Endothelial nitric oxide synthase gene polymorphisms and the renal hemodynamic response to L-arginine
2008; Elsevier BV; Volume: 75; Issue: 3 Linguagem: Inglês
10.1038/ki.2008.574
ISSN1523-1755
AutoresDavid Z.I. Cherney, James W. Scholey, Joyce Zhou, Joseph Zimpelmann, C. Kennedy, Kevin D. Burns, Vesta Lai, Judith Miller,
Tópico(s)Renin-Angiotensin System Studies
ResumoNitric oxide is generated from L-arginine by nitric oxide synthase (NOS), an enzyme that exists in several isoforms. Some studies found that a polymorphism (G894T) in the endothelial NOS gene was associated with decreased nitric oxide bioactivity and vascular complications. However, it is not known whether the enzyme had a reduced activity. Here we measured the effect of an infusion of L-arginine on renal hemodynamic function in subjects segregated by the presence or absence of the T allele. If this polymorphism represented a functional variant, subjects with the GT/TT form should exhibit a blunted renal hemodynamic response to L-arginine compared to those with a GG allele. All subjects were given a diet controlled for sodium and protein intake. GG subjects had lower mean arterial pressure and an augmented glomerular filtration rate at baseline. In response to a graded L-arginine infusion, this group had significant changes in effective renal plasma flow, glomerular filtration rate, filtration fraction, renal vascular resistance, and renal blood flow. The renal response to L-arginine in GT/TT subjects was blunted. Circulating cGMP levels and endothelial NOS mRNA expression, measured in skin biopsies by real-time PCR, did not differ between the groups. Our study shows that the G894T allele of endothelial NOS is associated with a blunted response to L-arginine, suggesting this polymorphism may be a functional variant in humans. Nitric oxide is generated from L-arginine by nitric oxide synthase (NOS), an enzyme that exists in several isoforms. Some studies found that a polymorphism (G894T) in the endothelial NOS gene was associated with decreased nitric oxide bioactivity and vascular complications. However, it is not known whether the enzyme had a reduced activity. Here we measured the effect of an infusion of L-arginine on renal hemodynamic function in subjects segregated by the presence or absence of the T allele. If this polymorphism represented a functional variant, subjects with the GT/TT form should exhibit a blunted renal hemodynamic response to L-arginine compared to those with a GG allele. All subjects were given a diet controlled for sodium and protein intake. GG subjects had lower mean arterial pressure and an augmented glomerular filtration rate at baseline. In response to a graded L-arginine infusion, this group had significant changes in effective renal plasma flow, glomerular filtration rate, filtration fraction, renal vascular resistance, and renal blood flow. The renal response to L-arginine in GT/TT subjects was blunted. Circulating cGMP levels and endothelial NOS mRNA expression, measured in skin biopsies by real-time PCR, did not differ between the groups. Our study shows that the G894T allele of endothelial NOS is associated with a blunted response to L-arginine, suggesting this polymorphism may be a functional variant in humans. Several polymorphisms of the endothelial nitric oxide synthase (eNOS) gene have been identified, including the G894T polymorphism.1.Colombo M.G. Paradossi U. Andreassi M.G. et al.Endothelial nitric oxide synthase gene polymorphisms and risk of coronary artery disease.Clin Chem. 2003; 49: 389-395Crossref PubMed Scopus (148) Google Scholar, 2.Erbs S. Mobius-Winkler S. Linke A. et al.Both T-786C and G894T polymorphism of endothelial nitric oxide synthase affect in-vitro endothelium-dependent relaxation of internal mammary artery rings from patients with coronary artery disease.Eur J Cardiovasc Prev Rehabil. 