This Article 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 Iadecola, C. Articles by Gorelick, P. B. Search for Related Content PubMed PubMed Citation Articles by Iadecola, C. Articles by Gorelick, P. B.

(Stroke. 2004;35:348.)
© 2004 American Heart Association, Inc.

Advances in Stroke 2003

Hypertension, Angiotensin, and Stroke: Beyond Blood Pressure

Costantino Iadecola, MD Philip B. Gorelick, MD, MPH, FACP

From the Division of Neurobiology (C.I.), Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY; and Stroke Service (P.B.G.), Department of Neurology and Rehabilitation, University of Illinois College of Medicine, Chicago, Ill.

Correspondence to C. Iadecola, MD, Division of Neurobiology, Weill Medical College of Cornell University, 411 East 69th St, KB410, New York, NY 10021. E-mail coi2001{at}med.cornell.edu

Key Words: Advances in Stroke • angiotensins • hypertension • stroke

Hypertension (HTN) is a major risk factor for all stroke subtypes, infarction as well as hemorrhage.^1,2 Evidence from clinical trials shows that control of blood pressure (BP) leads to a substantially lower risk of stroke.³ HTN exerts detrimental actions on the cerebral circulation that play a critical role in its ability to promote cerebrovascular diseases. Angiotensin II (Ang II) is a key mediator by which HTN exerts its deleterious vascular effects. Recent findings raise the possibility that some of the detrimental actions of Ang II are independent of the associated elevation in BP. Here we will discuss the effect of HTN on stroke in light of recent advances indicating that the renin angiotensin system (RAS) may a play a role greater than previously believed in the deleterious cerebrovascular actions of HTN and, as such, is a promising target for stroke prevention.

Hypertension Is a Major Risk Factor for Stroke

HTN is the most prevalent and powerful modifiable risk factor for stroke, irrespective of geographic region and ethnic group.^1,4 Persons with HTN are about 3 or 4 times more likely to have a stroke.² Whereas diastolic BP was once thought to be the most important predictor of stroke, the relationship between stroke and HTN may be stronger for systolic than for diastolic BP.⁵ The association between BP and stroke risk seems to occur on a continuum rather than as a threshold effect.⁶ The majority of strokes have been reported among persons with only "borderline" or "mild" HTN, and both persons classified as "hypertensive" as well as "normotensive" may benefit from BP lowering. Therefore, although the highest BP levels predict the highest relative risk of stroke, the conceptual pendulum has swung in the direction of the continuum of absolute BP levels and somewhat away from the construct of "hypertension" per se. Furthermore, as discussed below, recent evidence points to the fact that mediators of HTN, such as Ang II, may influence stroke risk independently of BP elevation.

Hypertension Has Profound Effects on the Cerebral Circulation

Why is HTN such a strong predictor of stroke risk? HTN exerts powerful effects on the cerebral circulation. In cerebral blood vessels, HTN produces hypertrophy and remodeling, defined as a reduction in the external diameter of the vessels.⁷ These proliferative changes increase vascular compliance and promote atherosclerosis.⁸ In addition, HTN alters the ability of endothelial cells to release vasoactive factors and increases the constrictor tone of systemic and cerebral arteries.⁹ HTN also alters cerebrovascular autoregulation, a property of cerebral arterioles that maintains cerebral blood flow (CBF) relatively constant despite variations in perfusion pressure within a certain range, usually 70 to 150 mm Hg.⁷ Chronic HTN shifts the autoregulated range toward higher pressures, rendering the brain more vulnerable to reductions in perfusion pressure.⁷ These structural and functional alterations increase the susceptibility of the brain to ischemic injury. For example, due to the shift in autoregulation and increased vascular compliance, the drop in perfusion pressure occurring distal to an occluded artery is likely to produce a greater reduction in CBF. Furthermore, the failure of endothelium-dependent relaxation impairs the ability of cerebral arterioles to dilate and supply collateral flow to the ischemic area.

