Cardiovascular Research

Cardiovascular Research 1999 43(2):274-278; doi:10.1016/S0008-6363(99)00134-0
© 1999 by European Society of Cardiology

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Copyright © 1999, European Society of Cardiology

Tetrahydrobiopterin and endothelial nitric oxide synthase activity

Francesco Cosentino^a,b and Thomas F Lüscher^a,*

^aCardiology, University Hospital and Cardiovascular Research, Institute of Physiology, Zürich, Switzerland
^bIRCCS Neuromed, Pozzilli (IS), Italy

^* Corresponding author. Tel.: +41-1-255-2121; fax: +41-1-255-4251 100771.1237{at}compuserve.com

Received 30 December 1998; accepted 18 March 1999

	1 Introduction

Top 1 Introduction 2 Effects of tetrahydrobiopterin... 3 Conclusions References

 
Nitric oxide (NO) plays a crucial role in the regulation of vascular tone and maintenance of vascular integrity [1–3]. Indeed, nitric oxide reduces vascular tone, inhibits leucocytes adhesion to the endothelium, platelet-vessel wall interaction, as well as vascular smooth muscle cell proliferation and migration. Accordingly, major risk factors for atherosclerotic vascular disease such as hypercholesterolemia, diabetes, hypertension and smoking, have been associated with impaired nitric oxide activity [4–11].

In vivo the activity of the L-arginine-NO pathway is a balance between the synthesis and breakdown of NO. Although, there are several reasons to believe that NO synthesis could be impaired [12–14], reduced NO activity could be caused by enhanced catabolism. Indeed, the in vivo half-life of NO is determined mainly by its reaction with oxyhemoglobin and superoxide anion [15]. Superoxide (O₂^–) may rapidly react with NO to produce peroxynitrite (OONO^–; [16]). This reaction is even faster than the one of O₂^– with superoxide dismutase to form hydrogen peroxide (H₂O₂) and molecular oxygen. High concentrations of ONOO^– are very toxic, ONNO^– can form peroxynitrous acid whose cleavage products are among the most reactive and damaging species in biological systems [17]. Taken together, these data indicate that catabolism of NO by its reaction with superoxide could be an important mechanism underlying endothelial dysfunction and oxidative vascular injury described in a number of vascular diseases [18,19]. It can be postulated that harmful concentrations of ONOO^– can be achieved in a dysfunctional endothelium in which O₂^– generation is increased by cyclooxygenase, xanthine oxidase, and NADH oxidoreductase [20–22]. However, recent evidence indicates that decreased availability of tetrahydrobiopterin may be responsible for a dysfunction of nitric oxide synthase leading to a shift in the balance between the production of protective NO and deleterious oxygen-derived free radicals (Fig. 1). Tetrahydrobiopterin is known to be a cofactor of aromatic amino acid monooxygenases, which are regarded as key enzymes in the biosynthesis of several neurotransmitters, including catecholamines and serotonin [23]. It is indeed well established that inborn errors of tetrahydrobiopterin metabolism lead to cofactor deficiency, hyperphenylalaninemia, and neurological impairment [24]. In contrast, an important role of tetrahydrobiopterin in cardiovascular system has been recognized only recently. The first step of tetrahydrobiopterin biosynthesis involves activation of guanosine triphosphate (GTP)-cyclohydrolase I, which catalyzes the conversion of GTP to dihydroneopterin triphospahte [25]. Intracellular levels of tetrahydrobiopterin can also be increased by treating cells or animals with sepiapterin, which is converted to tetrahydrobiopterin via the so-called ‘salvage pathway’. This review will briefly discuss the complex interaction between tetrahydrobiopterin and nitric oxide synthase and its role in the control of vascular tone.

View larger version (13K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Schematic representation of nitric oxide synthase (NO synthase) reaction leading to L-citrulline and nitric oxide (NO) from L-arginine and oxygen (O2) (top). The activation of NO synthase at suboptimal levels (dashed line) of (6R)-5,6,7,8-tetrahydrobiopterin (H4 Biopterin) generates superoxide anion (O2–) followed by the production of hydrogen peroxide (H2O2) and/or peroxynitrite (ONOO–) from the rapid reaction of O2– and NO (bottom) (modified from ref. [38]).

 

	2 Effects of tetrahydrobiopterin on NOS activity

Top 1 Introduction 2 Effects of tetrahydrobiopterin... 3 Conclusions References

 
NO is synthesized from L-arginine by nitric oxide synthase (NOS) through a five electron oxidation. Three distinct NOS isoforms have been identified by molecular cloning [26]. Two of them are expressed constitutively in neurones (neuronal) and vascular endothelial cells (endothelial) and are activated by increased intracellular calcium levels. The expression of a third isoform is induced, in a calcium-independent fashion, by various cytokines in macrophages and a number of other nucleated mammalian cells including hepatocytes and vascular smooth muscle (inducible). Purification and cloning of NOS isoforms have revealed that they are self-sufficient one-component cytochrome P-450s, which contain a prosthetic heme group catalyzing the reductive activation of molecular oxygen requisite for L-arginine oxidation, as well as tightly bound flavins shuttling NADPH-derived electrons to the heme (Fig. 2; [27]). Classical cytochrome P-450 hydroxylating systems would operate perfectly with these cofactors being properly bound, but NO synthases do not. All three NOS isoforms additionally require tetrahydrobiopterin for catalytic activity. Tetrahydrobiopterin (H₄B) appears to mediate coupling of oxygen reduction to heme-catalyzed L-arginine oxidation to form NO and L-citrulline, but the molecular mechanism of this effect is still unknown. It could involve either an allosteric effect on the NOS protein or redox activity of H₄B, or both [25]. A close link between cellular H₄B availability and NO synthesis was recently demonstrated for a number of different cell types: murine endothelial cells, vascular smooth muscle cells, porcine and human endothelial cells, suggesting that the pathways for H₄B and NO synthesis are tightly coupled [25]. Indeed, in porcine and human vascular endothelial cells, inhibition of H₄B synthesis reduces production of NO in response to the calcium ionophore A23187 [GenBank] or bradykinin [28,29]. These studies provided evidence that in cultured endothelial cells, an optimal concentration of tetrahydrobiopterin is essential for agonist-induced, calcium-dependent production of nitric oxide.

View larger version (12K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 NO is produced by NOS, which incorporates molecular oxygen into the substrate L-arginine. The NOS itself has binding sites for tetrahydrobiopterin (H4B), L-arginine and heme. Electrons donated by reduced nicotinamide-adenine dinucleotide phosphate (NADPH) are shuttled through the reduced flavins, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) toward the oxidase domain. The built-in electron transport system is used to oxidize L-arginine to NO and L-citrulline. This reaction is dependent on the presence of H4B.

 
Although, the precise role of this cofactor in regulation of NOS catalytic activity is still not completely understood [25], it has been postulated that H₄B plays an important role in whether the electron flow, within the enzyme, can be directed to L-arginine. Indeed, several biochemical studies demonstrated that activation of purified constitutive NOS in the presence of suboptimal levels of tetrahydrobiopterin results in uncoupling of oxygen reduction and arginine oxidation, thereby generating superoxide anions and subsequently hydrogen peroxide [30–32]. In agreement with these results, we recently demonstrated that in isolated canine coronary arteries depleted of tetrahydrobiopterin endothelial nitric oxide synthase may become a source of oxygen-free radicals [33]. Ever since, growing evidence indicates that, under certain pathological conditions, decreased tetrahydrobiopterin availability may be responsible for dysfunction of endothelial NOS.

Very intriguing are recent findings showing that endothelial cells that were incubated with LDL released superoxide, which could be inhibited by the NOS inhibitor L-NAME [34]. These data suggest that NOS itself can be an important source for endothelial superoxide production in hypercholesterolemia. Indeed, enhanced oxidative degradation of NO is a major determinant of impaired NO activity in hypercholesterolemia [35–37]. Deficiency of tetrahydrobiopterin causes both impaired NO activity and increased oxygen radical formation [33,38]. In this regard, we further demonstrated that infusion of tetrahydrobiopterin into the brachial artery of patients with hypercholesterolemia restores endothelial dysfunction by increasing production of NO [39]. Therefore, increased breakdown of nitric oxide could be explained from a decreased availability of tetrahydrobiopterin. Cofactor supplementation may restore NO activity by decreasing oxygen radical formation. Tetrahydrobiopterin can also improve abnormal endothelium-dependent coronary vasomotion in response to acetylcholine in patients with coronary artery disease [40]. Furthermore, administration of tetrahydrobiopterin is capable of restoring endothelium-dependent vasodilation in experimental diabetes [41], smoking [42,43], and reperfusion injury [44]. Such effect of exogenous tetrahydrobiopterin is consistent with the concept of an altered tetrahydrobiopterin-NOS interaction which may lead to the above-mentioned dysfunctional activity of the enzyme.

Interestingly enough, an impaired synthesis of H₄B occurs in adrenal cortex of spontaneously hypertensive rats (SHR; [45]). This metabolic dysfunction was detected in prehypertensive animals suggesting that it may contribute to the development of hypertension and/or its complications. We reported [38] that in isolated aortas from prehypertensive SHR, H₄B supplementation diminished the NOS-dependent generation of superoxide and its dismutase product hydrogen peroxide, while it increased the net production of NO (Fig. 3). Although, the levels of H₄B from SHR were not different when compared to Wistar-Kyoto (WKY) aortas, NOS activity in response to exogenous H₄B was significantly higher in the latter. These results suggest that an increased requirement for H₄B may trigger an uncoupling of the oxidative and reductive domain of the enzyme resulting in dysfunctional NOS activity. Whether oxygen free radicals formed via NOS plays a role in the development of hypertension remains to be determined.

View larger version (24K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Bar graphs showing the basal and calcium ionophore A23187-stimulated concentration of superoxide (O2–) and hydrogen peroxide (H2O2) in aortic tissue from 4-week old Wistar-Kyoto rats (WKY, top) and spontaneously hypertensive rats (SHR, bottom). Note that after tetrahydrobiopterin (H4B) supplementation and in the presence of NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) the A23187-induced concentrations of O2– and its dismutase product H2O2 were significantly reduced only in SHR (reprinted from ref. [38]).

 

	3 Conclusions

Top 1 Introduction 2 Effects of tetrahydrobiopterin... 3 Conclusions References

 
All together these observations strongly support the concept of a dysfunctional NOS as a new source of reactive oxygen metabolites. This NOS-catalyzed formation of O₂^– and its subsequent transformation into HONOO cleavage products, or its dismutation into H₂O₂ and Fenton reaction product OH, may play a pivotal role in the endothelial dysfunction and oxidative vascular injury described in a number of vascular diseases. Therefore, reduced availability of H₄B may represent an important mechanism underlying conditions associated with impaired NO activity and accelerated atherosclerosis. Although the background for such a deficiency is not clear, these findings warrant further exploration for a better understanding of signal transduction pathways sustaining the formation of H₄B in the endothelium. The present knowledge not only underscore the relevance of H₄B as crucial cofactor for NO synthesis but also may initiate research into new therapeutic approaches to reduce cardiovascular risk.

Time for primary review 23 days.

	Acknowledgements

 
This work was supported in part by the Swiss National Research Foundation grant 32-510069.97 and the Italian Research Council project 97000983.PF34.

	References

Top 1 Introduction 2 Effects of tetrahydrobiopterin... 3 Conclusions References

 

1. Palmer R.M.J., Ferrige A.G., Moncada S. Nitric release accounts for the biological activity of endothelial-derived relaxing factor. Nature (1987) 327:534–536.
2. Furchgott R., Zawadzki J.V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature (1980) 299:373–376.
3. Lüscher T.F., Noll G. The pathogenesis of cardiovascular disease: role of the endothelium as target and mediator. Atherosclerosis (1995) 188(Suppl.):S81–S90.
4. Creager M., Cooke J.P., Mendelsohn M.E., et al. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic patients. J Clin Invest (1990) 86:228–234.[Web of Science][Medline]
5. Egashira K., Inou T., Hirooka Y., et al. Impaired coronary blood flow response to acethylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest (1993) 91:29–37.[Web of Science][Medline]
6. Egashira K., Inou T., Hirooka Y., et al. Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans. Circulation (1993) 88:77–81.[Abstract/Free Full Text]
7. Stroes E.S.G., Koomans H.A., de Bruin T.W.A., Rabelink T.J. Vascular function in the forearm of hypercholseterolemic patients off and on lipid-lowering medication. Lancet (1995) 346:467–471.[CrossRef][Web of Science][Medline]
8. Panza J.A., Garcia C.E., Kilcoyne C.M., Quyyumi A.A., Cannon R.O. Impaired endothelium-dependent vasodilation in essential hypertension. Circulation (1995) 91:1732–1738.[Abstract/Free Full Text]
9. Johnstone M.T., Creager S.J., Scales K.M., et al. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes. Circulation (1993) 88:2510–2516.[Abstract/Free Full Text]
10. Ting H.T., Timimi F.K., Boles K.S., et al. Vitamins C improves endothelium-dependent vasodilation in patients with non insulin-dependent diabetes mellitus. J Clin Invest (1996) 97:22–28.[Web of Science][Medline]
11. Heitzer T.S., Yla-Herttuala S., Luoma J., et al. Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia. Circulation (1996) 93:1346–1353.[Abstract/Free Full Text]
12. Freeman J.E., Kuo W.Y., Drenger B., et al. Analysis of lysophosphatidylcholine-induced endothelial dysfunction. J Cardiovasc Pharmacol (1996) 28:345–352.[CrossRef][Web of Science][Medline]
13. Bode-Boger S.M., Boger R.H., Kienke S., Junker W., Frolich J.C. Elevated L-arginine/dimethylarginine ratio contributes to enhanced systemic NO production by dietary L-arginine in hypercholesterolemic rabbits. Biochem Biophys Res Commun (1996) 219:598–603.[CrossRef][Web of Science][Medline]
14. Cooke J.P., Tsao P.S. Arginine: a new therapy for atherosclerosis? Circulation (1997) 95:311–312.[Free Full Text]
15. Beckman J.S., Koppenol W.H. Nitric oxide, superoxide, and peroxynitrite: the good, the bad and the ugly. Am J Physiol (1996) 271:C1424–C1437.[Web of Science][Medline]
16. Kobayashi K., Miki M. Frontiers of reactive oxygen species in biology & medicine. Asada K., Yoshikawa T., eds. (1994) Amsterdam: Elsevier Science B.V. 223–224.
17. Beckman J.S., Chen J., Ischiropoulos H., Crow J.P. Part C, Oxygen radicals in biological systems. Packer L., ed. (1994) 233. San Diego, CA: Academic Press Inc. 229–240. Methods of enzymology.[CrossRef]
18. Pryor W.A. Natural antioxidants in human health and disease. Frei B., ed. (1994) Boston: Academic Press. 1–24.
19. Halliwell B. Free radicals, antioxidants, and human disease: curiosity, cause, or consequence? Lancet (1994) 344:721–724.[CrossRef][Web of Science][Medline]
20. Cosentino F., Sill J.C., Katusic Z.S. Role of superoxide anions in mediation of endothelium-dependent contractions. Hypertension (1993) 23:229–235.[Web of Science]
21. Kontos H.A. Oxygen radicals in cerebral vascular injury. Circ Res (1985) 57:508–516.[Abstract/Free Full Text]
22. Mohazzab K.M., Kaminski P.M., Wolin M.S. NADH oxidoreductase is a major source of superoxide anion in bovine artery endothelium. Am J Physiol (1994) 266:H2568–H2572.[Web of Science][Medline]
23. Kaufman S. New tetrahydrobiopterin-dependent systems. Annu Rev Nutr (1993) 13:261–286.[CrossRef][Web of Science][Medline]
