(Circulation. 1995;91:139-144.)
© 1995 American Heart Association, Inc.
Tetrahydrobiopterin and Dysfunction of Endothelial Nitric Oxide Synthase in Coronary Arteries
Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993.
From the Departments of Anesthesiology and Pharmacology, Mayo Clinic, Rochester, Minn.
Correspondence to Zvonimir S. Katu
i
, MD, PhD, Department
of Anesthesiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background The L-arginine/nitric oxide pathway plays a key role in the regulation of arterial tone. Biosynthesis of nitric oxide requires activation of nitric oxide synthase in the presence of tetrahydrobiopterin as a cofactor. Biochemical studies demonstrated that activation of purified nitric oxide synthase at suboptimal concentrations of tetrahydrobiopterin leads to production of hydrogen peroxide. The present experiments were designed to determine whether in coronary arteries inhibition of tetrahydrobiopterin synthesis may favor nitric oxide synthase–catalyzed production of hydrogen peroxide.
Methods and Results Primary branches of canine left anterior descending artery were incubated for 6 hours in minimum essential medium in the presence or in the absence of the tetrahydrobiopterin synthesis inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP; 10-2 mol/L). Arterial rings were suspended for isometric tension recording. Production of cGMP was measured by radioimmunoassay. Experiments were performed in the presence of indomethacin (10-5 mol/L). During contractions to the thromboxane A2/prostaglandin H2 receptor agonist U46619 (10-7 mol/L), calcium ionophore A23187 (10-9 to 10-6 mol/L) caused endothelium-dependent relaxations. A nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (3x10-4 mol/L), significantly inhibited these relaxations. In DAHP-treated arteries, relaxations to A23187 and its stimulating effect on cGMP production were significantly reduced in the presence of catalase (1200 U/mL). By contrast, catalase did not exert any effect in rings incubated in the absence of DAHP. Furthermore, the inhibitory effect of catalase on A23187-induced relaxations was abolished when coronary arteries were incubated in the presence of DAHP plus a liposoluble analogue of tetrahydrobiopterin, 6-methyltetrahydropterin (10-4 mol/L).
Conclusions The present study suggests that hydrogen peroxide may be a mediator of endothelium-dependent relaxations in coronary arteries depleted of tetrahydrobiopterin. This initially compensatory response, triggered by a dysfunctional nitric oxide synthase, may represent an important mechanism underlying oxidative vascular injury.
Key Words: endothelium-derived factors • arteries • endothelium
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The activity of both "constitutive" and "inducible" nitric oxide synthase and formation of nitric oxide are dependent on the presence of optimal concentrations of tetrahydrobiopterin as a cofactor.1 2 3 4 5 6 The first step of tetrahydrobiopterin biosynthesis involves activation of GTP cyclohydrolase I, which catalyzes the conversion of GTP to dihydroneopterin triphosphate (Fig 1
).4 7
In cultured aortic endothelial cells, inhibition of tetrahydrobiopterin
synthesis with the GTP cyclohydrolase I inhibitor
2,4-diamino-6-hydroxypyrimidine (DAHP) reduces formation of nitric
oxide in response to activation of constitutive enzyme with calcium
ionophore A23187 and bradykinin.8 9 Furthermore,
biochemical studies demonstrated that activation of purified nitric
oxide synthase at suboptimal concentrations of tetrahydrobiopterin
leads to production of hydrogen peroxide.10 11
Hydrogen
peroxide is a potent vasodilator in coronary arteries,12
and it may become a mediator of endothelium-dependent
relaxations in conditions associated with impaired synthesis of
tetrahydrobiopterin. However, hydrogen peroxide is also a powerful but
sluggish oxidant in its reactivity toward biological
compounds.13 14 Thus, prolonged increased
intracellular
production of hydrogen peroxide may lead to oxidative vascular injury.
The present study was designed to determine whether a dysfunctional
endothelial nitric oxide synthase may be a source of hydrogen peroxide
in coronary arteries. This concept may have very important implications
in understanding the mechanisms of oxidative vascular injury described
in a number of vascular diseases, including
atherosclerosis.15 16 17
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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The experiments were performed on rings (4 mm long) of coronary arteries (primary branches of left anterior descending artery) taken from dogs (15 to 20 kg) anesthetized with 30 mg/kg IV sodium pentobarbital. All procedures were in accordance with institutional guidelines. The arteries were initially incubated at 37°C for 1 or 6 hours in minimum essential medium (MEM, with Earle's salts, containing 0.1% BSA, 100 U/mL penicillin, and 100 µm/mL streptomycin) in the presence or in the absence of DAHP (10-2 mol/L); then they were placed in modified Krebs-Ringer bicarbonate solution (control solution, mmol/L: NaCl 118.3, KCl 4.7, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 25.0, calcium EDTA 0.026, and glucose 11.1). In certain rings, the endothelium was removed mechanically. To inhibit cyclooxygenase activity, all experiments were performed in the presence of indomethacin (10-5 mol/L). Each ring was connected to an isometric force transducer (Gould3000) and suspended in an organ chamber filled with 25 mL control solution (37°C, pH 7.4) gassed with 94% O2/6% CO2. Isometric tension was recorded continuously. Each ring was then gradually stretched to the optimal point of its length-tension curve (2.5 g) as determined by the contraction to U46619 (10-7 mol/L). The functional integrity of endothelium was tested by the presence of relaxations to acetylcholine (10-6 mol/L).
