DOWN-REGULATION OF CARDIAC L-TYPE CA2+-CURRENT BY ADENOSINE

In enzymatically isolated ventricular cardiomyocytes from rat and guinea pig, adenosine (ADO) reduced the basal (non-beta-adrenergically stimulated) L-type Ca2+-current (I-Ca) from 11 +/- 2.1 mu A/cm(2) to 3.1 +/- 0.7 mu A/cm(2) in a dose-dependent manner (K-D = 10 nM). Simultaneously, the free intracellular Ca2+ concentration [Ca2+](i) was elevated from 100 +/- 15 nM to 1,800 +/- 400 nM. Similar effects were observed with the ADO-Al-receptor agonist N-6-cyclopentyladenosine. The ADO effects were fully suppressed by the Al-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthin while the synthetic ADO-Az-receptor agonist CGS-21680 affected neither I-Ca nor [Ca2+](i). The inhibition of Ic, and the increase in [Ca2+](i) were not abolished by pretreating the cells with pertussis toxin 5 mu g/ml/37 degrees C/300 min, but GDP beta S (10 mu M) reduced the effects of ADO by 86.7 +/- 7%. Application of ryanodine thapsigargin 0.1 mu M, the Ca2+-chelator (0.1-10 mM) and low-molecular weight heparin (50mg/ml) suppressed the ADO-evoked responses while intracellular application of 50 mu M inositol 1,4,5-trisphosphate (IP3) and its non-hydrolyzable analogue IPS3 (10 mu M) mimicked the ADO effects. The results suggest that the inhibition of basal Ica by ADO occurs via stimulation of phospholipase C followed by IP3-induced intracellular Ca2+ release.