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The Role of Angiotensin and Oxidative Stress in Essential Hypertension


J. Carlos Romero, M.D.

Department of Physiology and Biophysics
Mayo School of Medicine
and Division of Hypertension, Mayo Clinic

Abstract

In this review we intend to examine the possibility that small increments of angiotensin II could be responsible for an increase in blood pressure and maintenance of hypertension through the stimulation of oxidative stress. It has been shown that a low dose of angiotensin II (2-10 ng/kg/min), which does not elicit an immediate pressor response, when given for 7-30 days by continuous intravenous infusion, can increase mean arterial pressure by 30-40 mmHg. This slow pressor response to angiotensin is accompanied by the stimulation of oxidative stress as measured by a significant increase in 8-iso-PGF2a (F2-isoprostanes), which is produced by the chemical combination of superoxide radicals and nitric oxide 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 has been shown to also stimulate oxidative stress. In this way a reduction in the concentration of nitric oxide (being 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, such as in essential and renovascular hypertension.

Index Terms: F2-isoprostane, endothelin, superoxide, peroxynitrite, extracellular fluid volume

Introduction

Despite the fact that essential hypertension is one of the most prevalent diseases of Western, developed societies and is an unequivocal risk factor for cardiovascular morbidity and mortality1, the underlying pathophysiologic abnormalities leading to the development of the elevated arterial pressure in this disorder remain elusive. However, in the last decade most clinicians have suggested that essential hypertension must be related to the renin angiotensin system and to an undefined renal dysfunction. 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 below normal2. Second, hypertension can be induced in normotensive humans or animals by transplantation of a kidney from hypertensive subjects3 or, alternatively, hypertension can be cured by transplanting a kidney from normotensive donors into previously hypertensive individuals3. Furthermore it has been recently shown that ang II can stimulate oxidative stress4 which could activate a number of vasopressor mechanisms that may potentiate the vasoconstrictor effect of ang II. An attempt to formulate a hypothesis about the basic elements involved in the pathogenesis of essential hypertension should take into consideration these characteristics. Such is the objective of this review.

Can normal concentrations of angiotensin in plasma induce and sustain hypertension?

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 unexplained2. It should be borne in mind that plasma renin activity is defined by the amount of ang II generated in plasma5 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 of most essential hypertensive patients is not different from that seen in normotensive individuals (50-60%)2. Furthermore, there is a subset in the population of hypertensives where the level of circulating ang II is significantly below those detected in normotensives (25-35%)2. However, these levels of ang II contribute to the maintenance of hypertension because blood pressure is markedly reduced by the administration of either converting enzyme inhibitors6 or angiotensin antagonists7. These paradoxical observations could be reconciled by the original observation of Dickinson and Lawrence8 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 produced, nonetheless, chronic hypertension. Two years later, McCubbin, et al.9 reported similar findings in dogs. These studies were very critical to determine the difference between the so-called fast- and slow-pressor effect of ang II10. 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 bolus11. The response reaches the maximal pressor response in seconds and returns to normal levels in 2-3 minutes. The intracellular signalling involved in mediating such a rapid angiotensin-induced vasoconstriction has been extensively investigated12. However, the mechanism(s) that could account for the slow pressor responses (SPR) remains unknown8-10. The SPR needs 5-10 hours to develop reaching a maximal peak 3-5 days after the onset of the infusion10. The important characteristics of SPR are: 1) it is not specific for any particular animal species since it has been demonstrated in man13, rats14, rabbits8, and dogs9. In our laboratory we have demonstrated similar responses in a swine model15. 2) It appears that the SPR evolves 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 angiotensin14,16. 3) SPR have also been produced by the continuous infusion of norepinephrine17-18. However, the rise in blood pressure is much less than that observed with ang II (no more than 12 mmHg) and higher doses of norepinephrine are needed with higher plasma concentrations (18-fold higher concentration) than those needed in the same preparation using ang II14. However, these latter findings are confounded by the fact that norepinephrine is capable of stimulating the release of renin because of its intrinsic beta adrenergic agonistic effect. The consistent delay of small subpressor doses of ang II to produce an increase in blood pressure suggests that there is a time requirement for the activation of additional vasoconstrictor processes which can then trigger an autocatalytic reaction accelerating or potentiating the vasoconstrictor effect of ang II. For example, Brown, et al.,14 demonstrated in rats that the administration of 20 ng/kg/min of ang II did not alter blood pressure during the first hour of infusion (see Table 1) but on the morning of the following day it was significantly increased by 14 mmHg. Thereafter it rose progressively reaching a peak on the seventh day where mean arterial pressure was 153±6 mmHg. The basal levels of blood pressure before starting infusion were 106±3 mmHg. In studies conducted in a separate group of animals these investigators also showed that the amount of angiotensin needed to infuse for 1 hr to achieve a comparable level of blood pressure (155±1.1 mmHg) was 810 ng/kg/min, while an infusion of 270 ng/kg/min produced an elevation of blood pressure up to 146±3 mmHg. In these studies, determination of circulating levels of ang II on day 7 of the infusion of 20 ng/kg/min was approximately 230 pg/ml which did not differ much from the 150 pg/ml found in animals during the infusion of 20 ng/kg/min for 1 hr. when blood pressure was still normal. In contrast, the levels of ang II found in acute hypertensive animals (146±3 mmHg) infused with 270 ng/kg/min for one hour was approximately 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 by an autopotentiation of the vasoconstrictor effects of ang II8.

