Effects of adenosine analogues on contractile response and CAMP content in guinea-pig isolated ventricular myocytes

Summary In the present study the effects of adenosine analogues were investigated on cAMP content and contractile response in guinea-pig ventricular myocytes. The adenosine analogues (–)-N⁶-phenylisopropyladenosine (R-PIA), 5-N-ethylcarboxamideadenosine (NECA) and (+)-N⁶-phenyl-isopropyladenosine (S-PIA) in the presence of 0.01 mol/l isoprenaline reduced contractile response concentration-dependently. R-PIA and NECA were about equipotent (IC₂₅: 0.01 mol/l and 0.039 mol/l respectively), while S-PIA was less potent (IC₂₅: 0.6 mol/l). Isoprenaline stimulated cAMP content was reduced by R-PIA (IC₂₅: 0.004 mol/l) and with lower potency by S-PIA (IC₂₅: 0.15 mol/l) but the extent of reduction of cAMP by R-PIA and S-PIA (to 55% and 64% respectively) was less than the reduction of contractile response (to 26% and 55% respectively). This suggests that the effects of R- and S-PIA on contractile response are only in part due to a reduction in cAMP content. In addition, NECA did not decrease cAMP content but decreased contractile response to the same extent as R-PIA. Similar results were obtained in the presence of the phosphodiesterase inhibitor Ro 20-1724. Time course studies revealed that the effects of R-PIA (1 mol/l) on cAMP content and contractile response coincided reaching steady state after 5 min and remained stable thereafter. The effects of NECA (1 µmol/l) on contractility also reached steady state within 5 min, whereas it did not change cAMP content. It is concluded that the reduction of contractility by adenosine analogues in the presence of isoprenaline can only in part be explained by a reduction of cAMP content. It is suggested that a cAMP-independent effect, possibly an activation of phosphatases, might be involved additionally.Abbreviations R-PIA (–)-N⁶-phenylisopropyladenosine - NECA 5-N-ethylcarboxamideadenosine - S-PIA (+)-N⁶-phenylisopropyl-adenosine - Ro 20-1724 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinoneSend offprint requests to J. Neumann at the above address