2006; 13: 826-831Crossref PubMed Scopus (25) Google Scholar, 3.Kim I.J. Bae J. Lim S.W. et al.Influence of endothelial nitric oxide synthase gene polymorphisms (-786T>C, 4a4b, 894G>T) in Korean patients with coronary artery disease.Thromb Res. 2007; 119: 579-585Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Previous studies have suggested that this missense mutation, which leads to a substitution of aspartate to glutamate in the eNOS protein at position 894, renders this molecular variant more susceptible to proteolytic cleavage, reduced enzymatic activity, and lower basal endothelial nitric oxide (NO) production.2.Erbs S. Mobius-Winkler S. Linke A. et al.Both T-786C and G894T polymorphism of endothelial nitric oxide synthase affect in-vitro endothelium-dependent relaxation of internal mammary artery rings from patients with coronary artery disease.Eur J Cardiovasc Prev Rehabil. 2006; 13: 826-831Crossref PubMed Scopus (25) Google Scholar Impaired eNOS activity may diminish arteriolar vasodilatation, thereby blunting protective vascular effects that have been attributed to NO.4.Murohara T. Asahara T. Silver M. et al.Nitric oxide synthase modulates angiogenesis in response to tissue ischemia.J Clin Invest. 1998; 101: 2567-2578Crossref PubMed Scopus (1083) Google Scholar, 5.Fairchild T.A. Fulton D. Fontana J.T. et al.Acidic hydrolysis as a mechanism for the cleavage of the Glu(298)-->Asp variant of human endothelial nitric-oxide synthase.J Biol Chem. 2001; 276: 26674-26679Crossref PubMed Scopus (146) Google Scholar, 6.Rudic R.D. Shesely E.G. Maeda N. et al.Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling.J Clin Invest. 1998; 101: 731-736Crossref PubMed Scopus (702) Google Scholar From a clinical perspective, decreased NO bioactivity may predispose patients to the development of hypertension, cardiovascular end-organ damage and nephropathy related to diabetes mellitus.1.Colombo M.G. Paradossi U. Andreassi M.G. et al.Endothelial nitric oxide synthase gene polymorphisms and risk of coronary artery disease.Clin Chem. 2003; 49: 389-395Crossref PubMed Scopus (148) Google Scholar, 2.Erbs S. Mobius-Winkler S. Linke A. et al.Both T-786C and G894T polymorphism of endothelial nitric oxide synthase affect in-vitro endothelium-dependent relaxation of internal mammary artery rings from patients with coronary artery disease.Eur J Cardiovasc Prev Rehabil. 2006; 13: 826-831Crossref PubMed Scopus (25) Google Scholar, 7.Shin Shin Y. Baek S.H. Chang K.Y. et al.Relations between eNOS Glu298Asp polymorphism and progression of diabetic nephropathy.Diabetes Res Clin Pract. 2004; 65: 257-265Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 8.Colombo M.G. Andreassi M.G. Paradossi U. et al.Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298-->Asp polymorphism) to the presence, extent, and severity of coronary artery disease.Heart. 2002; 87: 525-528Crossref PubMed Scopus (106) Google Scholar, 9.Lapu-Bula R. Quarshie A. Lyn D. et al.The 894T allele of endothelial nitric oxide synthase gene is related to left ventricular mass in African Americans with high-normal blood pressure.J Natl Med Assoc. 2005; 97: 197-205PubMed Google Scholar, 10.Miyamoto Y. Saito Y. Kajiyama N. et al.Endothelial nitric oxide synthase gene is positively associated with essential hypertension.Hypertension. 1998; 32: 3-8Crossref PubMed Scopus (485) Google Scholar The G894T eNOS gene polymorphism has been associated with impaired endothelial dependent vasodilatation, which may either be on the basis of augmented vasoconstrictor activity or a reduction in the generation of vasodilators, such as NO.4.Murohara T. Asahara T. Silver M. et al.Nitric oxide synthase modulates angiogenesis in response to tissue ischemia.J Clin Invest. 1998; 101: 2567-2578Crossref PubMed Scopus (1083) Google Scholar, 5.Fairchild T.A. Fulton D. Fontana J.T. et al.Acidic hydrolysis as a mechanism for the cleavage of the Glu(298)-->Asp variant of human endothelial nitric-oxide synthase.J Biol Chem. 2001; 276: 26674-26679Crossref PubMed Scopus (146) Google Scholar, 6.Rudic R.D. Shesely E.G. Maeda N. et al.Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling.J Clin Invest. 