Only 1 hour of incubation in MEM containing DAHP catalase did not
affect endothelium-dependent relaxations to calcium
ionophore A23187 (Table 1). These results suggested that
longer incubation time is required to inhibit tetrahydrobiopterin
biosynthesis.
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Radioimmunoassay of cGMP
A radioimmunoassay technique was
used to determine the levels of
cyclic 3',5'-guanosine monophosphate (cGMP). After the initial
incubation in the absence or in the presence of DAHP (10-2
mol/L), rings with endothelium were transferred to control solution
bubbled with 94% O2/6% CO2 gas mixture
and kept at 37°C. After 1 hour, rings were incubated for another 30
minutes in a fresh solution containing indomethacin (10-5
mol/L) and 3-isobutyl-1-methylxanthine (IBMX, 10-4 mol/L)
to inhibit cyclooxygenase activity and the degradation of cyclic
nucleotides by phosphodiesterases, respectively. When catalase (1200
U/mL) was used to scavenge hydrogen peroxide, it was added the last 5
minutes of the incubation period. After 1 minute in the presence of
A23187 (3x10-7 mol/L), all rings were removed from the
solution and frozen in liquid nitrogen. A cGMP radioimmunoassay kit
(Amersham) was used to perform the measurements.18
Drugs
The following pharmacological agents were used:
acetylcholine
chloride (Sigma Chemical Co), albumin, bovine fraction V (Sigma),
calcium ionophore A23187 (Sigma), catalase (C-100 from bovine liver;
58 000 U/mg protein, Sigma), DAHP (Sigma),
9,11-dideoxy-9
11a-methanoepoxy-prostaglandin F2
(U46619, Cayman Chemical Co), hydrogen peroxide (Sigma), IBMX (Sigma),
indomethacin (Sigma), 6-methyl-5,6,7,8-tetrahydropterin dihydrochloride
(Sigma), molsidomine (SIN-1, Cassella AG),
NG-nitro-L-arginine methyl
ester (L-NAME, Sigma), papaverine hydrochloride (Sigma), pentobarbital
sodium (Fort Dodge Laboratories, Inc), and penicillin-streptomycin
(Gibco BRL). Stock solutions of the drugs were prepared fresh every
day. DAHP was dissolved in 25 mL MEM (Gibco BRL) so that its final
concentration was 10-2 mol/L. The other drugs were
dissolved in distilled water so that volumes of <0.2 mL were added to
the organ chambers. Stock solution of 10-5 mol/L
indomethacin was prepared in equimolar concentrations of
Na2CO3. Stock solution of 10-6
mol/L A23187 was prepared in 1.5x10-4 mol/L dimethyl
sulfoxide. All concentrations are expressed as final molar
concentration in the bath solution.
Concentration-response curves were obtained cumulatively. Several rings cut from the same artery were studied in parallel; only one concentration-response curve was made per preparation. In quiescent preparations, indomethacin or catalase did not affect resting tension. Responses to calcium ionophore A23187 were obtained during submaximal contractions to U46619 (10-7 mol/L). Because L-NAME increased resting tension, care was taken to match the contractions induced by U46619 in control and treated rings. The incubation time was 30 minutes for indomethacin, 15 minutes for L-NAME, and 5 minutes for catalase. The relaxations were expressed as a percentage of maximal relaxations induced by papaverine (3x10-4 mol/L).
Statistical Analysis
The results are expressed as
mean±SEM; in each set of
experiments, n indicates the number of animals studied. Statistical
evaluation of the data was performed by Student's t test
for paired and unpaired observations. A value of P<.05 was
considered statistically significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Endothelium-Dependent Relaxations to A23187
Contractions to U46619 and endothelium-dependent relaxations to calcium ionophore A23187 were preserved in arteries incubated for 6 hours in MEM in the absence or in the presence of the tetrahydrobiopterin synthesis inhibitor DAHP (10-2 mol/L) (Figs 2 through 4
). L-NAME
(3x10-4 mol/L) significantly inhibited relaxations to
A23187 in arteries incubated in the absence of DAHP, whereas catalase
(1200 U/mL) did not affect these relaxations (Fig 2). In
DAHP-treated
arteries, relaxations to A23187 were significantly inhibited by L-NAME
(3x10-4 mol/L, Fig 4). Catalase (1200
U/mL) significantly
reduced endothelium-dependent relaxations to A23187 in
these preparations (Figs 3 and 4). However, the
inhibitory effect of
catalase on A23187-induced relaxations was abolished when coronary
arteries were incubated in the presence of DAHP plus a liposoluble
analogue of tetrahydrobiopterin, 6-methyltetrahydropterin
(10-4 mol/L, Fig 5).
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Hydrogen Peroxide–Induced Relaxations
During
contractions to U46619 (10-7 mol/L), hydrogen
peroxide (10-6 to 10-3 mol/L) caused
concentration-dependent relaxations (Fig 6, left). The
relaxations elicited by hydrogen peroxide were not affected in the
presence of DAHP (10-2 mol/L; Fig 6, right).
Catalase
(1200 U/mL) abolished hydrogen peroxide–induced relaxations in both
groups (Fig 6).
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A23187-Induced Production of cGMP
In rings with endothelium,
A23187 (10-7 mol/L)
significantly increased levels of cGMP (Fig 7). In
DAHP-treated arteries, the production of cGMP was significantly
greater. Catalase (1200 U/mL) did not affect A23187-induced production
of cGMP when coronary arteries were incubated in the absence of DAHP
(Fig 7). By contrast, in DAHP-treated arteries, catalase
inhibited the
stimulatory effect of calcium ionophore on cGMP production (Fig
7). In
rings incubated for 6 hours in MEM, the removal of endothelium almost
abolished basal production of cGMP (258±29 and 28±8.9 pmol/g wet
wt,
n=6, for rings with and without endothelium, respectively).
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P<.05 compared with A23187 in MEM.
Endothelium-Independent Relaxations to SIN-1
During
contractions induced with U46619, the nitric oxide donor
SIN-1 (10-9 to 10-4 mol/L) caused
concentration-dependent relaxations in DAHP-treated arteries without
endothelium. Catalase (1200 U/mL) did not affect the relaxations to
SIN-1 (Table 2).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The present study demonstrates that in isolated coronary arteries, suboptimal concentrations of tetrahydrobiopterin may favor nitric oxide synthase–catalyzed production of hydrogen peroxide, which may participate in mediation of endothelium-dependent relaxations. This conclusion is supported by several lines of evidence: (1) endothelium-dependent relaxations to A23187 were significantly inhibited by the nitric oxide synthase inhibitor L-NAME, in arteries incubated both in the absence and in the presence of the tetrahydrobiopterin synthesis inhibitor DAHP; (2) catalase inhibited these relaxations only in arteries with impaired synthesis of tetrahydrobiopterin; (3) in DAHP-treated arteries, replacement of tetrahydrobiopterin by 6-methyltetrahydropterin abolished the inhibitory effect of catalase; and (4) catalase selectively inhibited A23187-induced production of cGMP in arteries depleted of tetrahydrobiopterin.
It is generally accepted that nitric oxide synthase converts the guanidine group of L-arginine into nitric oxide and L-citrulline, with tetrahydrobiopterin acting as a cofactor.1 2 3 4 5 6 In porcine and human vascular endothelial cells, inhibition of tetrahydrobiopterin synthesis with DAHP reduces formation of nitric oxide induced by activation of constitutive enzyme with calcium ionophore A23187 or bradykinin.8 9 These studies provided evidence that in cultured endothelial cells, optimal concentration of tetrahydrobiopterin is essential for agonist-induced, calcium-dependent production of nitric oxide.
Molecular cloning of nitric oxide synthase revealed close amino acid sequence homology between nitric oxide synthase and cytochrome P-450 reductase.19 This similarity, together with the fact that cytochrome P-450 reductase is a well-known cellular source of superoxide anion, suggested that nitric oxide synthase may also, under certain conditions, generate reduced-oxygen species. This intriguing concept was further supported by the results of biochemical studies that demonstrated that hydrogen peroxide is produced during activation of isolated nitric oxide synthase at suboptimal concentrations of tetrahydrobiopterin.10 11 20 Our findings suggest that endothelial nitric oxide synthase may also become a source of hydrogen peroxide in isolated coronary arteries depleted of tetrahydrobiopterin.
To inhibit synthesis of tetrahydrobiopterin, we used the well-characterized inhibitor of GTP cyclohydrolase I, DAHP. The concentration of DAHP and the length of incubation were based on previous reports.4 8 In our experience, prolonged incubation of isolated canine arteries does not lead to induction of Ca2+-independent (inducible) nitric oxide synthase activity (Z.S.K, unpublished data, 1994). Indeed, contractions to thromboxane A2/prostaglandin H2 receptor agonist U46619 were preserved after 6 hours' incubation in MEM. Furthermore, the removal of endothelium almost abolished basal production of cGMP, clearly indicating that incubation did not induce nitric oxide synthase in smooth muscle cells.
All experiments in this study were performed in the presence of indomethacin to rule out the possibility that hydrogen peroxide is generated by activation of arachidonic acid metabolism by the cyclooxygenase pathway.21 22 Endothelium-dependent relaxations in response to calcium ionophore A23187 were preserved in coronary arteries incubated in the absence and in the presence of GTP cyclohydrolase I inhibitor. L-NAME significantly reduced these relaxations, demonstrating that the inhibitory effect of A23187 is mediated by activation of nitric oxide synthase. However, further analysis revealed that catalase inhibited endothelium-dependent relaxations to A23187 only in arteries with impaired synthesis of tetrahydrobiopterin, suggesting that hydrogen peroxide becomes a mediator of these relaxations after incubation with DAHP. Furthermore, incubation of the coronary arteries with DAHP plus 6-methyltetrahydropterin, which may enter endothelial cells and replace tetrahydrobiopterin as a cofactor for nitric oxide synthase,4 abolished the inhibitory effect of catalase on A23187-induced relaxations. This finding suggests that the effect of DAHP is due to selective inhibition of tetrahydrobiopterin synthesis.
