This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Raij, L. Search for Related Content PubMed PubMed Citation Articles by Raij, L.

(Hypertension. 1998;31:189.)
© 1998 American Heart Association, Inc.

Workshop on Vascular Biology & Hypertension: From Molecules to Humans

Nitric Oxide in Hypertension: Relationship With Renal Injury and Left Ventricular Hypertrophy

Leopoldo Raij

From the Department of Medicine, Veterans Affairs Medical Center and University of Minnesota Medical School, Minnesota, Minn.

Correspondence to Leopoldo Raij, MD, Nephrology/Hypertension (111J), VA Medical Center, One Veterans Drive, Minneapolis, MN 55417. E-mail raijx001{at}maroon.tc.umn.edu

	Abstract

Top Abstract Introduction The Kidney and NO:... Interaction Between AII and... Hypertensive Renal Injury NOS and Hypertensive Injury Link Between NOS Activity... References

 
Hypertension is accompanied by architectural changes in the kidney, heart, and vessels that are often maladaptive and can eventually contribute to end-organ disease such as renal failure, heart failure, and coronary disease. Nitric oxide, an endogenous vasodilator and antithrombotic agent synthesized in the endothelium by a constitutive nitric oxide synthase, inhibits growth-related responses to injury in vascular cells. Specifically, in the presence of hypertension, nitric oxide may work in the kidney by inhibiting both mesangial cell hypertrophy and hyperplasia as well as synthesis of extracellular matrix and in the heart and systemic vessels by modulating smooth muscle cell hypertrophy and hyperplasia. The effects of nitric oxide are antagonistic of the effects of angiotensin II. Shear stress and cyclic strain, physical forces known to operate in hypertension, are accompanied by increases in endothelial nitric oxide synthase expression, nitric oxide synthase protein, and nitric oxide synthase activity in endothelial cells. Experimental studies using genetic models of hypertension show a variation in hypertension-modulated vascular nitric oxide synthase activity in different strains of rats. These studies suggest that upregulation of vascular nitric oxide synthase activity is a homeostatic adaptation to increased hemodynamic workload in hypertension and that this may help prevent end-organ damage. If these findings apply to humans, differences in end-organ disease seen in patients with similar degrees of hypertension may be due in part to genetic differences in vascular nitric oxide synthase activity in response to hypertension.

Key Words: nitric oxide • hypertension • angiotensin II • renal injury • left ventricular hypertrophy

Abbreviations: ACE = angiotensin-converting enzyme • Ang II = angiotensin II • DS = Dahl salt-sensitive • ET-1 = endothelin-1 • LVH = left ventricular hypertrophy • NO = nitric oxide • NOS = nitric oxide synthase • SHR = spontaneously hypertensive rats

	Introduction

Top Abstract Introduction The Kidney and NO:... Interaction Between AII and... Hypertensive Renal Injury NOS and Hypertensive Injury Link Between NOS Activity... References

 
Epidemiological studies have demonstrated that in hypertensive patients, increased serum creatinine,¹ proteinuria,² and microalbuminuria³ are independent predictors of an increased cardiovascular morbidity/mortality due to LVH/heart failure and coronary artery disease.¹ Furthermore, in patients with end-stage renal failure who are receiving hemodialysis, the incidence of myocardial ischemia/infarction approaches 20 times that in the general population.⁴ In these patients the prevalence of cardiac death is higher during the first few years of dialysis, suggesting that cardiac disease is preexistent and not acquired during chronic hemodialysis. In the aggregate these studies clearly suggest that in hypertension end-organ injury is diffuse, affecting all organs (albeit the severity of the individual end-organ injury varies in different patients). On the other hand, it is also clear that in hypertensive patients the prevalence of LVH, renal failure, and coronary artery disease, which are the major causes of morbidity and mortality, varies in different populations of hypertensive patients, suggesting that susceptibility to cardiovascular and renal disease is not uniform.^2,5,6