24. Blau N., Thony B., Heizmann C.W., Dhont J.L. Tetrahydrobiopterin deficiency: from phenotype to genotype. Pteridines (1993) 4:1–10.
25. Mayer B., Werner E.R. In search of a function for tetrahydrobiopterin in the biosynthesis of nitric oxide. Naunyn-Schmied Arch Pharmacol (1995) 351:453–463.[Web of Science][Medline]
26. Knowles R.G., Moncada S. Mammalian nitric oxide synthase. Biochem J (1994) 298:249–258.[Web of Science][Medline]
27. Bredt D.S., Hwang P.M., Glatt C.E., et al. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature (1991) 351:714–718.[CrossRef][Medline]
28. Schmidt K., Werner E.R., Mayer B., Wachter H., Kukowetz W.R. tetrahydrobiopterin-dependent formation of endothelium-derived relaxing factor (nitric oxide) in aortic endothelial cells. Biochem J (1992) 281:297–300.[Web of Science][Medline]
29. Werner-Felmayer G., Werner E.G., Fuchs D., et al. Pteridine biosynthseis in human endothelial cells: impact on nitric oxide-mediated formation of cGMP. J Biol Chem (1993) 268:1842–1846.[Abstract/Free Full Text]
30. Stuher D.J., Cho H.J., Kwon N.S., Weise M.F., Nathan C.F. Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD and FMN-containing flavoprotein. Proc Natl Acad Sci USA (1991) 88:7773–7777.[Abstract/Free Full Text]
31. Heinzel B., John M., Klatt P., Bohme E., Mayer B. Ca²⁺/calmodulin dependent formation of hydrogen peroxide by brain nitric oxide synthase. Biochem J (1992) 281:627–630.[Web of Science][Medline]
32. Pou S., Pou W.S., Bredt D.S., Snyder S.H., Rosen G.M. Generation of superoxide by purified brain nitric oxide synthase. J Biol Chem (1992) 267:24173–24176.[Abstract/Free Full Text]
33. Cosentino F., Katusic Z.S. Tetrahydrobiopterin and dysfunction of endothelial nitric oxide synthase in coronary arteries. Circulation (1995) 91:139–144.[Abstract/Free Full Text]
34. Pritchard K.A., Groszek L., Smalley D.M., et al. Native low density lipoprotein increaseas endothelial cell nitric oxide synthase generation of superoxide anion. Circ Res (1995) 77:510–518.[Abstract/Free Full Text]
35. Harrison D.G., Ohara Y. Physiologic consequences of increased vascular oxidant stress in hypercholesterolemia and atherosclerosis: implications for impaired vasomotion. Am J Cardiol (1995) 75:75B–81B.[CrossRef][Medline]
36. Ohara Y., Peterson T.E., Harrison D.G. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest (1993) 91:2546–2551.[Web of Science][Medline]
37. Ting H.H., Timimi F.K., Haley E.A., et al. Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessel of humans with hypercholesterolemia. Circulation (1997) 95:2617–2622.[Abstract/Free Full Text]
38. Cosentino F., Patton S., d’Uscio L.V., et al. Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensive rats. J Clin Invest (1998) 101:1530–1537.[Web of Science][Medline]
39. Stroes E., Kastelein J., Cosentino F., et al. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest (1997) 99:41–46.[Web of Science][Medline]
40. Maier W., Cosentino F., Seiler C., et al. Tetrahydrobiopterin improves endothelial function in patients with coronary artery disease. Eur Heart J (1997) 18:15.[Abstract]
41. Pieper G.M. Acute amelioration of diabetic endothelial dysfunction with a derivative of the nitric oxide synthase cofactor, tetrahydrobiopterin. J Cardiovasc Pharmacol (1997) 29:8–15.[CrossRef][Web of Science][Medline]
42. Higman D.J., Strachan A.M.J., Buttery L., et al. Smoking impairs the activity of endothelial nitric oxide synthase in saphenous vein. Artherioscl Thromb Vasc Biol (1996) 16:546–552.
43. Heitzer T., Munzel T. The cofactor of the nitric oxide synthase tetrahydrobiopterin improves endothelial dysfunction in smokers. Circulation (1998) 98(17):I–735.
44. Tiefenbacher C.P., Chilian W.M., Mitchell M., DeFily D.V. Restoration of endothelium-dependent vasodilation after reperfusion injury by tetrahydrobiopterin. Circulation (1996) 94:1423–1429.[Abstract/Free Full Text]
45. Abou-Donia M.M., Daniels J.A., Nichol C.A., Viveros H.L. Chemistry and biology of pteridines. Blair J.A., ed. (1983) New York: Walter de Gruyter and Co. 783–787.

