Effects of Olmesartan on Endothelial Function

High Blood Press Cardiovasc Prev 2007; 14 (4): 221-227REVIEW ARTICLE 1120-9879/07/0004-0221/$44.95/0

© 2007 Adis Data Information BV. All rights reserved.

Effects of Olmesartan on Endothelial FunctionMassimo Volpe,1,2 Lorenzo Castello1 and Francesco Cosentino1

1 Department of Cardiology, II Faculty of Medicine, University of Rome “La Sapienza”, Rome, Italy2 IRCCS Neuromed – Pozzilli (Isernia), Isernia, Italy

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2211. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2212. The Renin-Angiotensin System and Endothelial Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2223. Effects of Olmesartan on Endothelial Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2224. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

It is well established that a functional endothelium contributes to maintain cardiovascular homeostasis mainlyAbstractthrough the activity of endothelium-derived nitric oxide (NO). However, in the presence of proatherogenic riskfactors including hypertension, diabetes mellitus and hypercholesterolaemia, the bioavailability of NO isreduced. This condition is defined as endothelial dysfunction and characterised by vasoconstriction, plateletaggregation, leucocyte adhesion and smooth muscle cell proliferation. A reduced availability of NO is mainlydue to an increase in reactive oxygen species (ROS) production, which is responsible for NO breakdown. A largebody of evidence indicates that, especially under pathological conditions, the activity of the renin-angiotensinsystem (RAS) is associated with angiotensin II (Ang II)-mediated ROS production, thus unbalancing endothelialfunction and leading to progressive vascular disease. The action of RAS is mostly linked to the downstreameffects of the binding with the Ang II subtype 1 receptors (AT1). Therefore, selective RAS blockade withangiotensin receptor blockers (ARBs) is able to restore endothelial function in patients with cardiovascular riskfactors. Olmesartan, an effective ARB, beyond its blood-pressure lowering effect, has been reported to affect theredox state of the vessel wall by restoring NO availability under different pathological conditions. Furthermore,it has been described that olmesartan exerts anti-inflammatory effects and increases endothelial progenitor cells.This article reviews the evidence linking olmesartan to vascular endothelial protection and examines thepossibility that this effect translates to beneficial clinical properties of this ARB.

Received for publication 2 October 2007; accepted for publication 26 October 2007.

Key words: nitric oxide, oxidative stress, endothelial dysfunction, angiotensin receptor blockers.

1. Background ponse to shear stress within the vasculature.[1] Indeed, pulsatileshear stress leads to an increased expression of endothelial NO

Endothelial cells (ECs) compose the inner single layer of the synthase (eNOS) responsible for NO production.[2] Once synthe-vessel wall directly in contact with blood flow. Structural and sised, NO diffuses through the endothelial membrane into smoothfunctional integrity of the endothelium is of particular importance muscle cells (SMCs) where it activates soluble guanylate cyclase.in maintaining vascular homeostasis under both physiological and As a result, intracellular concentration of cyclic guanosine mono-pathological conditions. ECs exert local control of vascular tone phosphate (cGMP) increases allowing SMCs relaxation and inhi-and blood flow through the release of nitric oxide (NO) in res- bition of platelet adhesion and aggregation.[3] Indeed, ECs re-

222 Volpe et al.

present a non-thrombogenic barrier between blood and vesselwall, regulating platelet and monocyte adhesion to the intimalayer.[4,5] Moreover, EC-derived NO inhibits proliferation andmigration of SMCs and type I and III collagen synthesis.[6,7] Takentogether, this evidence clearly indicates the central role of NO indetermining vascular homeostasis. A reduced NO bioavailabilityis commonly referred as ‘endothelial dysfunction’. This termdefines a pathophysiological condition associated with majorcardiovascular risk factors[8-12] and is characterised by the produc-tion of an array of vasoactive factors exerting opposite effects(endothelin-1 [ET-1], angiotensin II [Ang II], vasoconstrictorprostanoids, reactive oxygen species [ROS]), which, in the pres-ence of a dysfunctional state, become the mediator of vascular