In hypertension, an increase in pressure-workload fosters adaptive changes in the endothelium, the vascular smooth muscle, and the extracellular matrix of vessels and the heart. However, in many patients, the adaptive changes to hypertension, which occur in the kidney, heart, and vessels, are in fact maladaptive because they are harbingers of renal failure, cardiac failure, and coronary artery disease.⁵ Obviously, there is a need for ways to identify those patients who are at higher risk for development of end-organ disease. In this context, recent studies have shown that a deletion polymorphism of the ACE gene is associated with target-organ damage in hypertension. Specifically, the D allele of the ACE gene is associated with microalbuminuria, LVH, and coronary artery disease as well as the renal complications of insulin-dependent diabetes.^7,8

The endothelium plays a crucial role in the regulation of vascular tone and vascular remodeling.^9,10 No synthesized by a constitutive endothelial NOS is an endogenous vasodilator and antithrombogenic agent, which inhibits vascular smooth muscle and mesangial cell growth and therefore may participate in vascular as well as glomerular remodeling in response to hypertensive injury.^10,11

The association between increased activity of the local tissue renin-angiotensin system and vascular pathophysiology has been well demonstrated.¹⁰ No appears to be the major endogenous antagonist of the vascular actions of Ang II and, therefore, a balance between Ang II and No appears pivotal for the maintenance of vascular homeostasis¹⁰

Given the close association between abnormal renal parameters and cardiovascular morbidity/mortality and the growing evidence for NO in vascular physiology and pathology, recent studies have focused on the role of NO in hypertensive renal disease as well as its relationship with concomitant injury affecting the left ventricle and large vessels such as the aorta.^12–14

	The Kidney and NO: Relationship Between Structure and Function

Top Abstract Introduction The Kidney and NO:... Interaction Between AII and... Hypertensive Renal Injury NOS and Hypertensive Injury Link Between NOS Activity... References

 
The glomerulus is made up of the glomerular basement membrane, the epithelial cells outlining the glomerular basement membrane in the urinary space, and the mesangium forming the glomerular centrolobular area.^15,16 The glomerular basement membrane reflects over the mesangium between the capillary loops but is absent at the point of contact between the glomerular endothelial cells and the mesangial cells. A barrier between circulating glomerular blood and the mesangium is thus formed by the single layer of fenestrated endothelium. Passage of plasma carrying large as well as small molecules is possible through the mesangial area because of the large size of the glomerular endothelial fenestrae. The products synthesized by the endothelial and mesangial cells are able to reach each other in high concentrations because of their close proximity.^15,16

Mesangial cells contain actin-myosin filaments and change their contractile state in response to vasoactive substances, much as vascular smooth muscle cells do.^15,16 Agents such as Ang II, eicosanoids, ET-1, and NO synthesized and released locally can act on these cells in autocrine and/or paracrine fashion. The antagonistic interaction of locally synthesized Ang II and NO is important in the regulation of renal physiology and renal pathology. In the glomerulus, modulation of the glomerular microcirculation is possible under physiological and pathological conditions when these vasoactive agents act on the mesangium or the afferent and efferent arteriole, or both.^17–19 The responses of glomerular cells to injury and resulting architectural changes of the glomerulus such as mesangial hypertrophy, mesangial hyperplasia, and increased mesangial cell matrix production are often due to the added effects of hemodynamic (glomerular hypertension) and nonhemodynamic actions of these vasoactive agents, much as occurs in systemic vascular beds.¹⁰

Ang II has been found to control growth factors such as platelet-derived growth factor and transforming growth factor ß, which have been implicated in the pathological remodeling of the glomerulus in response to injury.^20,21 However, NO not only antagonizes the effects of Ang II on arteriolar tone and mesangial contraction but inhibits the response of mesangial cells to growth-stimulating signals driven by Ang II that lead to mesangial cell hypertrophy and/or hyperplasia as well as to increased matrix production.^20–22

A dose-dependent increase in blood pressure and renovascular resistance occurs in response to systemic administration of NO synthesis inhibitors. These changes are accompanied by a significant reduction in renal plasma flow and a moderate decrease in glomerular filtration rate.^18,23 NO inhibition also leads to an increase in afferent arteriolar resistance¹⁹ and to a decrease in the ultrafiltration coefficient, the latter probably being mediated by mesangial cell contraction.¹⁷ In addition, macula densa NO appears to control glomerular hemodynamics by way of tubuloglomerular feedback mechanisms.²⁴

