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(Hypertension. 1999;34:943-949.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Role of Angiotensin and Oxidative Stress in Essential Hypertension

J. Carlos Romero; Jane F. Reckelhoff

From the Department of Physiology and Biophysics, Mayo School of Medicine and Division of Hypertension, Mayo Clinic (J.C.R.) Rochester, Minn; and the Department of Physiology and Biophysics and the Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center (J.F.R.), Jackson, Miss.

Correspondence to J. Carlos Romero, MD, Department of Physiology, Mayo Clinic, Rochester, MN 55905.

	Abstract

Top Abstract Introduction Can Normal Concentrations of... Activation of Fast and... Role of Ang II,... Oxidative Stress Endothelin Isoprostanes Vascular Effects of... The Relationship Among Sodium... References

 
Abstract—In this review, we examine the possibility that small increments in angiotensin II are responsible for an increase in blood pressure and maintenance of hypertension through the stimulation of oxidative stress. A low dose of angiotensin II (2 to 10 ng · kg^-1 · min^-1, which does not elicit an immediate pressor response), when given for 7 to 30 days by continuous intravenous infusion, can increase mean arterial pressure by 30 to 40 mm Hg. This slow pressor response to angiotensin is accompanied by the stimulation of oxidative stress, as measured by a significant increase in levels of 8-iso-prostaglandin F₂ (F₂-isoprostane). Superoxide radicals and nitric oxide can combine chemically to form peroxynitrite, which can then oxidize arachidonic acid to form F₂-isoprostanes. F₂-isoprostanes exert potent vasoconstrictor and antinatriuretic effects. Furthermore, angiotensin II can stimulate endothelin production, which also has been shown to stimulate oxidative stress. In this way, a reduction in the concentration of nitric oxide (which is quenched by superoxide) along with the formation of F₂-isoprostanes and endothelin could potentiate the vasoconstrictor effects of angiotensin II. We hypothesize that these mechanisms, which underlie the development of the slow pressor response to angiotensin II, also participate in the production of hypertension when circulating angiotensin II levels appear normal, as occurs in many cases of essential and renovascular hypertension.

Key Words: isoprostane • endothelin • oxidative stress • hypertension, essential • angiotensin II

	Introduction

Top Abstract Introduction Can Normal Concentrations of... Activation of Fast and... Role of Ang II,... Oxidative Stress Endothelin Isoprostanes Vascular Effects of... The Relationship Among Sodium... References

 
Despite the fact that essential hypertension is one of the most prevalent diseases of developed Western societies and is an unequivocal risk factor for cardiovascular morbidity and mortality, the underlying pathophysiological abnormalities that lead to the development of the elevated arterial pressure in this disorder remain elusive.¹ However, in the past decade, many clinicians have suggested that essential hypertension must be related to the renin-angiotensin system and to an undefined renal dysfunction.² These assumptions are motivated first by the efficacy of converting-enzyme inhibitors or angiotensin receptor antagonists to reduce blood pressure in essential hypertension, even when plasma levels of angiotensin II (Ang II) are normal or slightly elevated.^{3 4 5} Second, hypertension can be induced in a normotensive human or animal by transplantation of a kidney from a hypertensive subject,² or, alternatively, hypertension can be cured by transplanting a kidney from a normotensive donor into a previously hypertensive individual.³ Third, studies recently have shown that Ang II can stimulate oxidative stress,⁶ which could activate several vasopressor mechanisms that may potentiate the vasoconstrictor effect of Ang II. Any hypothesis concerning the basic elements involved in the pathogenesis of essential hypertension should consider these characteristics. Such is the objective of this review.

	Can Normal Concentrations of Angiotensin in Plasma Induce and Sustain Hypertension?