Ang II Is a Major Causative Factor in the Cerebrovascular Effects of Hypertension

Ang II is a key mediator in the mechanisms of HTN.¹⁰ Ang II exerts its effects through specific G-protein–coupled receptors, 2 of which, AT1 and AT2, have been well characterized.¹¹ AT1 receptors mediate vasoconstriction, vascular proliferation, and inflammation, while AT2 receptors mediate vasodilatation, promote apoptosis, and inhibit proliferation.¹¹ Thus, AT1 receptors are thought to mediate the deleterious vascular effects of Ang II, while the AT2 receptors are potentially protective.¹¹ Ang II mimics some of the effect of HTN on cerebral blood vessels. Structurally, Ang II induces both cerebrovascular hypertrophy and remodeling.^12,13 Functionally, Ang II alters autoregulation, inhibits endothelium-dependent relaxation, and disrupts the blood-brain barrier.^14,15 Ang II also impairs the increase in CBF produced by neural activity.¹⁶ This phenomenon, termed functional hyperemia, is a critical adaptive mechanism by which the brain matches increased energy demands with increased delivery of substrates and removal of metabolic waste.¹⁷ The Ang II–induced impairment of functional hyperemia renders the brain more vulnerable to reductions in blood supply and more susceptible to cerebral ischemia. Some of the cerebrovascular effects of Ang II are independent of the elevation in BP. For example, remodeling of cerebral arteries occurs in hypertensive mice overexpressing human renin and angiotensinogen but not in BHP-2 mice, in which HTN is independent of RAS, while vascular hypertrophy is observed in both strains.¹² In addition, the alterations in endothelium-dependent relaxation and functional hyperemia are observed even if Ang II is applied directly on the cerebral cortex, bypassing systemic effects and HTN.^14,16 Thus, although Ang II is an important factor in the cerebrovascular correlates of HTN, some of its effects on cerebral blood vessels are independent of the elevation in BP.

Mechanisms of the Cerebrovascular Effect of Ang II

Activation of AT1 receptors by Ang II initiates a complex signaling cascade¹⁸ (Figure). Some but not all of the downstream effects of Ang II are mediated by reactive oxygen species (ROS) produced by the enzyme NADPH oxidase, a recently identified source of ROS in blood vessels.¹⁹ NADPH-derived ROS are responsible for the proliferative and pro-inflammatory effects of Ang II in the systemic circulation.¹⁹ Preliminary studies suggest that ROS, probably derived from NADPH oxidase, contribute also to the cerebrovascular effects of Ang II. The attenuation in functional hyperemia produced by Ang II is associated with free radical production and is rescued by free radical scavengers.²⁰ Furthermore, DPI, a flavoprotein inhibitor that blocks NADPH oxidase, prevents the attenuation of endothelium-dependent relaxation produced by Ang II in cerebral arterioles.¹⁴ Thus, NADPH-derived radicals may be an important pathogenic factor in the deleterious cerebrovascular effects of Ang II.

View larger version (38K): [in this window] [in a new window]   Effectors of Ang II-mediated signaling through AT1 receptors include kinases and transcription factors that are activated through ROS-dependent and independent pathways. Binding of Ang II to AT1 receptors leads to G protein Gq-induced activation of phospholipase C (PLC), which in turn increases intracellular Ca++ and activates protein kinase C (PKC).18 The major source of Ang II-derived ROS is NADPH oxidase, an enzyme composed of cytoplasmic and membrane-associated units that, on activation, assemble together and produce superoxide (O2-•).19 The assembly requires the tyrosine kinase c-Src and is critically dependent on the PKC-mediated phosphorylation of a serine residue in p47. Ang II signaling leads to vascular changes that increase the vulnerability of the brain to cerebral ischemia increasing the risk of stroke. AP-1 indicates activator protein 1; ERK1/2, extracellular regulated kinase 1/2; HIF1, hypoxia inducible factor 1; JNK, c-Jun N-terminal kinase; NFb, nuclear factor-kappa b; PI3K, phosphatidylinositol 3-kinase; STAT/JAK, signal transducer and activator of transcription/Janus kinase.