1998; 101: 731-736Crossref PubMed Scopus (702) Google Scholar For example, we have shown in a previous study that the presence of the T allele is associated with an exaggerated renal vasoconstrictive response to a graded infusion of angiotensin II (Ang II).11.Page A. Reich H. Zhou J. et al.Endothelial nitric oxide synthase gene/gender interactions and the renal hemodynamic response to angiotensin II.J Am Soc Nephrol. 2005; 16: 3053-3060Crossref PubMed Scopus (17) Google Scholar In spite of these studies, the functional status of this polymorphism remains controversial, because other studies have failed to detect functional differences between those with and without the T allele.5.Fairchild T.A. Fulton D. Fontana J.T. et al.Acidic hydrolysis as a mechanism for the cleavage of the Glu(298)-->Asp variant of human endothelial nitric-oxide synthase.J Biol Chem. 2001; 276: 26674-26679Crossref PubMed Scopus (146) Google Scholar Whether the G894T polymorphism influences renal hemodynamic functional responses to eNOS enzymatic activation in normal humans is not known. Accordingly, we examined the effect of a graded L-arginine infusion on renal hemodynamic function in two groups: the first group included subjects who were either homozygous or heterozygous for the T allele (GT/TT subjects), and the second group consisted of those without the T allele (GG subjects). Our rationale reflected the possibility that the pattern of renal hemodynamic responsiveness to L-arginine, the substrate for eNOS, might clarify whether the polymorphism is functional. We also measured baseline eNOS mRNA expression in skin biopsy specimens, hypothesizing that the presence of the T allele would predict a blunted renal hemodynamic response to L-arginine, in spite of similar eNOS expression. Baseline characteristics were similar in the GG (n=16) and GT/TT (n=14) groups (Table 1), except that the GT/TT group was older than the GG group. At baseline, the SBP was lower and the glomerular filtration rate (GFR) was higher in GG vs GT/TT subjects (P<0.05; Table 2). The GG group contained 6 men and 10 women and the GT/TT group 10 men and 5 women. These differences were not statistically significant.Table 1Baseline characteristics (mean±s.e.m.)ParameterGG groupGG/TT groupn=16n=14Age (years)24±128±1*P<0.05 vs GG subjects.Body mass index (kg/m2)23±124±1Estrogen (pmol/l in women)60±1680±14Sodium excretion (mmol/24 h)230±31270±31Protein intake (gram/kg/day)1.2±0.31.1±0.3* P<0.05 vs GG subjects. Open table in a new tab Table 2The hemodynamic response to L-arginine in men and women by eNOS genotype (mean±s.e.m.)Baseline100 mg/kg250 mg/kg500 mg/kgGG subjects SBP108±2110±3105±3109±3 DBP62±263±261±260±2 MAP78±279±276±375±3 GFR137±8143±4147±7149±6*P<0.05 vs within-group baseline value. ERPF693±26723±35*P<0.05 vs within-group baseline value.787±40*P<0.05 vs within-group baseline value.847±48*P<0.05 vs within-group baseline value. FF0.20±0.010.20±0.010.19±0.010.18±0.01*P<0.05 vs within-group baseline value. RBF1103±451151±59*P<0.05 vs within-group baseline value.1234±65*P<0.05 vs within-group baseline value.1300±73*P<0.05 vs within-group baseline value. RVR73±471±464±5*P<0.05 vs within-group baseline value.60±4*P<0.05 vs within-group baseline value.GT/TT subjects SBP116±3†P<0.05 for between-group differences.117±3†P<0.05 for between-group differences.114±4†P<0.05 for between-group differences.114±3 DBP64±264±263±262±2 MAP80±380±277±379±3 GFR126±6†P<0.05 for between-group differences.120±5†P<0.05 for between-group differences.125±6†P<0.05 for between-group differences.131±7†P<0.05 for between-group differences. ERPF686±49668±43§P<0.05 for the response vs GG subjects.721±49§P<0.05 for the response vs GG subjects.754±48*P<0.05 vs within-group baseline value.,§P<0.05 for the response vs GG subjects. FF0.18±0.010.19±0.010.18±0.010.18±0.01 RBF1164±1041109±801181±891220±87 RVR75±878±664±7*P<0.05 vs within-group baseline value.67±7*P<0.05 vs within-group baseline value.ERPF, effective renal plasma flow in ml/min per 1.73 m2; FF, filtration fraction; GFR, glomerular filtration rate in ml/min per 1.73 m2; MAP, mean arterial pressure (mm Hg); RBF, renal blood flow in ml/min per 1.73 m2; RVR, renal vascular resistance in mm Hg/l/min.