Top Abstract Introduction Can Normal Concentrations of... Activation of Fast and... Role of Ang II,... Oxidative Stress Endothelin Isoprostanes Vascular Effects of... The Relationship Among Sodium... References

 
The functional mechanisms that are responsible for long-term maintenance of hypertension in the presence of so-called "normal" levels of plasma renin activity remain unexplained.^{3 4 5} Note that plasma renin activity is defined by the amount of Ang I generated in plasma⁷ during a given period of incubation and under predefined laboratory conditions (pH, peptidase inhibitors, etc). Therefore, the amount of Ang II generated in the plasma in most essential hypertensive patients is not different from that seen in normotensive individuals (50% to 60%).^{3 4 5} Furthermore, a subset of the population of hypertensives exists in whom the level of circulating Ang II is significantly less than that detected in normotensives (25% to 35%).³ However, these levels of Ang II may contribute to the maintenance of hypertension, because blood pressure is markedly reduced by the administration of either converting enzyme inhibitors⁴ or angiotensin antagonists.⁵ These seemingly paradoxical observations can be reconciled by the original observation of Dickinson et al,⁸ who demonstrated in 1963 in rabbits that the infusion of very small amounts of Ang II that were not sufficient to elicit an immediate elevation of blood pressure nonetheless produced chronic hypertension. Two years later, McCubbin et al⁹ reported similar findings in dogs. These studies were critical to the determination of the difference between the so-called fast and slow pressor effects of Ang II.¹⁰ The fast pressor responses are produced by relatively high concentrations of Ang II, which induce a rapid contraction of the smooth muscle when administered as a bolus.¹¹ The response reaches the maximal pressor response in seconds and returns to normal levels in 2 to 3 minutes. The intracellular signaling involved in mediating such a rapid angiotensin-induced vasoconstriction has been investigated extensively.¹² However, the mechanisms that could account for the slow pressor responses remain unknown.^{8 9 10} Slow pressor responses need 5 to 10 hours to develop and reach a maximal peak 3 to 5 days after the onset of the infusion.¹⁰ The important characteristics of slow pressor responses are as follows: (1) these responses are not specific for any particular animal species and have been demonstrated in man,¹³ rats,¹⁴ rabbits,⁸ and dogs.⁹ In our laboratory, we have demonstrated similar responses in a swine model.¹⁵ (2) Slow pressor responses appear to evolve at doses of Ang II that are insufficient not only to produce an immediate elevation of blood pressure, but also to stimulate steroidogenic and dipsogenic actions typical of blood-borne angiotensin.^{14 16} (3) Slow pressor responses also have been produced by the continuous infusion of norepinephrine.^{17 18} However, the rise in blood pressure is much lower than that observed with Ang II (12 mm Hg), but significantly higher plasma concentrations of norepinephrine (18-fold higher) are required to produce a similar pressor response as Ang II.¹⁴ These latter findings are confounded by the fact that norepinephrine can stimulate the release of renin because of its intrinsic ß-adrenergic agonist effect. The consistent delay of small subpressor doses of Ang II to produce an increase in blood pressure suggests a time requirement for the activation of additional vasoconstrictor processes, which can then trigger an autocatalytic reaction that accelerates or potentiates the vasoconstrictor effect of Ang II. For example, Brown et al¹⁴ demonstrated in rats that the administration of 20 ng · kg^-1 · min^-1 of Ang II did not alter blood pressure during the first hour of infusion (see Table), but on the morning of the following day, blood pressure was significantly increased, by 15 mm Hg. Thereafter, blood pressure rose progressively and peaked on the seventh day, at which time mean arterial pressure was 153±6 mm Hg. The basal levels of blood pressure before infusion were 103±4 mm Hg. In studies conducted in a separate group of animals, these investigators also showed that the amount of angiotensin needed for a 1-hour infusion to achieve a comparable level of blood pressure (155±1.1 mm Hg) was 810 ng · kg^-1 · min^-1 Ang II (Figure 1), whereas an infusion of 270 ng · kg^-1 · min^-1 of Ang II produced an elevation of blood pressure of 146±3 mm Hg. Furthermore, the circulating level of Ang II on day 7 of the infusion of 20 ng · kg^-1 · min^-1 Ang II was determined to be 230 pg/mL, which did not differ considerably from the 150 pg/mL found in animals during the infusion of 20 ng · kg^-1 · min^-1 of Ang II for 1 hour when blood pressure was still normal (Figure 1). In contrast, the level of Ang II found in acutely hypertensive animals (146±3 mm Hg) infused with 270 ng · kg^-1 · min^-1 Ang II for 1 hour was 2500 pg/mL. These observations unequivocally prove that small subpressor doses of Ang II, continuously infused, are capable of raising blood pressure without a concomitant increase in plasma levels of Ang II. This phenomenon has been best explained as an autopotentiation of the vasoconstrictor effects of Ang II.⁸ In an extensive review on this subject, Lever¹⁰ ruled out the participation of other mechanisms such as the central nervous system, vascular hypertrophy, etc. In this survey, we examine the possibility that the slow responses to Ang II may be due to the vasoconstrictor effects of oxidative stress.

