Supplemention With Tetrahydrobiopterin Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats

Abstract

Abstract-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. Key Words: nitric oxide synthase Ⅲ peroxynitrite Ⅲ rats, inbred SHR Ⅲ superoxide Ⅲ biopterin I ncreased superoxide formation occurs in spontaneously hypertensive rats (SHR). 1 Superoxide may induce inducible NO synthase (iNOS) and then cause overproduction of NO. 2 The formation of massive amounts of NO via iNOS has a potentially cytotoxic effect, whereas relatively small amounts of NO formed via endothelial NO synthase (eNOS) have a cytoprotective action on the cardiovascular system. 3 In addition, the parallel time course of the generation of superoxide anion and iNOS indicates an efficient simultaneous reaction: NOϩO 2 *3 ONOOϪ (peroxynitrite). 4 Peroxynitrite is a short-lived and potently damaging oxidant that contributes significantly to pathological oxidative stress in living tissues. 5 Moreover, the unique chemical reactions of peroxynitrite, such as protein nitration, DNA single-strand breakage, and guanidine nitration, are not only cytotoxic but also mutagenic. 6 These findings suggest that increased production of superoxide in SHR may lead to the development of hypertension through chronic damage of the cardiovascular system, especially endothelium, induced by massive amounts of NO and peroxynitrite. Because peroxynitrite formation was previously identified through immunostaining of nitrotyrosine at the local site of infected organs, 4 in the present study we used a Western blotting assay to detect nitrotyrosine expression in the thoracic aorta as indirect eviden...

Tetrahydrobiopterin: a novel antihypertensive therapy

“…Aortae of spontaneously hypertensive rats had higher production of superoxide and reduced release of NO compared with normotensive rats, an effect that was blunted in the presence of exogenous BH 4 . 19,24 Our present study confirms these experimental observations in human subjects with essential hypertension in whom oral BH 4 reduced BP, likely by reversing the uncoupling of NO synthase and improving NO bioavailability. A previous study by Higashi et al 25 showed that parenteral infusion of BH 4 improved endothelial function in hypertensive patients, but this is the first study demonstrating the effects of oral BH 4 on endothelial function and BP.…”

“…In addition, NO mediates many of the protective functions of the endothelium, including inhibition of vascular smooth muscle proliferation, platelet aggregation and expression of proinflammatory cytokines. 19,20 NO is generated from L-arginine in the vascular endothelium by constitutive eNOS in the presence of reduced BH 4 that is an essential cofactor of eNOS. Insufficiency of BH 4 or its oxidation to dihydrobiopterin by peroxynitrite or other oxidants leads to uncoupling of eNOS that promotes generation of superoxide instead of NO.…”

Gene Transfer of Human Guanosine 5′-Triphosphate Cyclohydrolase I Restores Vascular Tetrahydrobiopterin Level and Endothelial Function in Low Renin Hypertension

“…An arterial BH 4 deficiency exists in cardiovascular diseases, including hypertension, 5,6 diabetes, 7,8 hypercholesterolemia and therosclerosis, 9,30 -32 and chronic smoking, 33 resulting in impaired endothelium-dependent NO-mediated vasodilations. However, the cellular mechanisms underlying BH 4 deficiency are not well understood.…”

“…1,2 Loss of BH 4 availability causes formation of O 2 Ϫ instead of NO after eNOS activation and is an important contributor to endothelial dysfunction in cardiovascular diseases, including hypertension. [1][2][3][4][5][6] A BH 4 deficiency results in endothelial dysfunction in hypertension, 5,6 diabetes, 7,8 and atherosclerosis, 9 and BH 4 supplementation improves endothelium-dependent vasodilation under these conditions. It has been hypothesized that either an increase in oxidative stress or a decrease of expression of guanosine 5Ј-triphosphate (GTP) cyclohydrolase I (GTPCH I), the first and rate-limiting enzyme for BH 4 biosynthesis, results in reduced BH 4 levels.…”

Impaired Regulation of Renal Oxygen Consumption in Spontaneously Hypertensive Rats

“…On the other hand, evidence of increased expression of NO synthesizing enzymes (eNOS and inducible NO synthase), increased NO production, or both have also been noted (12)(13)(14)(15)(16)(17)(18), both before and after the onset of hypertension. One possible explanation for this discrepancy is inactivation of NO, explaining increased production but less effect in SHR.…”