate cyclase activity. Such an effect was only detected in the presence of ADA so that endogenous adenosine can obviously mask small effects of PIA on adenylate cyclase activity or the cyclic AMP content. In addition, the negative inotropic effect of NECA in the presence of isoprenaline was not accompanied by a reduction but an increase in the cyclic AMP content. It is conceivable that this increase occurs in non-muscle cells that are present in papillary muscles. We propose that other factors beside alterations in the cyclic AMP content, for instance inhibition of cyclic AMP action, can account for the negative inotropic effect of adenosine analogues in the presence of Iso.