View this table: [in this window] [in a new window]   Table 1. Fast and Slow Responses to Intravenous Infusion of Ang II

View larger version (13K): [in this window] [in a new window]   Figure 1. Plasma Ang II concentration in 5 groups of rats receiving either 1-hour or 7-day intravenous infusions of dextrose or Ang II. Bars=±SEM.

	Activation of Fast and Slow Intracellular Signaling Modalities by Ang II

Top Abstract Introduction Can Normal Concentrations of... Activation of Fast and... Role of Ang II,... Oxidative Stress Endothelin Isoprostanes Vascular Effects of... The Relationship Among Sodium... References

 
Like fast pressor responses, slow pressor responses are triggered by the binding of Ang II to AT₁ receptors.¹⁹ After binding AT₁ receptors, angiotensin activates a G-protein, which subsequently may stimulate different signaling pathways, depending on the length of the stimulation of the AT₁ receptors. Ang II can trigger rapid smooth-muscle contraction through the phosphoinositide-Ca²⁺–protein kinase C effector system.^{20 21 22 23 24} The binding of a vasoconstrictor substance such as Ang II to its receptor activates phospholipase C. This enzyme induces the hydrolysis of phosphatidylinositol bisphosphate and thus liberates inositol triphosphate (IP₃), which releases Ca²⁺ from intracellular stores, and diacylglycerol, which activates protein kinase C.^{20 21 22} Protein kinase C regulates Ca²⁺ transmembrane flux. An important concept concerning the interrelationship of Ang II with the phosphoinositide-Ca²⁺ system was proposed by Rasmussen and Barrett.²⁵ They suggested that the stimulation of the IP₃-Ca²⁺ system accounts for the initial effect of Ang II, namely rapid development of smooth-muscle contraction. In contrast, the sustained actions of Ang II (chronic smooth-muscle contraction) could be primarily maintained through protein kinase C, which stimulates calcium channels and thus perpetuates contractile response (1) by facilitation of the entrance of extracellular Ca²⁺, (2) by stimulation of lipoxygenase production, or (3) by the release of other autocoids that may potentiate the vasoconstrictor response to Ang II. A difficult but critical task will be to determine whether the activation of this intracellular pathway differs from the stimulation of other mechanisms that are also affected by the chronic administration of Ang II, such as the synthesis of proto-oncogenes, tissue hypertrophy, and inflammatory processes.²⁶ Among the several mechanisms stimulated by Ang II, the effects on oxidative stress appear to be the most likely to potentiate Ang II, because these involve a reduction in nitric oxide (NO) along with the release of potent vasoconstrictors.

	Role of Ang II, Oxidative Stress, NO, and Isoprostanes in the Slow Responses to Ang II

Top Abstract Introduction Can Normal Concentrations of... Activation of Fast and... Role of Ang II,... Oxidative Stress Endothelin Isoprostanes Vascular Effects of... The Relationship Among Sodium... References

