Endogenous adenosine contributes to renal sympathetic neurotransmission via postjunctional A1receptor-mediated coincident signaling

Adenosine A(1) receptor antagonists have diuretic/natriuretic activity and may be useful for treating sodium-retaining diseases, many of which are associated with increased renal sympathetic tone. Therefore, it is important to determine whether A(1) receptor antagonists alter renal sympathetic neurotransmission. In isolated, perfused rat kidneys, renal vasoconstriction induced by renal sympathetic nerve simulation was attenuated by 1) 1,3-dipropyl-8-p-sulfophenylxanthine (xanthine analog that is a nonselective adenosine receptor antagonist, but is cell membrane impermeable and thus does not block intracellular phosphodiesterases), 2) xanthine amine congener (xanthine analog that is a selective A(1) receptor antagonist), 3) 1,3-dipropyl-8-cyclopentylxanthine (xanthine analog that is a highly selective A(1) receptor antagonist), and 4) FK453 (nonxanthine analog that is a highly selective A(1) receptor antagonist). In contrast, FR113452 (enantiomer of FK453 that does not block A(1) receptors), MRS-1754 (selective A(2B) receptor antagonist), and VUF-5574 (selective A(3) receptor antagonist) did not alter responses to renal sympathetic nerve stimulation, and ZM-241385 (selective A(2A) receptor antagonist) enhanced responses. Antagonism of A(1) receptors did not alter renal spillover of norepinephrine. 2-Chloro-N(6)-cyclopentyladenosine (highly selective A(1) receptor agonist) increased renal vasoconstriction induced by exogenous norepinephrine, an effect that was blocked by 1,3-dipropyl-8-cyclopentylxanthine, U73122 (phospholipase C inhibitor), GF109203X (protein kinase C inhibitor), PP1 (c-src inhibitor), wortmannin (phosphatidylinositol 3-kinase inhibitor), and OSU-03012 (3-phosphoinositide-dependent protein kinase-1 inhibitor). These results indicate that adenosine formed during renal sympathetic nerve stimulation enhances the postjunctional effects of released norepinephrine via coincident signaling and contributes to renal sympathetic neurotransmission. Likely, the coincident signaling pathway is: phospholipase C → protein kinase C → c-src → phosphatidylinositol 3-kinase → 3-phosphoinositide-dependent protein kinase-1.