Renal sodium excretion may also be affected by the direct action of NO on the tubules and its ability to modify medullary blood flow and interstitial pressure.²⁵ Selective inhibition of NO synthesis in the renal medullary interstitium decreases papillary blood flow and diminishes urinary sodium excretion but does not alter glomerular filtration rate or systemic blood pressure.²⁵

	Interaction Between AII and NO

Top Abstract Introduction The Kidney and NO:... Interaction Between AII and... Hypertensive Renal Injury NOS and Hypertensive Injury Link Between NOS Activity... References

 
Increased actions of Ang II or NO may be due to an actual increase in the local concentration of the individual agent and/or to a concomitant decrease in the concentration of the other.²⁶ Moreover, chronic NO synthesis inhibition induces glomerular and tubulointerstitial injury¹⁴ as well as coronary vascular remodeling and LVH that is accompanied by increased ACE expression and activity.²⁷ This would suggest that decreased vascular NO bioactivity due to endothelial dysfunction as seen in hypertension may promote vascular hypertrophy due to a combined deficit of NO and local excess of Ang II. Indeed, experimentally, in vivo transfection of excess ACE to arterial segments results in localized vascular hypertrophy mediated by Ang II.²⁸

Ang II has been reported to activate NADH/NADPH oxidase in vascular smooth muscle cells²⁹ and more recently in mesangial cells,³⁰ leading to the cells’ protracted synthesis of O₂^-. O₂^- has great affinity for NO, causing interaction between the two and resulting in either NO inactivation or the production of toxic peroxynitrite.³¹ Furthermore, in the glomerulus as in the vasculature in general, decreased NO bioactivity not only reduces the ability of NO to counteract Ang II actions on vascular tone but also diminishes the homeostatic role of NO in preventing vascular thrombosis, leukocyte adhesion to endothelium, and Ang II-driven mesangial cell hypertrophy/hyperplasia and production of extracellular matrix.¹¹

ET-1, a powerful vasoconstrictor, is capable of reducing renal blood flow and glomerular filtration rate by acting on preglomerular resistances and inducing mesangial cell contraction.³² The interaction between NO and ET-1 appears to be more important under pathological than under physiological conditions. In addition, ET-1 synthesis is upregulated by Ang II³³ and downregulated by NO.³⁴ ET-1 may thus play its role late rather than early in renal pathophysiological processes in that its importance may build as the renal bioactivity of NO decreases.

	Hypertensive Renal Injury

Top Abstract Introduction The Kidney and NO:... Interaction Between AII and... Hypertensive Renal Injury NOS and Hypertensive Injury Link Between NOS Activity... References

 
Capillary pressures and flows in the glomerulus are regulated by independent changes in resistance of the afferent and efferent arterioles and coordinated by the concomitant contraction (or relaxation) of the mesangium.^17–19,35 Under normal physiological conditions, an increase in systemic blood pressure is accompanied by an increase in preglomerular resistances (autoregulation), permitting the coexistence of systemic hypertension and glomerular normotension. Glomerular injury has been shown to occur in experimental models in which a deficient preglomerular resistance results in elevated glomerular intracapillary pressures (glomerular hypertension); this scenario also occurs in the presence of diabetes,³⁶ in surgical ablation of renal mass,³⁶ and in hypertensive DS rats.³⁷

Comparative studies in genetic models of hypertension, such as SHR and DS rats and their normotensive counterparts, have been particularly illuminating in providing insight into the relationship between hypertension, endothelial function, and end-organ injury^{12–14,37–39} (Figs 1 and 2). Similar to the situation in some populations of humans, hypertension develops in DS rats given diets high in salt but not those given low or normal dietary salt.^40,41 SHR, however, develop hypertension without high levels of dietary salt. We have previously shown that glomerular hypertension and glomerular injury develop in DS rats but not SHR at similar levels of systemic hypertension.³⁷ Indeed, preglomerular resistances are regulated poorly in DS rats, while in SHR, appropriate autoregulation and effective increase in preglomerular resistances prevent glomerular hypertension.³⁷

View larger version (24K): [in this window] [in a new window]   Figure 1. NOS in aortas and kidneys from normotensive DS and Wistar-Kyoto (WKY) rats and hypertensive DS and SHR. Systolic blood pressure, mm Hg: DS-0.5% 133±3; DS-4.0% 211±7; WKY 137±3; and SHR 219±12. *P<.5 vs DS-0.5%. **P<.05 vs WKY. Values are mean ± SE.12 Dahl rats were from the Brookhaven strain.