* P<0.05 vs within-group baseline value.† P<0.05 for between-group differences.§ P<0.05 for the response vs GG subjects. Open table in a new tab ERPF, effective renal plasma flow in ml/min per 1.73 m2; FF, filtration fraction; GFR, glomerular filtration rate in ml/min per 1.73 m2; MAP, mean arterial pressure (mm Hg); RBF, renal blood flow in ml/min per 1.73 m2; RVR, renal vascular resistance in mm Hg/l/min. Although the systemic impact of L-arginine was similar in the two groups (Table 2), the increased SBP in GT/TT subjects was sustained at the 100 and 250 mg/kg doses of L-arginine. In GG genotype subjects, the L-arginine infusion was associated with increases in GFR, estimated renal plasma flow (ERPF), and renal blood flow (RBF), and a decline in renal vascular resistance (RVR; Table 2; Figures 1 and 2). GFR values were also significantly higher in GG subjects at the 100, 250, and 500 mg/kg doses of L-arginine (Table 2). In contrast, in the GT/TT group, the renal hemodynamic changes were limited to a rise in ERPF at the highest infusion rate, and a decline in RVR. The between-group rise in ERPF in response to L-arginine was augmented in GG subjects at the 100, 250, and 500 mg/kg doses (P 0.05 for gender).Figure 2The effect of L-arginine on ERPF in GG vs GT/TT subjects (mean±s.e.m.). ERPF=effective renal plasma flow in ml/min per 1.73 m2, *P<0.05 vs baseline value, §P 0.05).Table 3Circulating RAS mediators and cGMP in response to L-arginine in men and women analyzed by eNOS genotype (mean±s.e.m.)Baseline100 mg/kg250 mg/kg500 mg/kgGG Aldosterone289±6279±12*P<0.05 vs within-group baseline.70±12*P<0.05 vs within-group baseline.82±16*P<0.05 vs within-group baseline. Angiotensin II8.9±1.66.5±1.4*P<0.05 vs within-group baseline.4.8±0.9*P<0.05 vs within-group baseline.3.3±0.7*P<0.05 vs within-group baseline. cGMP4.4±0.44.6±0.44.7±0.56.1±0.5*P<0.05 vs within-group baseline. PRA1.2±0.30.7±0.2*P<0.05 vs within-group baseline.0.5±0.1*P<0.05 vs within-group baseline.0.6±0.2*P<0.05 vs within-group baseline. Renin21±412±2*P<0.05 vs within-group baseline.12±3*P<0.05 vs within-group baseline.12±4*P<0.05 vs within-group baseline.GT/TT Aldosterone346±6588±13*P<0.05 vs within-group baseline.86±17*P<0.05 vs within-group baseline.88±14*P<0.05 vs within-group baseline. Angiotensin II12.1±2.27.3±1.0*P<0.05 vs within-group baseline.5.4±0.7*P<0.05 vs within-group baseline.4.9±1.2*P<0.05 vs within-group baseline. cGMP4.2±0.34.9±0.55.1±0.66.3±0.7*P<0.05 vs within-group baseline. PRA1.3±0.30.5±0.1*P<0.05 vs within-group baseline.0.9±0.40.7±0.2 Renin20±412±213±2*P<0.05 vs within-group baseline.16±5*P<0.05 vs within-group baseline.cGMP, cyclic 3′,5′-guanosine monophosphate; PRA, plasma renin activity.* P Asp polymorphism) to the presence, extent, and severity of coronary artery disease.Heart. 2002; 87: 525-528Crossref PubMed Scopus (106) Google Scholar, 9.Lapu-Bula R. Quarshie A. Lyn D. et al.The 894T allele of endothelial nitric oxide synthase gene is related to left ventricular mass in African Americans with high-normal blood pressure.J Natl Med Assoc. 2005; 97: 197-205PubMed Google Scholar however this association remains controversial.5.Fairchild T.A. Fulton D. Fontana J.T. et al.Acidic hydrolysis as a mechanism for the cleavage of the Glu(298)-->Asp variant of human endothelial nitric-oxide synthase.J Biol Chem. 2001; 276: 26674-26679Crossref PubMed Scopus (146) Google Scholar The aim of this study was to determine if the G894T polymorphism influences the renal hemodynamic response to eNOS enzymatic activation with L-arginine in healthy men and women, thereby suggesting that it is a functional polymorphism. Our major findings were that in healthy subjects segregated into two groups on the basis of the presence or absence of the T allele: (1) SBP was significantly lower, and GFR significantly higher, in the GG group compared to the GT/TT group at baseline; (2) The renal hemodynamic response to the eNOS substrate, L-arginine, was blunted in the GT/TT group compared to those with the GG genotype; (3) The different hemodynamic responses were not a function of eNOS expression levels or circulating cGMP or RAS mediators, as these were similar between the two groups. NO is synthesized from the amino acid L-arginine by the enzyme NOS.12.Palmer R.M. Ashton D.S. Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine.Nature. 1988; 333: 664-666Crossref PubMed Scopus (4118) Google Scholar In the vascular endothelium, NO regulates vasodilator tone13.Haynes W.G. Noon J.P. Walker B.R. et al.L-NMMA increases blood pressure in man.Lancet. 1993; 342: 931-932Abstract PubMed Scopus (60) Google Scholar by activating soluble guanylate cyclase and increasing the production of cGMP.14.Ignarro L.J. Biosynthesis and metabolism of endothelium-derived nitric oxide.Annu Rev Pharmacol Toxicol. 1990; 30: 535-560Crossref PubMed Scopus (1223) Google Scholar Under normal physiologic conditions, eNOS, neuronal NOS and inducible NOS are expressed in renal tissue and are directly involved in the regulation of ERPF, GFR, and tubuloglomerular feedback.15.Bachmann S. Bosse H.M. Mundel P. Topography of nitric oxide synthesis by localizing constitutive NO synthases in mammalian kidney.Am J Physiol. 1995; 268: F885-F898PubMed Google Scholar, 16.Patzak A. Persson A.E. Angiotensin II-nitric oxide interaction in the kidney.Curr Opin Nephrol Hypertens. 2007; 16: 46-51Crossref PubMed Scopus (47) Google Scholar Intravenous administration of the substrate for eNOS, L-arginine, results in a rise in ERPF and GFR in animals17.Klahr S. Morrissey J. L-arginine as a therapeutic tool in kidney disease.Semin Nephrol. 2004; 24: 389-394Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar and in normal humans.18.Biggi A. Carra N. Cabassi A. et al.Impaired renal haemodynamic response to L-arginine in essential hypertension: role of buffering anion and tubuloglomerular feedback.J Hypertens. 2007; 25: 679-688Crossref PubMed Scopus (7) Google Scholar, 19.Schlaich M.P. Jacobi J. John S. et al.Is l-arginine infusion an adequate tool to assess endothelium-dependent vasodilation of the human renal vasculature?.Clin Sci (Lond). 2000; 99: 293-302Crossref PubMed Google Scholar, 20.Koller-Strametz J. Wolzt M. Fuchs C. et al.Renal hemodynamic effects of L-arginine and sodium nitroprusside in heart transplant recipients.Kidney Int. 1999; 55: 1871-1877Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar In addition to these renal hemodynamic effects, previous work has suggested that NO acts as a tonic vasodilator in the systemic circulation thereby influencing arterial blood pressure regulation.13.Haynes W.G. Noon J.P. Walker B.R. et al.L-NMMA increases blood pressure in man.Lancet. 1993; 342: 931-932Abstract PubMed Scopus (60) Google Scholar Clinical studies have demonstrated that the G894T eNOS gene polymorphism is associated with the development of atherosclerosis and cardiovascular events, such as ischemic heart disease, hypertension, carotid atherosclerosis, and diabetic nephropathy.1.Colombo M.G. Paradossi U. Andreassi M.G. et al.Endothelial nitric oxide synthase gene polymorphisms and risk of coronary artery disease.Clin Chem. 2003; 49: 389-395Crossref PubMed Scopus (148) Google Scholar, 2.Erbs S. Mobius-Winkler S. Linke A. et al.Both T-786C and G894T polymorphism of endothelial nitric oxide synthase affect in-vitro endothelium-dependent relaxation of internal mammary artery rings from patients with coronary artery disease.Eur J Cardiovasc Prev Rehabil. 2006; 13: 826-831Crossref PubMed Scopus (25) Google Scholar, 7.Shin Shin Y. Baek S.H. Chang K.Y. et al.Relations between eNOS Glu298Asp polymorphism and progression of diabetic nephropathy.Diabetes Res Clin Pract. 2004; 65: 257-265Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 8.Colombo M.G. Andreassi M.G. Paradossi U. et al.Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298-->Asp polymorphism) to the presence, extent, and severity of coronary artery disease.Heart. 