To more precisely characterize the reactivity of coronary arteries to hydrogen peroxide in our experimental conditions, we examined the effect of exogenous hydrogen peroxide. In arteries studied after incubation in MEM, hydrogen peroxide caused concentration-dependent relaxations. The inhibitory effect of hydrogen peroxide was not affected by the presence of DAHP and was abolished by catalase. These results show that prolonged incubation and treatment with DAHP do not affect reactivity of the coronary arteries to hydrogen peroxide. They are also in agreement with the previously demonstrated inhibitory effect of hydrogen peroxide in isolated coronary arteries.12
Hydrogen peroxide causes relaxations of aorta and pulmonary arteries by activation of soluble guanylate cyclase and increases in levels of cGMP in smooth muscle cells.23 24 In large coronary arteries, relaxations to hydrogen peroxide appear to be mediated by hyperpolarization of smooth muscle cells.25 It is interesting to note that in our study, catalase inhibited A23187-induced production of cGMP only in DAHP-treated arteries, whereas it did not affect cGMP levels when coronary arteries were incubated in the absence of DAHP. This selective effect of catalase, after inhibition of tetrahydrobiopterin synthesis, is consistent with the concept that activation of soluble guanylate cyclase in smooth muscle cells may be mediated by hydrogen peroxide. We ruled out the possibility that hydrogen peroxide is produced in smooth muscle cells of DAHP-treated arteries. Indeed, catalase did not affect relaxations to a nitric oxide donor SIN-1 in coronary arteries without endothelium.
Previous studies demonstrated that in canine coronary arteries and rabbit aorta, hydrogen peroxide causes endothelium-dependent relaxations.12 26 Pharmacological analysis of these relaxations revealed that hydrogen peroxide is a potent activator of endothelial nitric oxide synthase.26 These observations may explain the significantly higher production of cGMP detected in the coronary arteries incubated with DAHP. It is very likely that hydrogen peroxide may mediate endothelium-dependent relaxations not only by its effect on smooth muscle cells but also by stimulation of nitric oxide synthase activity and increased production of nitric oxide in the endothelium, leading to higher production of cGMP in DAHP-treated arteries. This explanation is based on the fact that in endothelial cells depleted of tetrahydrobiopterin, a portion of nitric oxide synthase is still functional and can generate nitric oxide.8 Our results do not allow any conclusion regarding the relative amount of hydrogen peroxide versus nitric oxide produced by a dysfunctional nitric oxide synthase.
The present study suggests that hydrogen peroxide may become a mediator of endothelium-dependent relaxations in coronary arteries depleted of tetrahydrobiopterin. It is tempting to speculate that nitric oxide synthase–catalyzed production of hydrogen peroxide may initially serve as a compensatory mechanism in conditions associated with low concentrations of tetrahydrobiopterin. However, hydrogen peroxide can react with superoxide anion in the presence of iron to yield the potent oxidizing agent, the hydroxyl radical.13 14 Membrane-associated polyunsaturated fatty acids are readily attacked by the hydroxyl radical in a free radical process that results in lipid peroxidation and cell lysis.27 Thus, prolonged increased intracellular production of hydrogen peroxide, triggered by a dysfunctional nitric oxide synthase, may represent an important mechanism underlying oxidative vascular injury.
Impaired synthesis of tetrahydrobiopterin has been described in adrenal cortex of spontaneously hypertensive rats.28 Interestingly, this metabolic dysfunction was detected in prehypertensive animals, suggesting that it may contribute to the development of increased vascular resistance and hypertension. Existing evidence suggests that the L-arginine/nitric oxide signal transduction pathway is impaired in vascular endothelial cells of spontaneously hypertensive rats or patients with essential hypertension.29 30 31 Whether impairment of nitric oxide production reflects decreased synthesis of tetrahydrobiopterin remains to be determined.
The role of tetrahydrobiopterin in regulation of vascular endothelial function deserves further investigation. De novo synthesis of tetrahydrobiopterin is regulated by activity of GTP cyclohydrolase I.4 7 Identification of signal transduction pathways involved in control of gene expression and activity of GTP cyclohydrolase I will provide a basis for understanding how impairment of tetrahydrobiopterin biosynthesis with subsequent endothelial dysfunction may take place.
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Acknowledgments |
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This work was supported in part by US Public Health Service grant HL-44116 and the Mayo Foundation. Dr Cosentino was supported by a grant from Bristol-Myers Squibb, Italy, for cardiovascular research.We would like to thank Dr Christopher Sill for help with cGMP measurements. We would also like to thank Leslie Phelps, Cindy Uhl, and Rita Nelson for technical assistance; Rebecca Wilson and Robert Lorenz for preparing the figures; and Janet Beckman for typing the manuscript.