View larger version (20K): [in this window] [in a new window]   Figure 2. Urinary protein excretion (UproV), glomerular injury score (GIS), LVH, and tubular injury score (TIS) in hypertensive DS-4.0% (systolic blood pressure 211±7 mm Hg) and SHR (systolic blood pressure 219±12 mm Hg), matched for systolic blood pressure and duration of hypertension. *P<.05 vs SHR. Values are mean ± SE.12–14 Dahl rats were from the Brookhaven strain.

The endothelium and the mesangium are the most vulnerable glomerular structures in glomerular hypertension. The endothelial dysfunction and pathological remodeling that occur in the kidney as well as in other vascular beds as a consequence of increased blood pressure may not be entirely explained by the increased hemodynamic workload imposed by hypertension, however, except perhaps when it is very severe.^12–14,37

	NOS and Hypertensive Injury

Top Abstract Introduction The Kidney and NO:... Interaction Between AII and... Hypertensive Renal Injury NOS and Hypertensive Injury Link Between NOS Activity... References

 
In vitro studies have demonstrated that hemodynamic forces such as shear stress⁴² and cyclic strain⁴³ increase vascular NO production by increasing endothelial NOS expression, NOS protein, and NOS activity.

Our laboratory has used age-matched SHR and DS rats with hypertension of similar severity and duration to investigate the relationship between hypertension and vascular NOS activity.^12–14 Endothelium-dependent relaxation mediated by NO is normal in hypertensive SHR, whereas it is dramatically impaired in DS rats. Aortic calcium-dependent NOS activity measured by the conversion of L-[14C] arginine to L-[14C]citrulline was increased 106% in SHR but reduced by 73% in DS rats compared with their normotensive counterparts.^12,13 These results explain why endothelium-dependent relaxation mediated by NO is impaired in DS rats but not in SHR. Endothelium-dependent relaxation was also impaired in renal and mesenteric vessels of hypertensive DS rats.^12–13 Increased NOS activity in SHR would thus suggest that these rats are able to upregulate and maintain high levels of vascular NOS in response to hypertension.^12–14 These findings also suggest that, by contrast, the endothelium of DS rats not only fails to increase NOS activity but in fact decreases it in response to hypertension.^12–16 Hence, heightened vascular NOS activity probably represents "normal physiological" adaptation to the increased hemodynamic forces (ie, cyclic strain) in hypertensive states. On a similar note, serum levels of NO₂/NO₃, which are stable metabolites of NO, increase in Sprague-Dawley rats rendered hypertensive by placement of a clip in one of the renal arteries.⁴⁴

High dietary salt did not foster hypertension, cardiac and aortic hypertrophy, or renal injury in Dahl salt-resistant rats.^12–14 Concomitantly, in DS rats, antihypertensive therapy consisting of an ACE inhibitor and a diuretic prevented hypertension, the fall in NOS and abnormal aortic endotheli-um-dependent relaxation, LVH, and renal injury.¹³ This further supports the notion that in DS rats, end-organ injury and the fall in NOS activity are a consequence and not a cause of hypertension. If these observations made in the genetic rat models of hypertension apply to humans, they may provide important insights into the pathogenesis and therapy of cardiovascular disease.

	Link Between NOS Activity and Renal, Vascular, and Cardiac Injury in Experimental Hypertension

Top Abstract Introduction The Kidney and NO:... Interaction Between AII and... Hypertensive Renal Injury NOS and Hypertensive Injury Link Between NOS Activity... References

 
Findings in comparative studies of SHR and hypertensive DS rats suggesting a link between NOS activity, vascular remodeling, and end-organ injury are particularly striking. In SHR, aortic hypertrophy did not occur and LVH increased only 15%.¹² In hypertensive DS rats on the other hand, the aorta and left ventricle hypertrophied 36% and 88%, respectively, and there was in fact a significant negative correlation between NOS activity and aortic and left ventricular hypertrophy.^12–14 In the kidney, increased NOS activity in SHR was accompanied by minimal glomerular and tubulointerstitial disease as well as minimal urinary protein excretion. In hypertensive DS rats, however, renal NOS activity fell, and severe glomerular injury, heavy proteinuria, and marked tubulointerstitial disease occurred¹⁴ (Figs 1 and 2).