2002; 87: 525-528Crossref PubMed Scopus (106) Google Scholar, 9.Lapu-Bula R. Quarshie A. Lyn D. et al.The 894T allele of endothelial nitric oxide synthase gene is related to left ventricular mass in African Americans with high-normal blood pressure.J Natl Med Assoc. 2005; 97: 197-205PubMed Google Scholar, 10.Miyamoto Y. Saito Y. Kajiyama N. et al.Endothelial nitric oxide synthase gene is positively associated with essential hypertension.Hypertension. 1998; 32: 3-8Crossref PubMed Scopus (485) Google Scholar For example, Miyamoto et al. demonstrated that the G894T eNOS polymorphism is strongly linked with essential hypertension,10.Miyamoto Y. Saito Y. Kajiyama N. et al.Endothelial nitric oxide synthase gene is positively associated with essential hypertension.Hypertension. 1998; 32: 3-8Crossref PubMed Scopus (485) Google Scholar and others have demonstrated associations with endothelial dysfunction, inflammation, and vasoconstriction.2.Erbs S. Mobius-Winkler S. Linke A. et al.Both T-786C and G894T polymorphism of endothelial nitric oxide synthase affect in-vitro endothelium-dependent relaxation of internal mammary artery rings from patients with coronary artery disease.Eur J Cardiovasc Prev Rehabil. 2006; 13: 826-831Crossref PubMed Scopus (25) Google Scholar, 21.Antoniades C. Tousoulis D. Vasiliadou C. et al.Genetic polymorphism on endothelial nitric oxide synthase affects endothelial activation and inflammatory response during the acute phase of myocardial infarction.J Am Coll Cardiol. 2005; 46: 1101-1109Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar This may be due to a variety of factors, including lower eNOS mRNA expression,22.Dosenko V.E. Zagoriy V.Y. Haytovich N.V. et al.Allelic polymorphism of endothelial NO-synthase gene and its functional manifestations.Acta Biochim Pol. 2006; 53: 299-302PubMed Google Scholar diminished enzymatic activity,23.Tesauro M. Thompson W.C. Rogliani P. et al.Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs glutamate at position 298.Proc Natl Acad Sci USA. 2000; 97: 2832-2835Crossref PubMed Scopus (470) Google Scholar augmented vasoconstrictive responses to Ang II and phenylephrine, and increased generation of reactive oxygen species.11.Page A. Reich H. Zhou J. et al.Endothelial nitric oxide synthase gene/gender interactions and the renal hemodynamic response to angiotensin II.J Am Soc Nephrol. 2005; 16: 3053-3060Crossref PubMed Scopus (17) Google Scholar, 24.Philip I. Plantefeve G. Vuillaumier-Barrot S. et al.G894T polymorphism in the endothelial nitric oxide synthase gene is associated with an enhanced vascular responsiveness to phenylephrine.Circulation. 1999; 99: 3096-3098Crossref PubMed Scopus (171) Google Scholar Previous data have not, however, been unanimous regarding the functional nature of the G894T eNOS polymorphism.25.Wattanapitayakul S.K. Mihm M.J. Young A.P. et al.Therapeutic implications of human endothelial nitric oxide synthase gene polymorphism.Trends Pharmacol Sci. 2001; 22: 361-368Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Whether this polymorphism exerts an effect on cardiovascular or renal hemodynamic physiology therefore remains unclear. Accordingly, we assessed the impact of L-arginine, which is the substrate for eNOS, on systemic and renal hemodynamic function. Our first major finding was that the SBP was lower in the GG group compared to the GT/TT group at baseline and during the 100 and 250 mg/kg doses of L-arginine. These differences were no longer significantly different at the highest dose of L-arginine. Our findings of a higher baseline SBP and a lower GFR in a small sample of normal, young adults may suggest a state of relative vasoconstriction, as suggested in previous experimental and human studies.2.Erbs S. Mobius-Winkler S. Linke A. et al.Both T-786C and G894T polymorphism of endothelial nitric oxide synthase affect in-vitro endothelium-dependent relaxation of internal mammary artery rings from patients with coronary artery disease.Eur J Cardiovasc Prev Rehabil. 