AT1

COX

PGH2TXA2

ET-1

SMC constriction SMC relaxation

NADPH ox

ROS

AT2

NOS

NO

Ang II

−

−

Fig. 1. Relationship between the renin-angiotensin system and endothelialdysfunction. Ang II = angiotensin II; AT1 = angiotensin II subtype 1 recep-tor; AT2 = angiotensin II subtype 2 receptor; COX = cyclo-oxygenase; ET-1= endothelin-1; NADPH ox = the reduced form of nicotinamide-adeninedinucleotide phosphate oxidase; NO = nitric oxide; NOS = nitric oxidesynthase; PGH2 = prostaglandin H2; ROS = reactive oxygen species; SMC= smooth muscle cell; TXA2 = thromboxane A2.

damage. Although the precise mechanisms leading to endothelialbeen reported that in an experimental model of Ang II-induceddysfunction are not well established, it has been shown that aendothelial dysfunction, blockade of AT1 restores vascular NOdecreased NO bioavailability might be induced by an excessiverelease and reduces cyclo-oxygenase-dependent generation of vas-production of ROS leading to NO breakdown. The term ‘oxidativeoconstrictor prostanoids, improving acetylcholine-induced vasodi-stress’ defines an impairment of the balance between the genera-lation.[23] Moreover, in the presence of AT1 blockade, Ang II maytion of ROS and their inactivation by antioxidant scavenger sys-activate AT2 subtype receptors, which exert a direct stimulatingtems.[13] In this setting, superoxide anion (O2–) is the main inac-effect on NO synthesis.[24] Similarly, in spontaneously hyperten-tivator of NO, which promptly reacts with NO leading to thesive rats, it has been shown that long-term blockade of AT1 withformation of peroxynitrite (ONOO–), a powerful oxidant responsi-losartan is associated with AT2-dependent NO production, in-ble for cellular toxicity. A better understanding of oxidative stressduced by Ang II.[15,16] The observed crosstalk between Ang IIas the main mechanism responsible for endothelial dysfunctionreceptor subtypes may play an important role in the primaryprovides a pathophysiological rationale for the implementation ofprevention of hypertension-related vascular complications (ath-several therapeutic strategies that may exert an antioxidant effect.erosclerosis and target organ damage).[25] In this regard, recentdata obtained in the human microvasculature confirm that AT12. The Renin-Angiotensin System andselective blockade with AT1 blocker unmasks Ang II-mediatedEndothelial Functionvasorelaxation that is strictly linked to an upregulation of AT2,which, in turn, is mediated via a bradykinin/NO/cGMP path-The tight connection between the action of Ang II and theway.[17]

progressive development of vascular disease was first describedmore than 30 years ago.[14] In the last three decades, the availabili-ty of experimental models[15,16] and of drugs inhibiting the renin- 3. Effects of Olmesartan on Endothelial Functionangiotensin system (RAS) has permitted further clarification ofsome key features of the pathogenic role of Ang II in vascular This section will focus on the evidence available in the litera-disease.[17] Much of the close relationship between RAS activity ture demonstrating the vascular protective effect of olmesartan inand vascular pathological abnormalities has been attributed to both animal models and humans. Table I summarises mechanismsendothelial dysfunction, as schematically shown in figure 1. Ang through which olmesartan medoxomil may protect vessels.II, through its preferential binding to angiotensin II subtype 1 The evidence discussed in section 2 supports the rationale forreceptor (AT1), stimulates ECs to release ET-1, one of the most using AT1 blockers (ARBs) to restore endothelial function inpotent vasoconstrictor peptides, vasoconstrictor prostanoids (pros- patients with high cardiovascular risk. In agreement with animaltaglandin H2 and thromboxane A2) and may inhibit NOS activity studies, it has been shown that hypertensive patients treated withvia activation of protein kinase C.[18-20] ARBs show a decrease in oxidative stress, inflammation and

Further evidence suggests that ET-1 enhances Ang II-mediated endothelial dysfunction.[42] For example, treatment with losartanROS generation within endothelial cells and SMCs.[21,22] It has improves flow-mediated dilation in peripheral arteries by restoring

© 2007 Adis Data Information BV. All rights reserved. High Blood Press Cardiovasc Prev 2007; 14 (4)