Table 1: Fast and slow responses to intravenous infusion of angiotensin II (mmHg)

Ang II infusion

Time of Infusion

  Basal 1 hour 1 day 7 day
Dextrose control 103 ± 4 103 ± 4 107 ± 4 106 ± 6
20 ng/kg/min 106 ± 3 106 ± 6 117 ± 4* 153 ± 6*
270 ng/kg/min 101 ± 3 146 ± 3* -- --
810 ng/kg/min 101 ± 3 155 ± 1* -- --

*<0.05 when compared to control. Modified from ref. 14

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Fig. 1

Oxidative stress

Pryor, et al.,19 have shown that oxygen free radicals (O2-) are constantly being combined with NO, forming peroxynitrite (OONO), which is in equilibrium with peroxynitrous acid (O2- + NO ® -OONO Þ OONOH)19. Peroxynitrite has an oxidative capacity higher than any other compound19 (Fig. 1). An important observation that links superoxide production to an increased level of ang II, was obtained by Rajagopalan, et al4. This study showed that arteries isolated from rats rendered hypertensive by the administration of a large amount of ang II (270 µg/kg) 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 felt to be responsible for stimulating superoxide production, because norepinephrine infusion which raised blood pressure to similar levels as ang II, was not accompanied by activation of superoxide. Additional studies of Rajagopalan, et al.,4 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 and/or lipoxygenases because the response was unaffected by the administration of oxypurinol, rotenone, indomethacin, nitro-L-arginine-methyl ester (L-NAME) or nordihydroguayaretic acid, respectively4. We have recently shown that superoxide can be stimulated by very low doses of ang II in swine (Fig. 2).

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Fig. 2

Endothelin

Whether ET plays a role in mediating oxidative stress or is impacted upon by oxidative stress is not clear. Both ET production and NO synthesis can be stimulated by ang II20-23. In cultured endothelial cells inhibition of NO synthesis can stimulate the release of ET whose effects can be inhibited by bosantan, a non-specific ET antagonist24-25. NO can also regulate the vasoconstrictor effects of ET in VSM26-27. Supportive of the hypothesis that both NO reduction and ET stimulation play a role in mediating the oxidative stress induced as a consequence of SPR to ang II is the data in which the acute hypertension induced by NO synthase inhibition can be attenuated by acute non-selective ETA/ETB antagonism28-29, whereas chronic NO synthesis inhibition (4 weeks) cannot be attenuated by acute ETA specific receptor antagonism30. The role that ET plays in 2 kidney, 1 clip Goldblatt hypertension is not clear since oxidative stress, measured by production of ISOP, can induce the release of ET from smooth muscle cells31-33. 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 ISOP and these changes can be obliterated by ET antagonism34. 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 GFR and this would antagonize any hypertensive effect35-36.

Isoprostanes

ISOP are prostaglandin-like compounds produced by free radical-catalyzed peroxidation of arachidonic acid37. Although there are 64 compounds that can be theoretically formed by peroxidation of polyunsaturated fatty acids, there are four classes of regioisomers currently found in mammals of which the most abundant is F2 ISOP38-39 (Fig. 1). This compound is detected in plasma from healthy volunteers at levels of 35 ± 6 pg/ml while urine contained 1.6 ± 0.6 ng/mg of creatinine40-42. The levels of ISOP in plasma exceed by 10-20 times the levels of circulating prostaglandins40. ISOP is increased about 200 times after oxidant injury inflicted by carbon tetrachloride (CCl4) or the herbicide, diquat40-41. There is evidence showing that unlike PGs, ISOP can be formed while the molecule of arachidonic acid is still esterified to phospholipids from where it can subsequently be released by phospholipases43. This effect is clearly shown during the administration of CCl4 which increases the amount of ISOP bound to liver phospholipids (by 40 times at two hours) which are then released into circulation. Free ISOP peaks in the circulation eight hours after the administration of CCl444.