Received May 16, 1994; accepted September 20, 1994.
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E. R. Werner, A. C.F. Gorren, R. Heller, G. Werner-Felmayer, and B. Mayer Tetrahydrobiopterin and Nitric Oxide: Mechanistic and Pharmacological Aspects Experimental Biology and Medicine, December 1, 2003; 228(11): 1291 - 1302. [Abstract] [Full Text] [PDF]
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N. Thengchaisri and L. Kuo Hydrogen peroxide induces endothelium-dependent and -independent coronary arteriolar dilation: role of cyclooxygenase and potassium channels Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2255 - H2263. [Abstract] [Full Text] [PDF]
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B. M. Mitchell, A. M. Dorrance, and R. C. Webb GTP cyclohydrolase 1 inhibition attenuates vasodilation and increases blood pressure in rats Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2165 - H2170. [Abstract] [Full Text] [PDF]
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J.-S. Zheng, X.-Q. Yang, K. J. Lookingland, G. D. Fink, C. Hesslinger, G. Kapatos, I. Kovesdi, and A. F. Chen Gene Transfer of Human Guanosine 5'-Triphosphate Cyclohydrolase I Restores Vascular Tetrahydrobiopterin Level and Endothelial Function in Low Renin Hypertension Circulation, September 9, 2003; 108(10): 1238 - 1245. [Abstract] [Full Text] [PDF]
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S. Ulker, D. McMaster, P. P. McKeown, and U. Bayraktutan Impaired activities of antioxidant enzymes elicit endothelial dysfunction in spontaneous hypertensive rats despite enhanced vascular nitric oxide generation Cardiovasc Res, August 1, 2003; 59(2): 488 - 500. [Abstract] [Full Text] [PDF]
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T. Matsumoto, L. V. d'uscio, D. Eguchi, M. Akiyama, L. A. Smith, and Z. S. Katusic Protective Effect of Chronic Vitamin C Treatment on Endothelial Function of Apolipoprotein E-Deficient Mouse Carotid Artery J. Pharmacol. Exp. Ther., July 1, 2003; 306(1): 103 - 108. [Abstract] [Full Text] [PDF]
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 D. G Harrison, Hua Cai, U. Landmesser, and K. K Griendling The Pickering Lecture British Hypertension Society, 10th September 2002: Interactions of angiotensin II with NAD(P)H oxidase, oxidant stress and cardiovascular disease Journal of Renin-Angiotensin-Aldosterone System, June 1, 2003; 4(2): 51 - 61. [Abstract] [PDF]
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 M. Weis and J. P. Cooke Cardiac Allograft Vasculopathy and Dysregulation of the NO Synthase Pathway Arterioscler Thromb Vasc Biol, April 1, 2003; 23(4): 567 - 575. [Abstract] [Full Text] [PDF]
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 B. M. Mitchell, A. M. Dorrance, and R. C. Webb GTP Cyclohydrolase 1 Downregulation Contributes to Glucocorticoid Hypertension in Rats Hypertension, March 1, 2003; 41(3): 669 - 674. [Abstract] [Full Text] [PDF]
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H. Miura, J. J. Bosnjak, G. Ning, T. Saito, M. Miura, and D. D. Gutterman Role for Hydrogen Peroxide in Flow-Induced Dilation of Human Coronary Arterioles Circ. Res., February 7, 2003; 92 (2): e31 - e40. [Abstract] [Full Text] [PDF]
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Q. Fang, H. Sun, and W. G. Mayhan Impairment of nitric oxide synthase-dependent dilatation of cerebral arterioles during infusion of nicotine Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H528 - H534. [Abstract] [Full Text] [PDF]
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S. V. Brodsky, S. Gao, H. Li, and M. S. Goligorsky Hyperglycemic switch from mitochondrial nitric oxide to superoxide production in endothelial cells Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H2130 - H2139. [Abstract] [Full Text] [PDF]
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 S. Yamashiro, K. Noguchi, T. Matsuzaki, K. Miyagi, J. Nakasone, M. Sakanashi, K. Koja, and M. Sakanashi Beneficial effect of tetrahydrobiopterin on ischemia-reperfusion injury in isolated perfused rat hearts J. Thorac. Cardiovasc. Surg., October 1, 2002; 124(4): 775 - 784. [Abstract] [Full Text] [PDF]
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J. Vasquez-Vivar, D. Duquaine, J. Whitsett, B. Kalyanaraman, and S. Rajagopalan Altered Tetrahydrobiopterin Metabolism in Atherosclerosis: Implications for Use of Oxidized Tetrahydrobiopterin Analogues and Thiol Antioxidants Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1655 - 1661. [Abstract] [Full Text] [PDF]
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K. Panda, R. J. Rosenfeld, S. Ghosh, A. L. Meade, E. D. Getzoff, and D. J. Stuehr Distinct Dimer Interaction and Regulation in Nitric-oxide Synthase Types I, II, and III J. Biol. Chem., August 16, 2002; 277(34): 31020 - 31030. [Abstract] [Full Text] [PDF]