Beneficial Effects of RAS Inhibition Independent of BP Lowering

Although there is substantial epidemiological evidence that lowering of BP is associated with the reduction of stroke risk,² inhibition of RAS may have beneficial effects independent of BP. Recent clinical trials—Heart Outcomes Prevention Evaluation (HOPE), Perindopril Protection Against Recurrent Stroke Study (PROGRESS), Losartan Intervention for Endpoint Reduction in Hypertension study (LIFE), and Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)—provide new insights about possible non–BP lowering effects of RAS inhibition.^21–24 In HOPE, which featured the angiotensin-converting enzyme inhibitor (ACE-I) ramipril, there was modest BP lowering (3 mm Hg systolic and 2 mm Hg diastolic) compared with the placebo group, yet there was a 32% reduction in stroke.²² In PROGRESS, a trial designed as a BP lowering–type study,²³ there was a 28% reduction in recurrent stroke with the combination of the ACE-I perindopril and the thiazide-like diuretic indapamide. Although the reduction in stroke was generally greater as BP lowering increased, the higher-than-expected reduction of some cardiovascular disease outcomes, eg, nonfatal myocardial infarction, suggested beneficial non–BP lowering effects of the ACE-I.² In LIFE, there was greater reduction of stroke with the AT1 receptor blocker (AT1RB) losartan than with the beta-blocker atenolol, despite almost identical BP-lowering effects.²¹ The results of ALLHAT are more difficult to interpret because the findings were confounded by differences in BP lowering between the ACE-I (lisinopril), calcium channel blocker (amlodipine), and diuretic (chlorthalidone) treatment groups, with less BP lowering in the lisinopril group.^24,25 The results of these trials suggest that non–BP lowering effects of ACE-I and AT1RB may contribute to the reduction of stroke risk. Thus, BP-independent effects on cerebrovascular regulation and compliance, and, in the case of AT1RB, activation of potentially protective AT2 receptors, could play a role.

Conclusions

These basic and clinical findings indicate that BP, due to its profound effects on the cerebral circulation, is the most critical determinant of the risk of stroke. Therefore, it is unquestionable that reduction in BP should be the centerpiece of any strategy for stroke prevention. Any of the commonly used antihypertensive agents (ACE-Is, AT1RBs, calcium channel blockers, beta-blockers, diuretics) reduce the risk of stroke, with larger reductions in BP resulting in larger reduction in risk.²⁶ On the other hand, there is highly suggestive evidence from clinical trials that pharmacological strategies to inhibit the RAS reduce the risk of stroke beyond the degree expected from the reduction in BP. These clinical findings are supported by experimental evidence indicating that Ang II has powerful cerebrovascular effects unrelated to its ability to elevate BP. Therefore ACE-Is and AT1RBs may possess unique properties that influence reduction of stroke beyond BP lowering. More focused therapies targeting the mechanisms by which the RAS may increase the risk for stroke, such as inhibition of vascular NADPH oxidase, could more selectively counter the deleterious effects of Ang II, sparing the purported beneficial actions of AT2 receptor activation. However, in the clinical arena, the evidence for BP-related and unrelated stroke risk is not sufficiently strong to justify favoring the exclusive use of agents targeting the RAS system or its signaling pathways. Nevertheless, these new findings expand our views by emphasizing that agents involved in the mechanisms of cardiovascular diseases may exert their detrimental actions independently of their ability to elevate BP. This line of thinking may lead to new and more powerful treatments to limit the devastating cerebrovascular effects of HTN and its mediators.

Acknowledgments

This work was supported by NIH grants HL18974 (C.I.), NS38252 (C.I.), NS33430 (P.B.G.), and AG17934 (P.B.G.). Dr Iadecola is the recipient of a Javits award from NIH/NINDS.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.

Received November 28, 2003; accepted December 3, 2003.

