Suppression of the development of hypertension by the inhibitor of inducible nitric oxide synthase.
Our previous study demonstrated that the aortic inducible nitric oxide synthase (iNOS) expression and the plasma nitrite level in spontaneously hypertensive rats (SHR) were greater than that in age-matched Wistar-Kyoto rats (WKY). We subsequently hypothesized that the over-expression of iNOS might play an important role in the pathogenesis of hypertension in SHR. In the present study, pyrrolidinedithiocarbamate (PDTC, 10 mg kg(-1) day(-1), p.o., antioxidant and nuclear factor-kappa B inhibitor) and aminoguanidine (15 mg kg(-1) day(-1), p.o., selective inhibitor of iNOS) was used to treat SHR and WKY from age of 5 weeks through 16 weeks. We found that PDTC and aminoguanidine significantly suppressed the development of hypertension and improved the diminished vascular responses to acetylcholine in SHR but not in WKY. Likewise, the increase of iNOS expression, nitrotyrosine immunostaining, nitric oxide production and superoxide anion formation in adult SHR were also significantly suppressed by chronic treatment with PDTC and aminoguanidine. In conclusion, this study demonstrated that both PDTC and aminoguanidine significantly attenuated the development of hypertension in SHR. The results suggest that PDTC suppresses iNOS expression due to its anti-oxidant and/or nuclear factor-kappa B inhibitory properties. However, the effect of aminoguanidine was predominantly mediated by inhibition of iNOS activity, thereby reducing peroxynitrite formation. We propose that the development of a more specific and potent inhibitor of iNOS might be beneficial in preventing pathological conditions such as the essential hypertension.
Hong
H J
HJ
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.
Loh
S H
SH
Yen
M H
MH
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006146:Guanidines / Q000627:therapeutic use*; D006973:Hypertension / Q000378:metabolism / Q000517:prevention & control*; D007118:Immunoassay; D008297:Male; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D011392:Proline / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013481:Superoxides / Q000378:metabolism; D013859:Thiocarbamates / Q000627:therapeutic use*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000276:immunology; D014664:Vasodilation / Q000187:drug effects
D004791:Enzyme Inhibitors; D006146:Guanidines; D009566:Nitrates; D013859:Thiocarbamates; D013481:Superoxides; C066229:prolinedithiocarbamate; C039642:peroxynitric acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D011392:Proline; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine