Effects of angiotensin type 1 receptor blockade on arginine and ADMA synthesis and metabolic pathways in fawn-hooded hypertensive rats.

摘要

BACKGROUND: The fawn-hooded hypertensive (FHH) rat develops spontaneous glomerulosclerosis that is ameliorated by inhibition of the angiotensin II type 1 receptor (AT-1). Since kidney damage is associated with nitric oxide (NO) deficiency, we investigated how AT-1 antagonism influenced nitric oxide synthase (NOS), as well as NOS substrate [L-arginine (L-Arg)] and inhibitor [asymmetric dimethylarginine (ADMA)]. L-Arg is synthesized by renal argininosuccinate synthase/argininosuccinate lyase (ASS/ASL) and then either consumed within the kidney by arginase II or NOS or released into the circulation. L-Arg is then taken up from plasma into cells where it can be utilized by NOS and other pathways. The competitive inhibitor of NOS, ADMA, is degraded by dimethylarginine dimethylaminohydrolase (DDAH). METHODS AND RESULTS: Male FHH rats were put on a 40% casein diet for 13 weeks, and some received AT-1 antagonist which reduced blood pressure and kidney weight and prevented glomerulosclerosis and hyperfiltration. The AT-1 antagonist reduced the expression of DDAH2, increased DDAH1 and increased total DDAH activity in the kidney cortex, although there was no change in plasma or kidney cortex ADMA levels. The AT-1 antagonist caused no change in the expression of renal ASS/ASL, but reduced renal and aortic arginase expression and renal arginase activity, which could explain the increased plasma L-Arg. In separate studies, 1 week of AT-1 blockade in young FHH rats had no effect on any of these parameters. CONCLUSION: Thus, the net result of AT-1 antagonist was an improved L-Arg to ADMA ratio due to the prevention of renal and vascular arginase activation which favours increased NO production. Since 1 week of AT-1 blockade in the absence of kidney damage was without effect on arginases, this suggests that the reduction in arginase activity is secondary to the prevention of structural damage rather than a direct immediate effect of AT-1 antagonism.