References

1. Wolf PA. Hypertension. In: Norris J, Hachinski VC, eds. Stroke Prevention. New York: Oxford University Press; 2001: 93–105.
2. Gorelick PB. New horizons for stroke prevention: PROGRESS and HOPE. Lancet Neurol. 2002; 1: 149–156.[CrossRef][Medline] [Order article via Infotrieve]
3. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003; 289: 2560–2572.[Abstract/Free Full Text]
4. Wolf-Maier K, Cooper RS, Banegas JR, Giampaoli S, Hense HW, Joffres M, Kastarinen M, Poulter N, Primatesta P, Rodriguez-Artalejo F, et al. Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA. 2003; 289: 2363–2369.[Abstract/Free Full Text]
5. Staessen JA, Gasowski J, Wang JG, Thijs L, Den Hond E, Boissel JP, Coope J, Ekbom T, Gueyffier F, Liu L, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet. 2000; 355: 865–872.[CrossRef][Medline] [Order article via Infotrieve]
6. MacMahon S. Blood pressure and the risk of cardiovascular disease. N Engl J Med. 2000; 342: 50–52.[CrossRef][Medline] [Order article via Infotrieve]
7. Chillon JM, Baumbach GL. Autoregulation: arterial and intracranial pressure. In: Edvinsson L, Krause DN, eds. Cerebral Blood Flow and Metabolism. Philadelphia: Lippincott Williams & Wilkins; 2002: 395–412.
8. Ferrario CM. Use of angiotensin II receptor blockers in animal models of atherosclerosis. Am J Hypertens. 2002; 15: 9S–13S[CrossRef][Medline] [Order article via Infotrieve]
9. Faraci FM, Heistad DD. Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev. 1998; 78: 53–97.[Abstract/Free Full Text]
10. Reckelhoff JF, Romero JC. Role of oxidative stress in angiotensin-induced hypertension. Am J Physiol Regul Integr Comp Physiol. 2003; 284: R893–R912.[Abstract/Free Full Text]
11. Touyz RM, Schiffrin EL. Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacol Rev. 2000; 52: 639–672.[Abstract/Free Full Text]
12. Baumbach GL, Sigmund CD, Faraci FM. Cerebral arteriolar structure in mice overexpressing human renin and angiotensinogen. Hypertension. 2003; 41: 50–55.[Abstract/Free Full Text]
13. Chillon JM, Baumbach GL. Effects of an angiotensin-converting enzyme inhibitor and a beta-blocker on cerebral arteriolar dilatation in hypertensive rats. Hypertension. 2001; 37: 1388–1393.[Abstract/Free Full Text]
14. Didion SP, Faraci FM. Angiotensin II produces superoxide-mediated impairment of endothelial function in cerebral arterioles. Stroke. 2003; 34: 2038–2042.[Abstract/Free Full Text]
15. Saavedra JM, Nishimura Y. Angiotensin and cerebral blood flow. Cell Mol Neurobiol. 1999; 19: 553–573.[CrossRef][Medline] [Order article via Infotrieve]
16. Kazama K, Wang G, Frys K, Anrather J, Iadecola C. Angiotensin II attenuates functional hyperemia in the mouse somatosensory cortex. Am J Physiol Heart Circ Physiol. 2003; 285: H1890–H1899.[Abstract/Free Full Text]
17. Attwell D, Iadecola C. The neural basis of functional brain imaging signals. Trends Neurosci. 2002; 25: 621–625.[CrossRef][Medline] [Order article via Infotrieve]
18. Yan C, Kim D, Aizawa T, Berk BC. Functional interplay between angiotensin II and nitric oxide: cyclic GMP as a key mediator. Arterioscler Thromb Vasc Biol. 2003; 23: 26–36.[Abstract/Free Full Text]
19. Cai H, Griendling KK, Harrison DG. The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci. 2003; 24: 471–478.[CrossRef][Medline] [Order article via Infotrieve]
20. Kazama K, Anrather J, Wang G, Frys K, Iadecola C. Angiotensin II alters neurovascular coupling via production of reactive oxygen species. J Cereb Blood Flow Metab. 2003; 23 (suppl 1): 83.Abstract.
21. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359: 995–1003.[CrossRef][Medline] [Order article via Infotrieve]
22. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000; 342: 145–153.[Abstract/Free Full Text]
23. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001; 358: 1033–1041.[CrossRef][Medline] [Order article via Infotrieve]
24. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288: 2981–2997.[Abstract/Free Full Text]
25. Messerli FH. ALLHAT, or the soft science of the secondary end point. Ann Intern Med. 2003; 139: 777–780.[Abstract/Free Full Text]
26. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003; 362: 1527–1535.[CrossRef][Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				J. R. Jennings, M. F. Muldoon, J. Price, I. C. Christie, and C. C. Meltzer Cerebrovascular Support for Cognitive Processing in Hypertensive Patients Is Altered by Blood Pressure Treatment Hypertension, July 1, 2008; 52(1): 65 - 71. [Abstract] [Full Text] [PDF]