 
Ang II has been shown to stimulate the production of superoxide, which quenches NO.^{6 27} On the other hand, the chemical combination of superoxide with NO is known to yield peroxynitrite, which is a potent oxidant that could oxidize arachidonic acid and thus release a potent renal vasoconstrictor, antinatriuretic substance 8-iso-prostaglandin F₂ (isoprostane). This sequence of events is illustrated in Figure 2.²⁷ Additionally, Ang II may also stimulate endothelin (ET) synthesis,^{28 29 30} which can be further increased by the oxidative stress cascade mentioned above.^{31 32 33 34} Therefore, the reduced NO, increased isoprostane, and increased ET represent potent vasoconstrictor effects that can enhance the vasopressor action of Ang II and may explain how hypertension is maintained in pathological situations (such as 2-kidney, 1 clip Goldblatt hypertension or essential hypertension) in which the levels of angiotensin are frequently found to be normal.³⁵ The occurrence of this sequence of events, which is further examined below, deserves to be investigated, because it could be used to assess stages in the development of hypertension more accurately than measurement of the levels of plasma renin activity or angiotensin itself. In fact, the metabolites of oxidative stress have been proposed to play a critical role in the pathophysiology of renovascular hypertension and renal damage.^{36 37}

View larger version (18K): [in this window] [in a new window]   Figure 2. Ang II induces superoxidation that can be neutralized by superoxide dismutase or bound to nitric oxide to form peroxynitrite. This compound oxidizes arachidonic acid to form isoprostaglandin F2, which has a molecular structure similar to that of prostaglandin F2.

	Oxidative Stress

Top Abstract Introduction Can Normal Concentrations of... Activation of Fast and... Role of Ang II,... Oxidative Stress Endothelin Isoprostanes Vascular Effects of... The Relationship Among Sodium... References

 
Pryor and Squadrito²⁷ have shown that oxygen free radicals (superoxide) are constantly being combined with NO to form peroxynitrite, which is in equilibrium with peroxynitrous acid (superoxide+NOperoxynitrite OONO).²⁷ Peroxynitrite has a greater oxidative capacity than any other compound²⁷ (Figure 2). An important observation that links superoxide production to an increased level of Ang II was obtained by Rajagopalan et al.⁶ This study showed that arteries isolated from rats rendered hypertensive by the administration of a large amount of Ang II (0.7 mg/kg/dayx5 days) exhibited an impaired relaxation to acetylcholine associated with an increased level of superoxidation. These alterations were corrected by pretreating the rats with losartan (an Ang II antagonist) or by treatment of vessels with liposome-encapsulated superoxide dismutase. In this study, hypertension was not thought to be responsible for stimulating superoxide production because norepinephrine infusion, which raised blood pressure to levels similar to those of Ang II, was not accompanied by activation of superoxide. Additional studies⁶ showed that the stimulation of superoxide production in intact vascular segments was not related to the participation of xanthine oxidase, mitochondrial electron transport, cyclooxygenases, NO synthase, or lipoxygenases, because the response was unaffected by the administration of oxypurinol, rotenone, indomethacin, nitro-L-arginine-methyl ester (L-NAME), or nordihydroguayaretic acid, respectively. We have recently shown that oxidative stress can be stimulated by very low doses of Ang II in swine because it increases plasma unbound isoprostanes (Figure 3). This effect was not seen in age-matched control animals that were not treated with Ang II.

View larger version (46K): [in this window] [in a new window]   Figure 3. Changes in plasma-free isoprostane F2 in swine during the control period (light column) and 28 days after the continuous infusion of 10 ng · kg-1 · min-1 of Ang II (dark column).

	Endothelin

Top Abstract Introduction Can Normal Concentrations of... Activation of Fast and... Role of Ang II,... Oxidative Stress Endothelin Isoprostanes Vascular Effects of... The Relationship Among Sodium... References