Olmesartan and Endothelial Function 223

NO bioavailability in atherosclerotic arteries.[43-45] Furthermore, ous mechanisms including a decrease in adiponectin level.[46] Inview of its anti-atherogenic, anti-diabetic and anti-inflammatorythe evidence accumulated with olmesartan medoxomil highlightsproperties, adiponectin is emerging in recent years as a novelthe protective properties of this compound on endothelial function.marker of cardiovascular risk.[47] Recent findings have shown aIn an ET-1-induced hypertension rat model, the treatment withbeneficial role of olmesartan in restoring adiponectin levels in

olmesartan is able to prevent the development of both hyperten-adipose tissue. The AT1 blocker reduces the reduced form of

sion and ROS formation. This finding demonstrates that activationnicotinamide adenine dinucleotide phosphate (NADPH)-oxidase

of RAS, induced by long-term infusion of ET-1, can be preventedexpression affecting ROS generation and, hence, restoring the

by treatment with olmesartan.[26] Consistent results have beenbalance in favour of protective adipocytokines. Furthermore, treat-

obtained in rats with NG-nitro-L-arginine methyl ester (L-ment with olmesartan may also prevent the reduction of adiponec-

NAME)-induced hypertension.[31] In this model, the simultaneoustin levels in obese mice. This effect is, at least in part, occurring

administration of olmesartan lowered blood pressure and resultedthrough its anti-oxidative effect.[34]

in a significant increase of NO availability. The data, however,Further reports on the antioxidative properties of olmesartanclearly suggested a vascular protective role of olmesartan that goes

medoxomil are also available in the diabetic nephropathy. Inbeyond blood-pressure effects. Interestingly, nitroglycerine-asso-different animal models, this compound has been shown to reduceciated increase of ROS generation can also be prevented by theROS generation through the inhibition of NADPH oxidase expres-administration of olmesartan.[27] Another line of evidence generat-sion.[28]

ed by a different experimental approach also supports the benefi-

cial effects of olmesartan medoxomil on endothelial function. As far as human studies are concerned, increased plasma levelsVisceral obesity may elicit endothelial dysfunction through vari- of 8-isoprostane 15(S)-8-iso-prostaglandin F2α and the intrarenal

Table I. Mechanisms through which olmesartan medoxomil exerts a protective action on vascular structure and function

Action Biological effect Model References

↓ ROS formation ↓ Oxidative stress Rat, rabbit 26,27

↓ NADPH oxidase expression ↓ ROS formation and oxidative stress Mouse 28

↓ Plasmatic 8-isoprostane ↓ Oxidative stress Human 29

↓ Plasmatic oxidised albumin ↓ Oxidative stress Human 30

↑ NO availability Vascular homeostasis Rat 31

SMCs relaxation

inhibition of PLT activation

inhibition of SMCs proliferation

inhibition of type I/III collagen synthesis

↓ CRP, TNFα, IL-6, MCP, fibrinogen ↓ Inflammation Human 32,33

↑ Adiponectin Anti-atherogenic/diabetic/inflammatory activity Mouse 34

↓ Lipid deposition and adhesion molecules ↓ Atherosclerosis Monkey 35

↓ Macrophage accumulation ↓ Atherosclerosis Monkey, mouse 35,36

↓ Intimal volume/total aortic ratio ↓ Atherosclerosis Monkey 35

↓ Wall-to-lumen ratio ↓ Atherosclerosis Human 37

↓ IMT ↓ Atherosclerosis Human 38

↓ Plaque volume ↓ Atherosclerosis Human 38

↑ Number of EPCs ↑ Stem cell mobilization Mouse 39

↓ Expression of Ang II-stimulated VEGF ↓ Pathological angiogenesis ECs 40,41

Ang II = angiotensin II; CRP = C-reactive protein; ECs = endothelial cells; EPCs = endothelial progenitor cells; IL-6 = interleukin-6; IMT = intima-media

thickness; MCP = monocyte chemotactic protein; NADPH = the reduced form of nicotinamide-adenine dinucleotide phosphate; NO = nitric oxide; PLT =

platelet; ROS = reactive oxygen species; SMCs = smooth muscle cells; TNFα = tumour necrosis factor-α; VEGF = vascular endothelial growth factor; ↓indicates decrease; ↑ indicates increase.


