Ott et al. (1) reported that systemic nitric oxide (NO) synthase (NOS) inhibition with NG-monomethyl-l-arginine (L-NMMA) (2) acutely increased the urinary albumin-to-creatinine ratio in hypertensive patients with type 2 diabetes. The authors did not provide direct evidence of reduced NO synthesis by L-NMMA. The pressor response to the NOS inhibitors L-NMMA, asymmetric dimethylarginine (ADMA), and NG-nitro-l-arginine methyl ester (L-NAME) is relatively small, given their low inhibitory potency toward endothelial NOS (eNOS) activity (2). Release of thromboxane A2 (TxA2), a potent vasoconstrictor and thromboxane-prostanoid (PT) receptor agonist, and the F2-isoprostane 15(S)-8-iso-prostaglandin F2α (15(S)-8-iso-PGF2α), a vasoconstrictor and functional PT receptor agonist, could also be involved. In mice (3), L-NAME induced hypertension, caused cardiac hypertrophy, and elevated TxA2 and 15(S)-8-iso-PGF2α synthesis. In hypertensive type 2 diabetic subjects, the angiotensin 2 receptor inhibitor olmesartan reduced blood pressure and 15(S)-8-iso-PGF2α synthesis without changing eNOS activity and ADMA synthesis (4). We propose that in the study by Ott et al. (1), excessive renal TxA2 and 15(S)-8-iso-PGF2α synthesis and PT receptor activation may have contributed to albuminuria (5,6). Systemic infusion of unspecific eNOS inhibitors such as L-NMMA, L-NAME, or ADMA is not a specific procedure to determine local effects of eNOS inhibition in the kidney.
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