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P. J.M Best, J. C Burnett Jr., S. H Wilson, D. R Holmes Jr., and A. Lerman Dendroaspis natriuretic peptide relaxes isolated human arteries and veins Cardiovasc Res, August 1, 2002; 55(2): 375 - 384. [Abstract] [Full Text] [PDF]
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 K. Yokoyama, M. Tajima, H. Yoshida, M. Nakayama, G. Tokutome, H. Sakagami, and T. Hosoya Plasma pteridine concentrations in patients with chronic renal failure Nephrol. Dial. Transplant., June 1, 2002; 17(6): 1032 - 1036. [Abstract] [Full Text] [PDF]
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S. Verma, A. Maitland, R. D. Weisel, P. W. M. Fedak, N. C. Pomroy, S.-H. Li, D. A. G. Mickle, R.-K. Li, and V. Rao Novel cardioprotective effects of tetrahydrobiopterin after anoxia and reoxygenation: Identifying cellular targets for pharmacologic manipulation J. Thorac. Cardiovasc. Surg., June 1, 2002; 123(6): 1074 - 1083. [Abstract] [Full Text] [PDF]
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Y Fukuda, H Teragawa, K Matsuda, T Yamagata, H Matsuura, and K Chayama Tetrahydrobiopterin restores endothelial function of coronary arteries in patients with hypercholesterolaemia Heart, March 1, 2002; 87(3): 264 - 269. [Abstract] [Full Text] [PDF]
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G. Wiemer, G. Itter, T. Malinski, and W. Linz Decreased Nitric Oxide Availability in Normotensive and Hypertensive Rats With Failing Hearts After Myocardial Infarction Hypertension, December 1, 2001; 38(6): 1367 - 1371. [Abstract] [Full Text] [PDF]
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H. Sun, K. P. Patel, and W. G. Mayhan Tetrahydrobiopterin, a cofactor for NOS, improves endothelial dysfunction during chronic alcohol consumption Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1863 - H1869. [Abstract] [Full Text] [PDF]
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H.-J. Hong, G. Hsiao, T.-H. Cheng, and M.-H. Yen Supplemention With Tetrahydrobiopterin Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats Hypertension, November 1, 2001; 38(5): 1044 - 1048. [Abstract] [Full Text] [PDF]
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X.-L. Ma, F. Gao, A. H. Nelson, B. L. Lopez, T. A. Christopher, T.-L. Yue, and F. C. Barone Oxidative Inactivation of Nitric Oxide and Endothelial Dysfunction in Stroke-Prone Spontaneous Hypertensive Rats J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 879 - 885. [Abstract] [Full Text]
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Z. S. Katusic Vascular endothelial dysfunction: does tetrahydrobiopterin play a role? Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H981 - H986. [Abstract] [Full Text] [PDF]
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R. S. Marinos, W. Zhang, G. Wu, K. A. Kelly, and C. J. Meininger Tetrahydrobiopterin levels regulate endothelial cell proliferation Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H482 - H489. [Abstract] [Full Text] [PDF]
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Y. Hattori, S. Hattori, and K. Kasai 4-Hydroxynonenal Prevents NO Production in Vascular Smooth Muscle Cells by Inhibiting Nuclear Factor-{{kappa}}B-Dependent Transcriptional Activation of Inducible NO Synthase Arterioscler Thromb Vasc Biol, July 1, 2001; 21(7): 1179 - 1183. [Abstract] [Full Text] [PDF]
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C. P. Tiefenbacher Tetrahydrobiopterin: a critical cofactor for eNOS and a strategy in the treatment of endothelial dysfunction? Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2484 - H2488. [Full Text] [PDF]
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F. Cosentino, J. E. Barker, M. P. Brand, S. J. Heales, E. R. Werner, J. R. Tippins, N. West, K. M. Channon, M. Volpe, and T. F. Luscher Reactive Oxygen Species Mediate Endothelium-Dependent Relaxations in Tetrahydrobiopterin-Deficient Mice Arterioscler Thromb Vasc Biol, April 1, 2001; 21(4): 496 - 502. [Abstract] [Full Text] [PDF]
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J. B. Laursen, M. Somers, S. Kurz, L. McCann, A. Warnholtz, B. A. Freeman, M. Tarpey, T. Fukai, and D. G. Harrison Endothelial Regulation of Vasomotion in ApoE-Deficient Mice : Implications for Interactions Between Peroxynitrite and Tetrahydrobiopterin Circulation, March 6, 2001; 103(9): 1282 - 1288. [Abstract] [Full Text] [PDF]
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S. Verma, L. Yao, D. J. Stewart, A. S. Dumont, T. J. Anderson, and J. H. McNeill Endothelin Antagonism Uncovers Insulin-Mediated Vasorelaxation In Vitro and In Vivo Hypertension, February 1, 2001; 37(2): 328 - 333. [Abstract] [Full Text] [PDF]