 
Whether ET plays a role in mediating oxidative stress or is affected by oxidative stress is not clear. Both ET production and NO synthesis can be stimulated by Ang II.^{28 29 30 38} In cultured endothelial cells, inhibition of NO synthesis can stimulate the release of ET, whose effects can be inhibited by bosantan, a nonspecific ET antagonist.^{39 40} NO can also regulate the vasoconstrictor effects of ET in vascular smooth muscle.^{41 42} In support of the hypothesis that both NO reduction and ET stimulation play a role in mediating the oxidative stress induced as a consequence of slow pressor responses to Ang II are the data in which the acute hypertension induced by NO synthase inhibition can be attenuated by acute nonselective ET_A/ET_B antagonism,^{43 44} whereas chronic NO synthesis inhibition (4 weeks) cannot be attenuated by acute ET_A specific receptor antagonism.⁴⁵ The role that ET plays in 2-kidney, 1 clip Goldblatt hypertension is not clear, because oxidative stress, measured by production of isoprostanes, can induce the release of ET from smooth muscle cells.^{31 32 33} More directly we have recently observed that stimulation of oxidative stress by hypercholesterolemia in pigs evolves with a reduction in circulating NO and a significant increase in isoprostanes and that these changes can be obliterated by ET antagonism.⁴⁶ This indicates the need to evaluate whether ET stimulates oxidative stress or whether oxidative stress stimulates production of ET. Caution should be taken in ascribing to ET a definitive role in the hypertension experimental models, because it has been shown to have a potent diuretic and natriuretic effect at doses that do not lower glomerular filtration rate; this would antagonize any hypertensive effect.^{47 48}

	Isoprostanes

Top Abstract Introduction Can Normal Concentrations of... Activation of Fast and... Role of Ang II,... Oxidative Stress Endothelin Isoprostanes Vascular Effects of... The Relationship Among Sodium... References

 
Isoprostanes are prostaglandin-like compounds produced by free radical–catalyzed peroxidation of arachidonic acid.⁴⁹ Although 64 compounds can be theoretically formed by peroxidation of polyunsaturated fatty acids, 4 classes of regioisomers are currently found in mammals, of which the most abundant is F₂ isoprostane^{50 51} (Figure 2). This compound is detected in plasma from healthy volunteers at levels of 35±6 pg/mL, whereas urine contained 1.6±0.6 ng/mg of creatinine.^{52 53 54} The levels of isoprostanes in plasma exceed by 10 to 20 times the levels of circulating prostaglandins.⁵² Isoprostane is increased 200 times after oxidant injury inflicted by carbon tetrachloride (CCl₄) or the herbicide diquat.^{52 53} Evidence exists that shows that, unlike prostaglandins, isoprostanes can be formed while the molecule of arachidonic acid is still esterified to phospholipids, from which it subsequently can be released by phospholipases.⁵⁵ This effect is clearly shown during the administration of CCl₄, which increases the amount of isoprostane bound to liver phospholipids (by 40 times at 2 hours), which are then released into circulation. Unbound isoprostane peaks in the circulation 8 hours after the administration of CCl₄.⁵⁶

Arachidonic acid oxidation can also form iso-D₂/E₂, isothromboxane, and isoleukotrienes. Although some of these compounds can be detected in tissue, they are not detected in circulation under normal conditions.⁵¹ Another important issue is that isoprostane, the most abundant compound form in vivo, has been shown to be the most reliable index of lipid peroxidation.⁵⁷ This provides an important tool to evaluate oxidative stress in vivo. A good review on this issue has been recently published by Morrow and Roberts.⁵¹

Isoprostane can be produced locally in the kidney.^{31 52} Administration of isoprostanes into the rat (low nanomolar range) produces a potent renal vasoconstriction that reduces glomerular filtration rate and renal blood flow by 40% to 45%.^{31 52} These effects appear to be predominantly exerted on the afferent arteriole.^{31 32} Reckelhoff et al⁵⁸ have shown that aging rats (22 months old) exhibit 50% reduction in glomerular filtration rate and 3-fold increases in renal isoprostane versus young rats (3 to 4 months old). Chronic treatment (for 9 months) with the antioxidant vitamin E normalizes renal isoprostane levels and improves glomerular filtration rate significantly.⁵⁸ In rabbits and rats, isoprostane is a potent pulmonary artery vasoconstrictor, and it causes bronchoconstriction in the rat lung.^{59 60} In addition, isoprostane has been shown to induce a significant release of ET from bovine aortic endothelial cells.³⁴

An important characteristic concerning the biological activity of isoprostane is that the vasoconstrictor effects are blocked by thromboxane receptor antagonist SQ29548.³¹ However, much indirect evidence⁶¹ has shown that isoprostane interacts with a receptor in vascular smooth muscle that is distinct from the thromboxane receptor. Studies using molecular cloning strategies will be required to provide unequivocal proof for the existence of a unique isoprostane receptor.

