XAC, a functionalized congener of 1,3-dialkylxanthine, antagonizes A1 adenosine receptor-mediated inhibition of renin secretion in vitro.

Previous studies have shown that activation of A1 and A2 adenosine receptors leads to inhibition and stimulation respectively of renin secretion by rat renal cortical slices. In the present studies, rat renal cortical slices were incubated in the presence of adenosine deaminase, to destroy any adenosine released from the preparation. N6-cyclohexyladenosine (CHA) had a biphasic effect on renin secretion: submicromolar concentrations inhibited concentration-dependently, and there was an inflection in the dose-response curve near 1 microM CHA such that higher concentrations produced a concentration-dependent relative stimulation, which became an absolute stimulation (i.e., secretory rate was higher than control) at 50 microM. These findings are consistent with A1 and A2 adenosine receptor-mediated inhibition and stimulation of renin secretion, respectively. Xanthine amine congener ["XAC," 8-(4-((2-aminoethyl)-aminocarbonylmethyloxy)phenyl-1,3-dipropyl xant hine] has been shown by others to be a very potent adenosine receptor antagonist with selectivity for A1 receptors. It antagonized both CHA-induced inhibition (Ki approximately 2 x 10(-9) M) and CHA-induced stimulation (Ki approximately 5 x 10(-8) M) of renin secretion. Thus, XAC exhibited a 25-fold selectivity for CHA-induced inhibition of renin secretion in comparison with CHA-induced stimulation. In comparison with previous results, XAC is approximately 3 orders of magnitude more potent than theophylline. In conclusion, occupation of adenosine receptors can lead either to inhibition (A1 receptor-mediated) or stimulation (A2 receptor-mediated) of renin secretion, and XAC is a very potent and selective antagonist of CHA-induced changes in renin secretion.