In conclusion, our experimental findings and those of others strongly suggest that in hypertension, NOS activity is linked with end-organ disease and that impaired NOS activity may be more commonly seen in salt-sensitive models of hypertension.^12–14 Studies in humans have suggested a similar scenario: that salt-sensitive hypertensive patients are more prone to development of end-organ disease, particularly LVH and renal disease.^40,41 Further, clinical studies in humans have suggested that impaired endothelium-dependent relaxations mediated by NO may not be a universal finding in hypertension.^45,46 The prevalence of LVH, renal failure, and stroke, which are major causes of morbidity and mortality, varies in different populations of hypertensive patients.^2,5,47,48 In recent human studies, genetic polymorphism in the renin-angiotensin system has been associated with cardiovascular and renal disease in hypertension and in diabetes.^7,8 Inspired by these associations and the findings described, it is tempting to speculate that vascular NOS activity in response to hypertension is genetically determined and that the heterogeneity may at least partially explain the different rates of occurrence of end-organ disease in humans with hypertension of similar severity.^2,5,47,48

	Acknowledgments

 
This study was supported with funds from the Department of Veterans Affairs. I express thanks to Edgar Jaimes, MD, and Hiroshi Hayakawa, MD, for their scientific contributions; to Karen Coffee for technical assistance, and to Martha Heiberg, Betty Mart, and Barb Devereaux for secretarial support.

Received September 18, 1997; first decision October 17, 1997; accepted October 31, 2002.

	References

Top Abstract Introduction The Kidney and NO:... Interaction Between AII and... Hypertensive Renal Injury NOS and Hypertensive Injury Link Between NOS Activity... References

 
1. Shulman NB, Ford CE, Hall WD, Blaufox MD, Simon D, Langford HG, Schneider KA. Prognostic value of serum creatinine and effect of treatment of hypertension on renal function: results from the hypertension detection and follow-up program. The Hypertension Detection and Follow-up Program Cooperative Group. Hypertension. 1989; 13 (suppl): 180 –193.

2. Kannel WB, Stampfer MJ, Castelli WP, Verter J. The prognostic significance of proteinuria: the Framingham study. Am Heart J. 1984; 108 : 1347 –1352.[Medline] [Order article via Infotrieve]

3. Parving HH. Microalbuminuria in essential hypertension and diabetes. J Hypertens. 1996; 14 (suppl 2): S89 –S93.

4. Raine AEG, Margreit R, Brunner FG, Ehrich JHH, Geelings W, Landais P, Loirat C, Mallick NP, Selwood NH, Tufveson G, Valderrábano F. Report on management of renal failure in Europe, XXII. Nephrol Dial Transplant. 1992; 7 (suppl. 2): 7 –35.[Medline] [Order article via Infotrieve]

5. Kannel WB. Hypertension and the risk of cardiovascular disease. In: Laragh JH, Brenner BM. Hypertension. Pathophysiology, Diagnosis, and Management. New York, NY: Raven Press; 1990; 2 : 101 .

6. Kaplan NM. Primary hypertension: natural history. In: Kaplan, N. Clinical Hypertension. 4th ed. Baltimore. Md: Williams & Wilkins; 1986: 123 –146.

7. Pontremoli R, Sofia A, Tirotta A, Ravera M, Nicolella C, Viazzi F, Bezante GP, Borgia L, Bobola N, Ravazzolo R, Sacchi G, Deferrari G. The deletion of polymorphism of the angiotensin I-converting enzyme gene is associated with target organ damage in essential hypertension. J Am Soc Nephrol. 1996; 7 : 2250 –2258.