2006; 13: 826-831Crossref PubMed Scopus (25) Google Scholar, 10.Miyamoto Y. Saito Y. Kajiyama N. et al.Endothelial nitric oxide synthase gene is positively associated with essential hypertension.Hypertension. 1998; 32: 3-8Crossref PubMed Scopus (485) Google Scholar, 24.Philip I. Plantefeve G. Vuillaumier-Barrot S. et al.G894T polymorphism in the endothelial nitric oxide synthase gene is associated with an enhanced vascular responsiveness to phenylephrine.Circulation. 1999; 99: 3096-3098Crossref PubMed Scopus (171) Google Scholar, 26.Antoniades C. Tousoulis D. Vasiliadou C. et al.Genetic polymorphisms G894T on the eNOS gene is associated with endothelial function and vWF levels in premature myocardial infarction survivors.Int J Cardiol. 2006; 107: 95-100Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar This vasoconstrictive phenotype may be due to several factors. First, it may have been on the basis of diminished baseline eNOS enzymatic activity, as suggested by others.23.Tesauro M. Thompson W.C. Rogliani P. et al.Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs glutamate at position 298.Proc Natl Acad Sci USA. 2000; 97: 2832-2835Crossref PubMed Scopus (470) Google Scholar Second, the G894T eNOS polymorphism has been associated with a lack of NO tissue bioavailability and an increase in counterregulatory vasoconstrictive mechanisms, such as the generation of reactive oxygen species through interactions with asymmetric dimethyl arginine or inflammatory cytokines.26.Antoniades C. Tousoulis D. Vasiliadou C. et al.Genetic polymorphisms G894T on the eNOS gene is associated with endothelial function and vWF levels in premature myocardial infarction survivors.Int J Cardiol. 2006; 107: 95-100Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 27.Testa A. Spoto B. Tripepi G. et al.The GLU298ASP variant of nitric oxide synthase interacts with asymmetric dimethyl arginine in determining cardiovascular mortality in patients with end-stage renal disease.J Hypertens. 2005; 23: 1825-1830Crossref PubMed Scopus (25) Google Scholar This increase in the ratio of vasoconstrictors to vasodilators may contribute to the increased risk of hypertension10.Miyamoto Y. Saito Y. Kajiyama N. et al.Endothelial nitric oxide synthase gene is positively associated with essential hypertension.Hypertension. 1998; 32: 3-8Crossref PubMed Scopus (485) Google Scholar and impaired endothelial function26.Antoniades C. Tousoulis D. Vasiliadou C. et al.Genetic polymorphisms G894T on the eNOS gene is associated with endothelial function and vWF levels in premature myocardial infarction survivors.Int J Cardiol. 2006; 107: 95-100Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar that has been associated with the G894T eNOS polymorphism. In the kidney, low NO bioactivity may have been associated with a decline in GFR through a rise in preglomerular resistance,16.Patzak A. Persson A.E. Angiotensin II-nitric oxide interaction in the kidney.Curr Opin Nephrol Hypertens. 2007; 16: 46-51Crossref PubMed Scopus (47) Google Scholar or suppression of the ultrafiltration coefficient28.Gabbai F.B. Effects of nitric oxide synthase blockers on renal function.Nephrol Dial Transplant. 2001; 16: 10-13Crossref PubMed Scopus (32) Google Scholar Regardless of the underlying physiologic explanation, our study supports previous experimental and human findings, which emphasize the concept that the T allele favors a state of relative hypertension and vasoconstriction. Our second major finding was that subjects with the T allele exhibited a blunted renal vasodilatory response to the L-arginine infusion compared to GG subjects. Previous clinical studies have suggested that the G894T eNOS polymorphism is associated with diminished activity of the enzyme,22.Dosenko V.E. Zagoriy V.Y. Haytovich N.V. et al.Allelic polymorphism of endothelial NO-synthase gene and its functional manifestations.Acta Biochim Pol. 2006; 53: 299-
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