				H. Girouard, A. Lessard, C. Capone, T. A. Milner, and C. Iadecola The neurovascular dysfunction induced by angiotensin II in the mouse neocortex is sexually dimorphic Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H156 - H163. [Abstract] [Full Text] [PDF]

				K.-H. Jung, K. Chu, S.-T. Lee, S.-J. Kim, E.-C. Song, E.-H. Kim, D.-K. Park, D.-I. Sinn, J.-M. Kim, M. Kim, et al. Blockade of AT1 Receptor Reduces Apoptosis, Inflammation, and Oxidative Stress in Normotensive Rats with Intracerebral Hemorrhage J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1051 - 1058. [Abstract] [Full Text] [PDF]

				S. M. Greenberg Small Vessels, Big Problems N. Engl. J. Med., April 6, 2006; 354(14): 1451 - 1453. [Full Text] [PDF]

				K. Nakahata, H. Kinoshita, Y. Tokinaga, Y. Ishida, Y. Kimoto, M. Dojo, K. Mizumoto, K. Ogawa, and Y. Hatano Vasodilation Mediated by Inward Rectifier K+ Channels in Cerebral Microvessels of Hypertensive and Normotensive Rats Anesth. Analg., February 1, 2006; 102(2): 571 - 576. [Abstract] [Full Text] [PDF]

				D. H. Munzenmaier and A. S. Greene Chronic angiotensin II AT1 receptor blockade increases cerebral cortical microvessel density Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H512 - H516. [Abstract] [Full Text] [PDF]

				J. Andresen, N. I. Shafi, and R. M. Bryan Jr. Endothelial influences on cerebrovascular tone J Appl Physiol, January 1, 2006; 100(1): 318 - 327. [Abstract] [Full Text] [PDF]

				M. S.V. Elkind Implications of stroke prevention trials: Treatment of global risk Neurology, July 12, 2005; 65(1): 17 - 21. [Abstract] [Full Text] [PDF]

				T. E. Strandberg Editorial Comment: Secondary Prevention of Stroke Is Important: But All Hypertensive Drugs Are Not Created Equal? Stroke, June 1, 2005; 36(6): 1225 - 1226. [Full Text] [PDF]

				T. Ago, T. Kitazono, J. Kuroda, Y. Kumai, M. Kamouchi, H. Ooboshi, M. Wakisaka, T. Kawahara, K. Rokutan, S. Ibayashi, et al. NAD(P)H Oxidases in Rat Basilar Arterial Endothelial Cells Stroke, May 1, 2005; 36(5): 1040 - 1046. [Abstract] [Full Text] [PDF]

				K. Kazama, J. Anrather, P. Zhou, H. Girouard, K. Frys, T. A. Milner, and C. Iadecola Angiotensin II Impairs Neurovascular Coupling in Neocortex Through NADPH Oxidase-Derived Radicals Circ. Res., November 12, 2004; 95(10): 1019 - 1026. [Abstract] [Full Text] [PDF]

				I. Drenjancevic-Peric and J. H. Lombard Introgression of chromosome 13 in Dahl salt-sensitive genetic background restores cerebral vascular relaxation Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H957 - H962. [Abstract] [Full Text] [PDF]

				M. S.V. Elkind Implications of stroke prevention trials: Treatment of global risk Neurology, July 12, 2005; 65(1): 17 - 21. [Abstract] [Full Text] [PDF]

This Article 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 Iadecola, C. Articles by Gorelick, P. B. Search for Related Content PubMed PubMed Citation Articles by Iadecola, C. Articles by Gorelick, P. B.