Arachidonic acid oxidation can also form iso-D2/E2 along with isothromboxane and iso leukotrienes. Although some of these compounds can be detected in tissue; they are not detected in circulation under normal conditions39. Another important issue is that F2 isoprostane , the most abundant compound form in vivo, has been shown to be the most reliable index of lipid peroxidation45. This provides an important tool to evaluate oxidative stress in vivo. A good review on this issue has been recently published by Morrow and Roberts39.

ISOP can be locally produced in the kidney31,40. Administration of ISOP into the rat (low nanomol range) produces a potent renal vasoconstriction, reducing GFR and RBF by 40-45%31,40. These effects appear to be predominantly exerted on the afferent arteriole31-32. Reckelhoff, et al.46 have shown that aging rats (22 months) exhibit 50% reduction in glomerular filtration rate and 3 fold increases in renal F2-ISOP when compared to young rats, aged 3-4 months. Chronic treatment (9 months) with the antioxidant, vitamin E, normalizes renal ISOP levels and improves glomerular filtration rate significantly46. In rabbits and rats ISOP is also a potent pulmonary artery vasoconstrictor and causes bronchoconstriction in the rat lung47-48. In addition, F2 ISOP has been shown to induce a significant release of ET from bovine aortic endothelial cells49.

An important characteristic concerning the biological activity of ISOP is that the vasoconstrictor effects are blocked by thromboxane receptor antagonist, SQ2954831. Interestingly, when incubated with platelets, ISOP caused a slight shape change, but did not induce irreversible aggregation50. This contrasts with a strong aggregatory effect of thromboxane. The current interpretation of these effects is that specific ISOP receptors are located in the smooth muscle but not in platelets, while the ISOP receptors of the smooth muscle are blocked by nonspecific thromboxane receptor antagonism39.

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Fig. 3

The relationship between sodium intake, plasma renin activity, extracellular fluid volume, and the development of oxidative stress

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 approximately 10-fold higher than those on a normal sodium diet2. These conditions are illustrated in Fig. 3 which also shows that a progressive increase in sodium intake produces a proportional volume expansion which exhibits a tight inverse correlation with the circulating levels of plasma renin activity. As shown in the figure, 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 al.51 has suggested that this inverse relationship between fluid volume and plasma renin is extremely critical to maintain blood pressure within the normal limits (see Fig. 3). 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 angiotensin 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 (at the bottom of the figure). This assumption has led us to suggest that the circulating levels of angiotensin are "inappropriate" or "in excess" when compared with the level of extracellular fluid volume. This hypothesis is largely supported by the studies of DeClue, et al.52 who showed that when sodium intake is increased without allowing the circulating levels of angiotensin to be decreased because of a continuous intravenous infusion, then the levels of blood pressure becomes strictly determined by the level of sodium intake. The observations of DeClue, et al.52 have many physiological and clinical implications. From the physiological standpoint, it demonstrates that hypertension through SPR can be induced by small elevations of circulating angiotensin that are inappropriate with the existing levels of extracellular fluid volume and reciprocally, it shows 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.

Acknowledgements

This work was supported by National Institutes of Health grant HL16496, Mayo Foundation, the American Heart Association grant 9740007N, National Institutes of Health

Program Project grant HL51971 and a grant from Fundacion Barcelo Argentina.

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Co-Authors:
Jane F. Reckelhoff, PhD.
Department of Physiology and Biophysics
and the Center for Excellence in Cardiovascular-Renal Research,
University of Mississippi Medical Center

Luis A. Juncos, M.D.
Department of Physiology and Biophysics
Mayo School of Medicine
and Division of Hypertension, Mayo Clinic

Address for Correspondence:
J. Carlos Romero, M.D.
Department of Physiology
Mayo Clinic
Rochester, MN 55905
telephone no. 507-284-2322
telefax no. 507-284-8566

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Update
10/19/99