In 1999, Zou and colleagues made the fundamental discovery that in the kidney, adenosine A2 receptors vasodilate the medullary vasculature leading to natriuresis/diuresis. During the previous funding period for HL109002, we discovered that extracellular guanosine remarkably increases extracellular levels of adenosine by inhibiting the disposition of extracellular adenosine (we call this the guanosine-adenosine mechanism). We also discovered that 8-aminoguanosine [inhibitor of purine nucleoside phosphorylase (PNPase - the enzyme that metabolizes guanosine)] increases extracellular guanosine and thereby activates the guanosine- adenosine mechanism, i.e., increases adenosine levels. Combining Zou's conclusions with our findings prompted us to conduct preliminary experiments examining the effects of 8-aminoguanosine on renal function; and the results of these preliminary experiments suggest that 8-aminoguanosine does indeed induce natriuresis/diuresis and administered chronically is powerfully antihypertensive. Because 8-aminoguanine is 10-fold more potent as a PNPase inhibitor compared to 8-aminoguanosine, we also postulated that the renal effects of 8-aminoguanosine are mediated by conversion to 8-aminoguanine, a postulate that has withstood preliminary testing. Finally, because there are reports of 8-aminoguanosine in tissues (produced from peroxynitrite reacting with guanosine moieties followed by reduction of 8-nitroguanosine to 8- aminoguanosine), we developed a mass spectrometry-based assay for 8-aminoguanosine and 8- aminoguanine and demonstrated their existence both in kidneys and urine. Thus our preliminary findings support the exciting possibility that we have discovered a previously unrecognized system that regulates renal excretory function and blood pressure. In a nutshell, our hypothesis is that 8-aminoguanine is an endogenous purine that exerts natriuretic, diuretic, and antihypertensive activity and that 8- aminoguanine acts by blocking renal PNPase, which engages the guanosine-adenosine mechanism in the kidney. We propose to test this hypothesis in rats by: 1) Characterizing the diuretic/natriuretic, renal hemodynamic effects and effects on urinary purines of administering 8-aminoguanosine and 8-aminoguanine either intravenously (IV) or directly into the renal artery (IRA); 2) Determining using LC-MS/MS the effects of IV and IRA 8-aminoguanosine and 8-aminoguanine on renal interstitial levels and kidney tissue levels of 8- aminoguanosine, 8-aminoguanine, guanosine, adenosine, and inosine; 3) Determining whether 9- deazaguanine (specific PNPase inhibitor) can mimic the effects of 8-aminoguanosine and 8-aminoguanine on renal excretory function; 4) Determining, using knockout rats, whether the renal excretory effects of 8- aminoguanosine/8-aminoguanine require A2A or A2B, but not A1, receptors; 5) Testing whether peroxynitrite production determines the levels of endogenous 8-aminoguanosine/8-aminoguanine; and 6) Determining, using radiotelemetry, the long-term antihypertensive activity of oral 8-aminoguanosine/8-aminoguanine.
We believe we have discovered a natural system in the body that regulates kidney function and blood pressure. The purpose of this research project is to solidify the scientific evidence for this system and determine whether components of the system can be given orally to improve renal function, treat hypertension and prevent cardiovascular disease. Successful completion of the project very likely will lead to a novel class of antihypertensive and renal protective drugs.
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