	Vascular Effects of Peroxynitrite

Top Abstract Introduction Can Normal Concentrations of... Activation of Fast and... Role of Ang II,... Oxidative Stress Endothelin Isoprostanes Vascular Effects of... The Relationship Among Sodium... References

 
The postulation that peroxynitrite leads to a vasoconstrictor effect through the synthesis of isoprostane should be tempered by the discovery of parallel biochemical effects, the role of which remains undefined in the regulation of vascular tone. Some evidence indicates that peroxynitrite may not follow the oxidative pathway through arachidonic acid with the production of isoprostane but could combine with thiol groups of glutathione to produce S-nitroglutathione.⁶² This compound could subsequently degenerate to produce NO and vasodilatation.⁶² This effect has been postulated to explain the prolonged vasodepressor effect elicited by peroxynitrite in pulmonary arteries.⁶³

The extent to which peroxynitrite produces vasodilatation through S-nitroglutathione or by acting directly on the vasculature constitutes an important area of research. Some of the effects directly attributed to peroxynitrites are those induced by coronary ischemia-reperfusion.⁶⁴ Furthermore, a study conducted by Wei and colleagues⁶⁵ showed that the vasodilatation produced by peroxynitrite or hydrogen peroxide in cerebral arteries (topical application through cranial windows) is mediated by an ATP-sensitive potassium channel. Interestingly, superoxide generated by xanthine oxidase acting on xanthine also induced a cerebral vasodilatation, but that effect was mediated by stimulation of calcium-activated potassium channels.⁶⁵ No other studies have been conducted to determine whether this potassium channel–mediated effect is restricted to cerebral circulation. The notion that the vasodilator effects of peroxynitrite exerted through degeneration of S-nitroglutathione or through a specific potassium channel is further supported by the study of Benkusky et al,⁶⁶ which shows that the systemic administration of peroxynitrite significantly inhibited the vascular pressor responses elicited in hindquarters and renal, and mesenteric vasculature by the administration of different catecholamines (epinephrine, norepinephrine, and phenylephrine). These investigators thought that such an opposing effect was selective for catecholamines because peroxynitrite failed to protect against the vasoconstrictor effect of arginine vasopressin.⁶⁶

The difficulty in determining the physiological relevance of the previous studies is that they were conducted in in vitro preparations or using pharmacological doses of peroxynitrite. This does not allow for a great deal of speculation on the physiological effects of compounds whose formation depends on oxidative stress. Most importantly, one of the major characteristics of the administration of peroxynitrite in hindquarter, renal, and mesenteric vasculature is the development of rapid tachyphylaxis, which alters subsequent vascular responses to other dilators. In fact, a study conducted by Benkusky et al⁶⁷ showed that after the development of tachyphylaxis to peroxynitrite, the hemodynamic effect produced by the systemic administration of acetylcholine and prostacyclin was significantly attenuated. Interestingly, Villa et al⁶⁸ also observed that the peroxynitrite-dependent tachyphylaxis in coronary circulation was critically dependent on its concentration. The tachyphylaxis occurred at 3 µmol/L, which was subthreshold as a dilator, and at 1000 µmol/L, which was supermaximal. No tachyphylaxis developed during the administration of peroxynitrite at 30 and 100 µmol/L. This investigator interpreted these data as representing an important manifestation of vascular dysfunction produced by peroxynitrite because of tachyphylaxis to its own vasodilator actions and the long-lasting impairment of the response to other vasodilators.⁶⁸ Furthermore, the deleterious effect of peroxynitrite has also been suggested by Zou et al,⁶⁹ who provided evidence showing that peroxynitrite not only eliminated the vasodilatory, growth-inhibiting, antithrombotic, and antiadhesive effects of prostaglandin I₂ but also allowed and promoted action of the potent vasoconstrictor, prothrombotic agent, growth promoter, and leukocyte adherent prostaglandin H₂.⁶⁹

The case under discussion is that the prolonged administration of subpressor doses of Ang II produces a progressive vasoconstriction, which we think can be largely due to the concomitant reduction of NO and accumulation of isoprostane. The vasodilator effects of peroxynitrite should not be manifested if the concentration of this compound does not exceed 3 mmol/L, because these levels are below the physiological threshold and because they develop tachyphylaxis. At >3 µmol/L, the vasodilator effects of peroxynitrite may significantly decrease the level of hypertension produced by small doses of Ang II.