8. Marre M, Jeunemaitre X, Gallois Y, Rodier M, Chatellier G, Sert C, Dusselier L, Kahal Z, Chaillous L, Halimi S, Muller A, Sackmann H, Bauduceau B, Bled F, Passa P, Alhenc-Gelas F. Contribution of genetic polymorphism in the renin-angiotensin system to the development of renal complications in insulin-dependent diabetes: Genetique de la Nephropathie Diabetique (GENEDIAB) Study Group. J Clin Invest. 1997; 99 : 1585 –1595.[Medline] [Order article via Infotrieve]

9. Salter M, Knolls RAG, Moncada S. Widespread tissue distribution, species distribution and changes in activity of Ca²⁺-dependent and Ca²⁺-independent nitric oxide synthases. FEBS Lett. 1991; 291 : 145 –149.[Medline] [Order article via Infotrieve]

10. Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N Engl J Med., 1994; 330 : 1431 –1438. Review.[Free Full Text]

11. Raij L, Baylis C. Glomerular actions of nitric oxide. Kidney Int. 1995; 48 : 20 –32. Editorial Review.[Medline] [Order article via Infotrieve]

12. Hayakawa H, Raij L. The link among nitric oxide synthase activity, endothelial function, and aortic and ventricular hypertrophy in hypertension. Hypertension. 1997; 29 : 235 –241.[Abstract/Free Full Text]

13. Hayakawa H, Coffee K, Raij L. Endothelial dysfunction and cardio-renal injury in experimental salt sensitive hypertension: effects of antihypertensive therapy. Circulation. 1997; 96 : 2407 –2413.[Abstract/Free Full Text]

14. Hayakawa H, Raij L. Nitric oxide synthase activity and renal injury in genetic hypertension. Hypertension. 1998; 31 (part 2): 266 –270.[Abstract/Free Full Text]

15. Raij L, Keane WF. Glomerular mesangium: its function and relationship to angiotensin II. Am J Med. 1985; 79 (suppl 36): 24 –30.

16. Sweeney C, Shultz P, Raij L. Interactions of the endothelium and mesangium in glomerular injury. J Am Soc Nephrol. 1990; 1 : S13 –S20.[Medline] [Order article via Infotrieve]

17. Shultz PJ, Schorer AE, Raij L. Effects of endothelium derived relaxing factor and nitric oxide in rat mesangial cells. Am J Physiol. 1990; 258 : F162 –F167.[Medline] [Order article via Infotrieve]

18. Tolins JP, Palmer RM., Moncada S, Raij L. Role of endothelium-derived relaxing factor in regulation of renal hemodynamic responses. Am J Physiol. 1990; 258 : H655 –H662.[Medline] [Order article via Infotrieve]

19. Ito S, Johnson CS, Carretero OA. Modulation of angiotensin II-induced vasoconstriction by endothelium-derived relaxing factor in the isolated microperfused rabbit afferent arteriole. J Clin Invest. 1991; 87 : 1656 –1663.[Medline] [Order article via Infotrieve]

20. Ketteler M, Noble NA, Border WA. Transforming growth factor-ß and angiotensin II: the missing link from glomerular hyperfiltration to glomerulosclerosis? Annu Rev Physiol. 1995; 57 : 279 –295.[Medline] [Order article via Infotrieve]

21. Craven PA, Studer RK, Felder J, Phillips S, DeRubertis FR. Nitric oxide inhibition of transforming growth factor-ß and collagen synthesis in mesangial cells. Diabetes. 1997; 46 : 671 –681.[Abstract]

22. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromocyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989; 83 : 1774 –1777.[Medline] [Order article via Infotrieve]

23. Baylis C, Mitruka B, Deng A. Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest. 1992; 20 : 278 –281.

24. Wilcox CW, Welch WJ, Murad F, Gross SS, Taylor G, Levi R, Schmidt HHHW. Nitric oxide synthase in macula densa regulates glomerular capillary pressure. Proc Natl Acad Sci U S A. 1992; 89 : 11993 –11997.[Abstract/Free Full Text]

25. Mattson DL, Roman RJ, Cowley AWJ. Role of nitric oxide in renal papillary blood flow and sodium excretion. Hypertension. 1992; 19 : 766 –769.[Abstract/Free Full Text]

26. Tolins JP, Raij L. Effects of amino acid infusion on renal hemodynamics: role of endothelium-derived relaxing factor. Hypertension. 1991; 17 : 1045 –1051.[Abstract/Free Full Text]

27. Takemoto M, Egashira K, Usui M, Numaguchi K, Tomita H, Tsutsui H, Shimokawa H, Sueishi K, Takeshita A. Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats. J Clin Invest. 1997; 99 : 278 –287.[Medline] [Order article via Infotrieve]

28. Morishita R, Gibbons GH, Ellison KE, Lee W, Zhang L, Yu H, Kaneda Y, Ogihara T, Dzau VJ. Evidence for direct local effect of angiotensin in vascular hypertrophy. J Clin Invest. 1994; 94 : 978 –1097.[Medline] [Order article via Infotrieve]

29. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994; 74 : 1141 –1148.[Abstract/Free Full Text]

30. Galceran JM, Jaimes EA, Raij L. Pathogenetic role of angiotensin II (Ang II) in glomerular injury: is superoxide (O₂^-) the missing link? J Am Soc Nephrol. 1996; 7 : 1631 . Abstract.