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				D. Yang, N. Levens, J. N. Zhang, P. M. Vanhoutte, and M. Feletou Specific Potentiation of Endothelium-Dependent Contractions in SHR by Tetrahydrobiopterin Hypertension, January 1, 2003; 41(1): 136 - 142. [Abstract] [Full Text] [PDF]

				S. Cai, N. J Alp, D. McDonald, I. Smith, J. Kay, L. Canevari, S. Heales, and K. M Channon GTP cyclohydrolase I gene transfer augments intracellular tetrahydrobiopterin in human endothelial cells: effects on nitric oxide synthase activity, protein levels and dimerisation Cardiovasc Res, September 1, 2002; 55(4): 838 - 849. [Abstract] [Full Text] [PDF]

				M. E. Hyndman, S. Verma, R. J. Rosenfeld, T. J. Anderson, and H. G. Parsons Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2167 - H2172. [Abstract] [Full Text] [PDF]

				Y. Hattori, N. Nakanishi, and K. Kasai Statin enhances cytokine-mediated induction of nitric oxide synthesis in vascular smooth muscle cells Cardiovasc Res, June 1, 2002; 54(3): 649 - 658. [Abstract] [Full Text] [PDF]

				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]

				T. Gori, J. M. Burstein, S. Ahmed, S. E.S. Miner, A. Al-Hesayen, S. Kelly, and J. D. Parker Folic Acid Prevents Nitroglycerin-Induced Nitric Oxide Synthase Dysfunction and Nitrate Tolerance: A Human In Vivo Study Circulation, September 4, 2001; 104(10): 1119 - 1123. [Abstract] [Full Text] [PDF]

				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]

				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]

				A.H. Henderson 'It all used to be so simple in the old days'. A personal view Eur. Heart J., April 2, 2001; 22(8): 648 - 653. [PDF]

				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]

				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]

				S. Verma, F. Lovren, A. S. Dumont, K. J. Mather, A. Maitland, T. M. Kieser, C. R. Triggle, and T. J. Anderson Tetrahydrobiopterin improves endothelial function in human saphenous veins J. Thorac. Cardiovasc. Surg., October 1, 2000; 120(4): 668 - 671. [Abstract] [Full Text] [PDF]

				F. Brunner, G. Wolkart, S. Pfeiffer, J. C Russell, and T. C Wascher Vascular dysfunction and myocardial contractility in the JCR:LA-corpulent rat Cardiovasc Res, July 1, 2000; 47(1): 150 - 158. [Abstract] [Full Text] [PDF]

				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]

				M. E. Hyndman, S. Verma, R. J. Rosenfeld, T. J. Anderson, and H. G. Parsons Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2167 - H2172. [Abstract] [Full Text] [PDF]

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