	The Relationship Among Sodium Intake, Plasma Renin Activity, Extracellular Fluid Volume, and the Development of Oxidative Stress

Top Abstract Introduction Can Normal Concentrations of... Activation of Fast and... Role of Ang II,... Oxidative Stress Endothelin Isoprostanes Vascular Effects of... The Relationship Among Sodium... References

 
The proposition that small increments in plasma concentrations of Ang II are ultimately responsible for hypertension through the development of oxidative stress appears to be difficult to reconcile with the fact that during dietary sodium restriction the levels of plasma Ang II are 10-fold higher than during a normal sodium diet.³ These conditions are illustrated in Figure 4, which also shows that a progressive increase in sodium intake produces a proportional volume expansion that exhibits a tight inverse correlation with the circulating levels of plasma renin activity. As shown Figure 4, when the levels of extracellular fluid volume have achieved a maximal expansion with high sodium intake, plasma renin activity has virtually disappeared from circulation. Guyton et al⁷⁰ have suggested that this inverse relationship between fluid volume and plasma renin is extremely critical to maintaining blood pressure within the normal limits. If this relationship is altered, for example, if the levels of plasma Ang II are driven above those that correspond to a given level of either sodium intake or extracellular fluid volume, then the organism becomes susceptible to develop hypertension through slow responses to Ang II. This is shown in the figure where the levels of Ang II have been "inappropriately" increased in animal models to levels A, B, C, and D, which induce proportional increments in mean arterial pressure (Figure 4, bottom). This assumption has led us to suggest that the circulating levels of angiotensin are inappropriate or in excess considering the level of extracellular fluid volume. This hypothesis is largely supported by the studies of DeClue et al,⁷¹ who showed that when sodium intake is increased without allowing the circulating levels of angiotensin to be decreased, because of a continuous intravenous infusion, the level of blood pressure is strictly determined by the level of sodium intake. The observations of DeClue et al have many physiological and clinical implications. From the physiological standpoint, they demonstrate that hypertension, through slow pressor responses, can be induced by small elevations of circulating angiotensin that are inappropriate for the existing levels of extracellular fluid volume, and, reciprocally, they show that hypertension can also be produced if the intake of sodium is inappropriate with respect to the existing levels of circulating Ang II. The corollary of this conclusion is that the disruption of the reciprocal interaction between extracellular fluid volume and plasma renin activity (which serves to maintain blood pressure) appears to activate a permissive mechanism that renders oxidative stress susceptible to be stimulated by Ang II.

View larger version (21K): [in this window] [in a new window]   Figure 4. Reciprocal changes in plasma renin activity (PRA) and extracellular fluid volume (ECFV) that occur when a low sodium diet is shifted to a high sodium diet (top). This change contributes to the maintenance of mean arterial pressure (bottom). Infusion of different doses of Ang II (A, B, and C), which maintain the levels in plasma of this peptide inappropriately high with respect to ECFV, produces hypertension.

An alternative interpretation, suggested by Wilcox and colleagues,⁷² is that long-term effects of Ang II are characterized by stimulation of aldosterone and sympathetic activity and produce a simultaneous uncoupling of NO release and shear stress.⁷³ These investigators also have found that the administration of a superoxide dismutase mimetic to spontaneously hypertensive rats normalizes mean arterial pressure.⁷⁴ As is apparent, more studies are needed to unravel the specific pathways of oxidative stress that could affect blood pressure regulation.

	Acknowledgments

 
This work was supported by National Institutes of Health grant HL-16496 and program grant HL-51971, Mayo Foundation, the American Heart Association grant 9740007N, and a grant from Fundacion Barcelo Argentina.

Received May 8, 1999; first decision June 17, 1999; accepted July 15, 1999.

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