31. White CR, Brock TA, Chang L-Y, Crapo J, Briscoe P, Ku D, Bradley WA, Gianturco SH, Gore J, Freeman BA, Tarpey MM. Superoxide and peroxynitrite in atherosclerosis. Proc Natl Acad Sci U S A. 1994; 91 : 1044 –1048.[Abstract/Free Full Text]

32. King AJ, Brenner BM, Anderson S. Endothelin: a potent renal and systemic vasoconstrictor peptide. Am J Physiol. 1989; 256 : 1051 –1058.

33. Bakris GL, Re RN. Endothelin modulates angiotensin II-induced mitogenesis of human mesangial cells. Am J Physiol. 1993; 264 : F937 –F942.[Medline] [Order article via Infotrieve]

34. Boulanger C, Luscher TF. Release of endothelin from the porcine aorta: inhibition by endothelium-derived nitric oxide. J Clin Invest. 1990; 85 : 587 –590.[Medline] [Order article via Infotrieve]

35. Maddox DA, Brenner BM. Glomerular ultrafiltration. In: Brenner BM. The Kidney. Philadelphia, Pa: WB Saunders; 1991: 286 –333.

36. Meyer TW, Baboolal K, Brenner BM. Nephron adaptation to renal injury. In: Brenner BM. The Kidney. Philadelphia, Pa: WB Saunders; 1996; 2011 –2048.

37. Raij L, Azar S, Keane WF. Role of hypertension in progressive glomerular immune injury. Hypertension. 1985; 7 : 398 –404.[Abstract/Free Full Text]

38. Luscher TF, Vanhoutte PM. Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension. 1986; 8 : 344 –348.[Abstract/Free Full Text]

39. Luscher TF, Raij L, Vanhoutte PM. Endothelium-dependent vascular responses in normotensive and hypertensive Dahl rats. Hypertension. 1987; 9 : 157 –163.[Abstract/Free Full Text]

40. Campese VM, Tawadrous M, Bigazzi R, Bianchi S, Mann AS, Oparil S, Raij L. Salt intake and plasma atrial natriuretic peptide and nitric oxide in hypertension. Hypertension. 1996; 28 : 335 –340.[Abstract/Free Full Text]

41. Campese VM. Salt sensitivity in hypertension. Renal and cardiovascular implications (clinical conference). Hypertension. 1994; 23 : 531 –535.[Abstract/Free Full Text]

42. Buga GM, Gold ME, Fukuto JM, Ignarro LJ. Shear stress-induced release of nitric oxide from endothelial cells grown on beads. Hypertension. 1991; 17 : 187 –193.[Abstract/Free Full Text]

43. Awolesi MA, Widmann MD, Sessa WC, Sumpio BE. Cyclic strain increases endothelial nitric oxide synthase activity. Surgery. 1994; 116 : 439 –444.[Medline] [Order article via Infotrieve]

44. Dubey RK, Boegehold MA, Gillespie DG, Rosselli M. Increased nitric oxide activity in early renovascular hypertension. Am J Physiol. 1996; 39 : R118 –R124.

45. Panza JA, Garcia CE, Kilcoyne CM, Quyyumi AA, Cannon RO. Impaired endothelium-dependent vasodilation in patients with essential hypertension: evidence that nitric oxide abnormality is not localized to a single signal transduction pathway. Circulation. 1995; 91 : 1732 –1738.[Abstract/Free Full Text]

46. Taddei S, Virdis A, Mattei P, Ghiadoni L, Sudano I, Salvetti A. Defective L-arginine-nitric oxide pathway in offspring of essential hypertensive patients. Circulation. 1996; 94 : 1298 –1303.[Abstract/Free Full Text]

47. Rosansky SJ, Hoover DR, King L, Gibson J. The association of blood pressure levels and change in renal function in hypertensive and nonhypertensive subjects. Arch Intern Med. 1990; 150 : 2073 –2076.[Abstract/Free Full Text]

48. Devereux RB. Hypertensive cardiac hypertrophy: Patophysiologic and clinical characteristics. In: Laragh JH, Brenner BM. Hypertension. Pathophysiology, Diagnosis, and Management. New York, NY: Raven Press; 1990 .