224 Volpe et al.

vascular resistance in patients with type 2 diabetes mellitus are kidney disease characterised by a chronic inflammatory state,reduced by long-term treatment with olmesartan medoxomil.[29] olmesartan has been shown to be effective in blunting markersConsistent results have also been obtained in haemodialysis pa- such as CRP and fibrinogen.[33]

tients treated with olmesartan. In these patients, a lower amount of It is well known that both vascular inflammation and endotheli-oxidised albumin (marker of oxidative stress) was found.[30] Alto- al dysfunction contribute to the development of atherosclerosisgether, these findings support the concept of a crucial role of within the vascular system.[54-56] In this regard, the putative role ofoxidative stress played in the pathogenesis of diabetic nephropathy selective blockade of AT1 in preventing or restoring atherosclero-and highlight that the renal protection provided by olmesartan is sis has been evaluated with several studies using olmesartanpartially independent from its effect on blood pressure and appar- medoxomil. It has been reported that olmesartan reduces lipidently due to its potent antioxidative action. It has been suggested deposition, chemokines and adhesion molecules, and inhibits mac-that the antioxidant activity of olmesartan is probably related to the rophage accumulation in the intima layer in monkeys fed a high-molecular core structure of the drug and, hence, to the strong cholesterol diet, also improving acetylcholine-induced relaxation,insurmountable binding to AT1.[48] However, other mechanisms and ultimately reducing intimal volume/total aortic ratio.[35] Theare probably involved in the anti-oxidative activity of olmesartan, protective effect of such a compound has been shown in thesuch as the putative modulation of NADPH oxidase activity, and development of atherosclerotic lesions of the aortic valve in rab-need to be further addressed. bits fed a hypercholesterolaemic diet.[57] Olmesartan decreases

Beyond its anti-oxidative effect, olmesartan contributes to pro- macrophage accumulation and osteopontin expression in valvevide endothelial protection also through a strong anti-inflamma- leaflets. Moreover, it warrants valvular endothelium integrity,tory activity within the vascular system. The pro-inflammatory threatened by dietary cholesterol and inhibits endothelial cellsproperties of Ang II via an enhanced release of inflammatory trans-differentiation into myofibroblasts and/or osteoblasts in leaf-cytokines and expression of adhesion molecules are well establish- lets. Kato et al.[36] confirmed these findings in apolipoprotein E-ed.[49,50] Indeed, Ang II activates the nuclear transcription factor deficient mice fed a high-cholesterol diet. These results remark thekappa B (NF-κB) leading to expression of leucocyte adhesion effective anti-atherosclerotic activity of olmesartan even in dysli-molecules, tumour necrosis factor-α (TNFα), monocyte chemo- pidaemic settings. Subjects with elevated high-density lipoproteintactic protein (MCP), interleukin-6 (IL-6) and recruitment of (HDL) have been reported to have a better vasodilator and a lowermononuclear leucocytes into vascular walls.[51] Through these vasoconstrictor response as compared with lower HDL due to theactions, Ang II promotes both vascular inflammation and endothe- atheroprotective role of HDL.[58] Indeed, by interacting with alial dysfunction, triggering the development of atherosclerosis. scavenger receptor of the BI class (hSR-BI/CLA-1), HDL acti-

vates eNOS, thus increasing the level of NO production within theBased on these premises, the anti-inflammatory effect of thisvascular system.[59] Another line of evidence shows that the ex-ARB was evaluated in hypertensive patients in EUTOPIApression of hSR-BI/CLA-1 is suppressed by exposure to Ang II(EUropean Trial on Olmesartan and Pravastatin in Inflammationand that olmesartan effectively inhibits such repression.[60]and Atherosclerosis).[32] After 6 weeks of treatment with

