TY - JOUR
T1 - Inhibition of nitric oxide formation by guanidines
AU - Hasan, Khalid
AU - Heesen, Bart Jeroen
AU - Corbett, John A.
AU - McDaniel, Michael L.
AU - Chang, Katherine
AU - Allison, Wanda
AU - Wolffenbuttel, Bruce H.R.
AU - Williamson, Joseph R.
AU - Tilton, Ronald G.
N1 - Funding Information:
This study was made possible by support from the US National Institutes of Health (grants DK06181, F32DK08748, EY06600, HL39934, and DK20579), from the Department of Endocrinology and Metabolism (University Hospital Maastricht, Netherlands) and from the Kilo Diabetes and Vascular Research Foundation (St. Louis, MO, USA).
PY - 1993/11/2
Y1 - 1993/11/2
N2 - Aminoguanidine, N,N′-diaminoguanidine, methylguanidine, and 1,1-dimethylguanidine were compared to NG-monomethyl-L- arginine (L-NMMA) for their ability to inhibit nitric oxide (NO) formation by cytokine-inducible and vascular constitutive isoforms of NO synthase. These comparisons were performed by assessing (1) cytokine-induced production of nitrite by RINm5F cells, (2) vasoconstrictor responses of isolated rat mesenteric arteries, and (3) in vivo blood pressure responses following intravenous bolus injection into anesthetized rats. Aminoguanidine and L-NMMA were the most potent inhibitors of cytokine-induced NO formation in RINm5F cells, while the other guanidine compounds were 10 (1,1-dimethylguanidine) to 100 (methylguanidine) times less potent. L-NMMA and 1,1-dimethylguanidine were the most potent inhibitors of the vascular constitutive isoform of NO synthase in both assay systems, while aminoguanidine and N,N′-diaminoguanidine were the least potent. These results (1) confirm the selective inhibition of the inducible isoform of NO synthase by aminoguanidine, (2) indicate that N,N′-diaminoguanidine, while ∼ 30 times less potent than aminoguanidine in inhibiting inducible NO synthase, has very little effect on constitutive NO synthase activity, and (3) 1,1-dimethylguanidine, like L-NMMA, is a relatively potent inhibitor of both isoforms of NO synthase.
AB - Aminoguanidine, N,N′-diaminoguanidine, methylguanidine, and 1,1-dimethylguanidine were compared to NG-monomethyl-L- arginine (L-NMMA) for their ability to inhibit nitric oxide (NO) formation by cytokine-inducible and vascular constitutive isoforms of NO synthase. These comparisons were performed by assessing (1) cytokine-induced production of nitrite by RINm5F cells, (2) vasoconstrictor responses of isolated rat mesenteric arteries, and (3) in vivo blood pressure responses following intravenous bolus injection into anesthetized rats. Aminoguanidine and L-NMMA were the most potent inhibitors of cytokine-induced NO formation in RINm5F cells, while the other guanidine compounds were 10 (1,1-dimethylguanidine) to 100 (methylguanidine) times less potent. L-NMMA and 1,1-dimethylguanidine were the most potent inhibitors of the vascular constitutive isoform of NO synthase in both assay systems, while aminoguanidine and N,N′-diaminoguanidine were the least potent. These results (1) confirm the selective inhibition of the inducible isoform of NO synthase by aminoguanidine, (2) indicate that N,N′-diaminoguanidine, while ∼ 30 times less potent than aminoguanidine in inhibiting inducible NO synthase, has very little effect on constitutive NO synthase activity, and (3) 1,1-dimethylguanidine, like L-NMMA, is a relatively potent inhibitor of both isoforms of NO synthase.
KW - (L-NMMA)
KW - 1,1-Dimethylguanidine
KW - Aminoguanidine
KW - Methylguanidine
KW - N,N′-Diaminoguanidine
KW - N-Monomethyl-L-arginine
KW - Nitric oxide (NO)
KW - Nitric oxide synthase
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U2 - 10.1016/0014-2999(93)90667-7
DO - 10.1016/0014-2999(93)90667-7
M3 - Article
C2 - 7506664
AN - SCOPUS:0027374229
SN - 0014-2999
VL - 249
SP - 101
EP - 106
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-2
ER -