This article has been cited by other articles:

				M. S. Joshi, C. Mineo, P. W. Shaul, and J. A. Bauer Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear FASEB J, September 1, 2007; 21(11): 2655 - 2663. [Abstract] [Full Text] [PDF]

				Y. Bai, S. Ye, R. Mortazavi, V. Campese, and N. D. Vaziri Effect of renal injury-induced neurogenic hypertension on NO synthase, caveolin-1, AKt, calmodulin and soluble guanylate cyclase expressions in the kidney Am J Physiol Renal Physiol, March 1, 2007; 292(3): F974 - F980. [Abstract] [Full Text] [PDF]

				F. K. Johnson, W. Durante, K. J. Peyton, and R. A. Johnson Heme oxygenase-mediated endothelial dysfunction in DOCA-salt, but not in spontaneously hypertensive, rat arterioles Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1681 - H1687. [Abstract] [Full Text] [PDF]

				L. Gnudi, G. Viberti, L. Raij, V. Rodriguez, D. Burt, P. Cortes, B. Hartley, S. Thomas, S. Maestrini, and G. Gruden GLUT-1 Overexpression: Link Between Hemodynamic and Metabolic Factors in Glomerular Injury? Hypertension, July 1, 2003; 42(1): 19 - 24. [Abstract] [Full Text] [PDF]

				J. Redon, M. R. Oliva, C. Tormos, V. Giner, J. Chaves, A. Iradi, and G. T. Saez Antioxidant Activities and Oxidative Stress Byproducts in Human Hypertension Hypertension, May 1, 2003; 41(5): 1096 - 1101. [Abstract] [Full Text] [PDF]

				S. Gschwend, H. Buikema, R. H. Henning, Y. M. Pinto, D. de Zeeuw, and W. H. van Gilst Endothelial dysfunction and infarct-size relate to impaired EDHF response in rat experimental chronic heart failure Eur J Heart Fail, March 1, 2003; 5(2): 147 - 154. [Abstract] [Full Text] [PDF]

				S. Gschwend, H. Buikema, G. Navis, R. H. Henning, D. de Zeeuw, and R. P. E. van Dokkum Endothelial Dilatory Function Predicts Individual Susceptibility to Renal Damage in the 5/6 Nephrectomized Rat J. Am. Soc. Nephrol., December 1, 2002; 13(12): 2909 - 2915. [Abstract] [Full Text] [PDF]

				L. Raij Workshop: Hypertension and Cardiovascular Risk Factors : Role of the Angiotensin II-Nitric Oxide Interaction Hypertension, February 1, 2001; 37(2): 767 - 773. [Abstract] [Full Text] [PDF]

				D. Wang, X. Yu, R. A. Cohen, and P. Brecher Distinct Effects of N-Acetylcysteine and Nitric Oxide on Angiotensin II-induced Epidermal Growth Factor Receptor Phosphorylation and Intracellular Ca2+ Levels J. Biol. Chem., April 14, 2000; 275(16): 12223 - 12230. [Abstract] [Full Text] [PDF]

				R. G. Luke Hypertensive nephrosclerosis: pathogenesis and prevalence : Essential hypertension is an important cause of end-stage renal disease Nephrol. Dial. Transplant., October 1, 1999; 14(10): 2271 - 2278. [Full Text] [PDF]

				F. C. Luft, E. Mervaala, D. N. Muller, V. Gross, F. Schmidt, J. K. Park, C. Schmitz, A. Lippoldt, V. Breu, R. Dechend, et al. Hypertension-Induced End-Organ Damage : A New Transgenic Approach to an Old Problem Hypertension, January 1, 1999; 33(1): 212 - 218. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Raij, L. Search for Related Content PubMed PubMed Citation Articles by Raij, L.