Supplemention with tetrahydrobiopterin suppresses the development of hypertension in spontaneously hypertensive rats.
It has been suggested that tetrahydrobiopterin (H(4)B), a cofactor of NO synthase, can reverse endothelial dysfunction caused by cardiovascular diseases, including atherosclerosis, coronary artery disease, and hypertension. Moreover, an impairment of H(4)B biosynthesis in spontaneously hypertensive rats (SHR) was observed. Thus, we hypothesized that the defect of the H(4)B synthesis system may play an important role in the development of hypertension in SHR. In the present study H(4)B (10 mg/kg per day IP) was used to treat SHR and Wistar-Kyoto rats (WKY) from the age of 5 through 16 weeks. Results demonstrated that chronic treatment with H(4)B significantly improved the impaired vascular responses to acetylcholine and suppressed the development of hypertension in SHR but did not affect WKY. The increase of inducible NO synthase expression, nitrotyrosine immunostaining, NO production, and superoxide anion formation in adult SHR were also significantly suppressed by chronic treatment with H(4)B. In contrast, H(4)B had no effect on WKY. In conclusion, this study demonstrated that H(4)B significantly attenuated the development of hypertension in SHR. The antihypertensive effect of H(4)B might be mediated through its direct antioxidant activity and/or decreasing oxygen free radical production from NO synthase, thereby reducing inducible NO synthase expression and peroxynitrite formation. Thus, the present study proposed that supplementation with H(4)B might be beneficial in preventing pathological conditions such as essential hypertension.
Hong
H J
HJ
Graduate Institute of Life Sciences, Department of Pharmacology, National Defense Medical Center, Taipei Medical University, Taipei, Taiwan, Republic of China.
Hsiao
G
G
Cheng
T H
TH
Yen
M H
MH
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D046508:Culture Techniques; D019587:Dietary Supplements; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D030421:Peroxynitrous Acid / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D000975:Antioxidants; D009566:Nitrates; D013481:Superoxides; D030421:Peroxynitrous Acid; D001708:Biopterins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C003402:sapropterin; D000109:Acetylcholine