Abstract 5255: Differential Effect Of A Novel Adenosine-Agonist On Stimulation-Induced Norepinephrine Release From Rat Hearts

Abstract

Presynaptic modulation of norepinephrine (NE) release plays a major role in the regulation of cardiac sympathetic activity. We tested the effect of the novel, highly selective adenosine A1 subtype agonist BAY 68–4986 on stimulation-induced NE release. Isolated rat hearts (Wistar or SHR) were perfused with a modified Krebs-Henseleit solution (Langendorff technique). Exocytotic NE release was induced by electrical field stimulation with 5 V, 6 Hz for 1 minute. NE was detected by HPLC. Two stimulations (S1, S2) were performed to compare intraindividually NE release under control conditions (S1) and with BAY 68–4986 30ug/ml, 300 ug/ml or CCPA 10–6M (S2). Neuronal uptake was inhibited by desipramine (100 nM) in order to prevent amine elimination and nonexocytotic release of NE. Stimulation of adenosine A1 receptors with BAY 68–4986 led to a concentration dependent decrease of the stimulation-induced NE release only in SHR rats, whereas no effect could be seen in Wistar rats (SHR: S2/S1 = 0.90 +/− 0.08 with 30 ug/l, S2/S1 = 0.54 +/− 0.02 with 300 ug/l, Wistar: S2/S1 = 1.05 +/− 0.12 with 30 ug/l, S2/S1 = 1.03 +/− 0.09 with 300 ug/l, p=0.003). The effect of BAY 68–4986 on stimulation-induced NE release in SHR was similar to the effect of 10–6 M CCPA (S2/S1 = 0.59 ± 0.05). This differential effect in genetically different rats was also observed in vivo, with a blunted increase of the heart rate during stress reaction only in SHR rats, when treated with BAY 68–4986. We could demonstrate that the novel, highly selective A1-adenosine agonist BAY 68–4986 has a differential effect on stimulation-induced NE release and stress responde in SHR rats compared to Wistar rats.