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D. G. Johns, A. M. Dorrance, N. L. Tramontini, and R. C. Webb Glucocorticoids Inhibit Tetrahydrobiopterin-Dependent Endothelial Function Experimental Biology and Medicine, January 1, 2001; 226(1): 27 - 31. [Abstract] [Full Text]
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R. H. Steinhorn, J. A. Russell, S. Lakshminrusimha, S. F. Gugino, S. M. Black, and J. R. Fineman Altered endothelium-dependent relaxations in lambs with high pulmonary blood flow and pulmonary hypertension Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H311 - H317. [Abstract] [Full Text] [PDF]
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C. P. Tiefenbacher, T. Bleeke, C. Vahl, K. Amann, A. Vogt, and W. Kubler Endothelial Dysfunction of Coronary Resistance Arteries Is Improved by Tetrahydrobiopterin in Atherosclerosis Circulation, October 31, 2000; 102(18): 2172 - 2179. [Abstract] [Full Text] [PDF]
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R. S. Barlow, A. M. El-Mowafy, and R. E. White H2O2 opens BKCa channels via the PLA2-arachidonic acid signaling cascade in coronary artery smooth muscle Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H475 - H483. [Abstract] [Full Text] [PDF]
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M. S. Wolin Interactions of Oxidants With Vascular Signaling Systems Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1430 - 1442. [Abstract] [Full Text] [PDF]
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D. Lang, S. I. Mosfer, A. Shakesby, F. Donaldson, and M. J. Lewis Coronary Microvascular Endothelial Cell Redox State in Left Ventricular Hypertrophy : The Role of Angiotensin II Circ. Res., March 3, 2000; 86(4): 463 - 469. [Abstract] [Full Text] [PDF]
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R. Golser, A. C. F. Gorren, A. Leber, P. Andrew, H.-J. Habisch, E. R. Werner, K. Schmidt, R. C. Venema, and B. Mayer Interaction of Endothelial and Neuronal Nitric-oxide Synthases with the Bradykinin B2 Receptor. BINDING OF AN INHIBITORY PEPTIDE TO THE OXYGENASE DOMAIN BLOCKS UNCOUPLED NADPH OXIDATION J. Biol. Chem., February 25, 2000; 275(8): 5291 - 5296. [Abstract] [Full Text] [PDF]
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D. Lang, M. B. Kredan, S. J. Moat, S. A. Hussain, C. A. Powell, M. F. Bellamy, H. J. Powers, and M. J. Lewis Homocysteine-Induced Inhibition of Endothelium-Dependent Relaxation in Rabbit Aorta : Role for Superoxide Anions Arterioscler Thromb Vasc Biol, February 1, 2000; 20(2): 422 - 427. [Abstract] [Full Text] [PDF]
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A. Leber, B. Hemmens, B. Klosch, W. Goessler, G. Raber, B. Mayer, and K. Schmidt Characterization of Recombinant Human Endothelial Nitric-oxide Synthase Purified from the Yeast Pichia pastoris J. Biol. Chem., December 31, 1999; 274(53): 37658 - 37664. [Abstract] [Full Text] [PDF]
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R. Busse and I. Fleming A critical look at cardiovascular translational research Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1655 - H1660. [Full Text] [PDF]
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A. Koller and A. Huang Development of Nitric Oxide and Prostaglandin Mediation of Shear Stress-Induced Arteriolar Dilation With Aging and Hypertension Hypertension, November 1, 1999; 34(5): 1073 - 1079. [Abstract] [Full Text] [PDF]
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R. A. Schmid, S. Hillinger, R. Walter, A. Zollinger, U. Stammberger, R. Speich, A. Schaffner, W. Weder, and G. Schoedon THE NITRIC OXIDE SYNTHASE COFACTOR TETRAHYDROBIOPTERIN REDUCES ALLOGRAFT ISCHEMIA-REPERFUSION INJURY AFTER LUNG TRANSPLANTATION J. Thorac. Cardiovasc. Surg., October 1, 1999; 118(4): 726 - 732. [Abstract] [Full Text] [PDF]
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I. Fleming and R. Busse Signal transduction of eNOS activation Cardiovasc Res, August 15, 1999; 43(3): 532 - 541. [Abstract] [Full Text] [PDF]
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F. Cosentino and T. F Luscher Tetrahydrobiopterin and endothelial nitric oxide synthase activity Cardiovasc Res, August 1, 1999; 43(2): 274 - 278. [Full Text] [PDF]
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S. Kerr, M. J. Brosnan, M. McIntyre, J. L. Reid, A. F. Dominiczak, and C. A. Hamilton Superoxide Anion Production Is Increased in a Model of Genetic Hypertension : Role of the Endothelium Hypertension, June 1, 1999; 33(6): 1353 - 1358. [Abstract] [Full Text] [PDF]
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K. M. Mohazzab-H., R. Agarwal, and M. S. Wolin Influence of glutathione peroxidase on coronary artery responses to alterations in PO2 and H2O2 Am J Physiol Heart Circ Physiol, January 1, 1999; 276(1): H235 - H241. [Abstract] [Full Text] [PDF]
