Effect of hyperhomocysteinemia on plasma or tissue adenosine levels and renal function.
BACKGROUND
Hyperhomocysteinemia (hHcys) is considered an independent risk factor of cardiovascular diseases. Recent studies in our laboratory have shown that hHcys produced glomerular dysfunction and sclerosis independently of hypertension. However, the mechanism mediating these pathogenic effects of homocysteine (Hcys) is poorly understood. Because Hcys and adenosine (Ado) are simultaneously produced via hydrolysis of S-adenosylhomocysteine (SAH), we hypothesized that hHcys may produce its pathogenic effects by decrease in plasma or tissue Ado concentrations.


RESULTS
L-Hcys (1.5 micromol/min per kilogram) was infused intravenously for 60 minutes to produce acute hHcys in Sprague-Dawley rats. Plasma Hcys levels increased from 6.7+/-0.4 to 14.7+/-0.5 micromol/L, but Ado decreased from 141.7+/-15.1 to 52.4+/-6.8 nmol/L in these rats with acute hHcys. This hHcys-induced reduction of Ado was also observed in the kidney dialysate. In rats with chronic hHcys, plasma Ado levels were also significantly decreased. By kinetic analysis of the enzyme activities, decrease in renal Ado levels in hHcys was shown to be associated with inhibition of SAH hydrolase but not 5'-nucleotidase. Functionally, intravenous infusion of Hcys was found to decrease renal blood flow, glomerular filtration rate, and sodium and water excretion, which could be blocked by the Ado receptor antagonist 8-SPT.


CONCLUSIONS
These results strongly suggest that hHcys decreases plasma and tissue Ado concentrations associated with inhibition of SAH hydrolase. Decrease in plasma and tissue Ado may be an important mechanism mediating the pathogenic effects of Hcys.
Departments of Physiology and Pharmacology Toxicology, Medical College of Wisconsin, Milwaukee, Wis 53226, USA.
Ya-Fei
YF
Chen
Pin-Lan
PL
Li
Ai-Ping
AP
Zou
D000241:Adenosine / Q000032:analysis* / Q000097:blood*; D043383:Adenosylhomocysteinase; D000818:Animals; D002318:Cardiovascular Diseases / Q000209:etiology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005453:Fluorescence; D006439:Hemodynamics / Q000187:drug effects; D006710:Homocysteine / Q000032:analysis / Q000494:pharmacology; D006867:Hydrolases / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000097:blood* / Q000150:complications / Q000201:enzymology / Q000503:physiopathology*; D007668:Kidney / Q000737:chemistry / Q000201:enzymology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards; D012307:Risk Factors; D014372:Tubercidin / Q000494:pharmacology
D004791:Enzyme Inhibitors; C018258:3-deazaadenosine; D006710:Homocysteine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine; D014372:Tubercidin