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K. M. Channon, H. Qian, V. Neplioueva, M. A. Blazing, E. Olmez, G. A. Shetty, S. A. Youngblood, J. Pawloski, T. McMahon, J. S. Stamler, et al. In Vivo Gene Transfer of Nitric Oxide Synthase Enhances Vasomotor Function in Carotid Arteries From Normal and Cholesterol-Fed Rabbits Circulation, November 3, 1998; 98(18): 1905 - 1911. [Abstract] [Full Text] [PDF]
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Y. Xia, A.-L. Tsai, V. Berka, and J. L. Zweier Superoxide Generation from Endothelial Nitric-oxide Synthase. A Ca2+/CALMODULIN-DEPENDENT AND TETRAHYDROBIOPTERIN REGULATORY PROCESS J. Biol. Chem., October 2, 1998; 273(40): 25804 - 25808. [Abstract] [Full Text] [PDF]
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R. S. Barlow and R. E. White Hydrogen peroxide relaxes porcine coronary arteries by stimulating BKCa channel activity Am J Physiol Heart Circ Physiol, October 1, 1998; 275(4): H1283 - H1289. [Abstract] [Full Text] [PDF]
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M. C. Verhaar, R. M. F. Wever, J. J. P. Kastelein, T. van Dam, H. A. Koomans, and T. J. Rabelink 5-Methyltetrahydrofolate, the Active Form of Folic Acid, Restores Endothelial Function in Familial Hypercholesterolemia Circulation, January 27, 1998; 97(3): 237 - 241. [Abstract] [Full Text] [PDF]
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E. Stroes, T. de Bruin, H. de Valk, W. Erkelens, J.-D. Banga, H. van Rijn, H. Koomans, and T. Rabelink NO activity in familial combined hyperlipidemia: potential role of cholesterol remnants Cardiovasc Res, December 1, 1997; 36(3): 445 - 452. [Abstract] [Full Text] [PDF]
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K. Hishikawa and T. F. Luscher Pulsatile Stretch Stimulates Superoxide Production in Human Aortic Endothelial Cells Circulation, November 18, 1997; 96(10): 3610 - 3616. [Abstract] [Full Text]
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R. R. Giraldez, A. Panda, Y. Xia, S. P. Sanders, and J. L. Zweier Decreased Nitric-oxide Synthase Activity Causes Impaired Endothelium-dependent Relaxation in the Postischemic Heart J. Biol. Chem., August 22, 1997; 272(34): 21420 - 21426. [Abstract] [Full Text] [PDF]
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A. F.Y. Chen, T. O'Brien, M. Tsutsui, H. Kinoshita, V. J. Pompili, T. B. Crotty, D. J. Spector, and Z. S. Katusic Expression and Function of Recombinant Endothelial Nitric Oxide Synthase Gene in Canine Basilar Artery Circ. Res., March 1, 1997; 80(3): 327 - 335. [Abstract] [Full Text]
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C. P. Tiefenbacher, W. M. Chilian, M. Mitchell, and D. V. DeFily Restoration of Endothelium-Dependent Vasodilation After Reperfusion Injury by Tetrahydrobiopterin Circulation, September 15, 1996; 94(6): 1423 - 1429. [Abstract] [Full Text]
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D. J. Higman, A. M.J. Strachan, L. Buttery, R. C.J. Hicks, D. R. Springall, R. M. Greenhalgh, and J. T. Powell Smoking Impairs the Activity of Endothelial Nitric Oxide Synthase in Saphenous Vein Arterioscler Thromb Vasc Biol, April 1, 1996; 16(4): 546 - 552. [Abstract] [Full Text]
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C. E. Garcia, C. M. Kilcoyne, C. Cardillo, R. O. Cannon III, A. A. Quyyumi, and J. A. Panza Effect of Copper-Zinc Superoxide Dismutase on Endothelium-Dependent Vasodilation in Patients With Essential Hypertension Hypertension, December 1, 1995; 26(6): 863 - 868. [Abstract] [Full Text]
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R. A. Cohen and P. M. Vanhoutte Endothelium-Dependent Hyperpolarization : Beyond Nitric Oxide and Cyclic GMP Circulation, December 1, 1995; 92(11): 3337 - 3349. [Full Text]
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K. A. Pritchard Jr, L. Groszek, D. M. Smalley, W. C. Sessa, M. Wu, P. Villalon, M. S. Wolin, and M. B. Stemerman Native Low-Density Lipoprotein Increases Endothelial Cell Nitric Oxide Synthase Generation of Superoxide Anion Circ. Res., September 1, 1995; 77(3): 510 - 518. [Abstract] [Full Text]
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T. Scott-Burden Regulation of Nitric Oxide Production by Tetrahydrobiopterin Circulation, January 1, 1995; 91(1): 248 - 250. [Full Text]
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W. Wang, S. Wang, L. Yan, P. Madara, A. Del Pilar Cintron, R. A. Wesley, and R. L. Danner Superoxide Production and Reactive Oxygen Species Signaling by Endothelial Nitric-oxide Synthase J. Biol. Chem., May 26, 2000; 275(22): 16899 - 16903. [Abstract] [Full Text] [PDF]
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