olmesartan, several markers of inflammation (e.g. high-sensitivity Therefore, taken together, these findings suggest that olmesar-C-reactive protein [CRP], TNFα, IL-6 and MCP) were measured tan provides protection against developing atherosclerosis by act-and the values obtained were compared with those of the placebo ing at different levels from inhibiting plaque formation to thegroup. Olmesartan significantly reduced the levels of the in- regression of existing lesions. These results have been confirmedflammatory markers, whereas placebo did not. Among these para- in VIOS[37,61] (Vascular Improvement with Olmesartan medox-meters, CRP seems to play a major role in the atherogenic process. omil Study) showing that olmesartan, but not atenolol, reduces theIndeed, CRP favours expression of adhesion molecules on endo- wall-to-lumen ratio in small resistance arteries of hypertensivethelial cells. Moreover, CRP may enhance IL-6 and lower NO subjects after 1 year of treatment. The effect of ARBs on smallbioavailability within endothelial cells.[52,53] These findings further resistance peripheral vessels could be extended to other sites suchunderline a putative strong protective role of olmesartan in as the myocardium and renal glomeruli, suggesting an importantpreventing atherosclerosis-related cardiovascular disease besides systemic protection provided by this compound in terms of targetits blood-pressure lowering effect. Olmesartan has been recently organ damage. The MORE (Multicenter Olmesartan atherosclero-reported to be effective in reducing some inflammatory markers, sis Regression Evaluation) study[38] was designed to compare thesuch as CRP and fibrinogen. Accordingly, in patients with chronic effects of olmesartan versus atenolol on intima-media thickness



(IMT) of the common carotid artery and the volume of atheroscle- section 3, previous reports have demonstrated the capability ofrotic plaques in hypertensive patients. Both drugs achieved quite olmesartan to restore endothelial function, measured as increasedcomparable blood-pressure lowering effects and reductions in NO bioavailability. Evidence also highlights the positive action ofIMT; however, the plaque volume was significantly lower only in olmesartan in the setting of target organ damage, particularly inthe olmesartan arm. This suggests that olmesartan may be effec- post-ischaemic left ventricular remodelling.[72] Such a pleiotropictive in the reduction of atherosclerosis progression independent or effect of olmesartan represents the rationale to choose the com-in addition to its blood-pressure lowering action. pound particularly in high-risk patients in whom a simple blood-

pressure lowering effect may not be sufficient to prevent cardio-Endothelial dysfunction is significantly correlated with a re-vascular events.duced number of endothelial progenitor cells (EPCs).[62] The EPCs

play a crucial role in the endothelial repair process.[63,64] Indeed,they guarantee the re-endothelialisation of damaged vessel walls Acknowledgementsmainly contributing to the process of vascular repair.[65,66] In orderto determine whether olmesartan exerts a beneficial effect on No sources of funding were used to assist in the preparation of this review.EPCs growth and proliferation, diabetic mice were treated either The authors have no conflicts of interest that are directly relevant to the

content of this review.with olmesartan or placebo for 12 weeks. The mice receivingolmesartan showed an increased number of EPCs as comparedwith controls.[39] These results indicate a potentially favourable

Referencesaction of olmesartan on stem cell mobilisation. On the other hand,

1. Vallance P, Chan N. Endothelial function and nitric oxide: clinical relevance. Heartolmesartan seems also to provide effective protection against 2001; 85: 342-50

2. Marsden PA, Heng HH, Scherer SW, et al. Structure and chromosomal localizationpathological angiogenesis. In this regard, there is also evidenceof the human constitutive endothelial nitric oxide synthase gene. J Biol Chem

that olmesartan inhibits the expression of Ang II-stimulated vascu- 1993; 268 (23): 17478-883. Radomski MW, Palmer RM, Moncada S. The anti-aggregating properties oflar endothelial growth factor in in vitro endothelial cells via a

vascular endothelium: interactions between prostacyclin and nitric oxide. Br Jdecrease in NADPH-oxidase-mediated ROS generation.[40,41] Oth-Pharmacol 1987; 92: 639-46

er data about the putative role of olmesartan in reducing angio- 4. De Caterina R, Libby P, Peng HB, et al. Nitric oxide decreases cytokine-inducedendothelial activation: nitric oxide selectively reduces endothelial expression ofgenesis have demonstrated that olmesartan may blunt advancedadhesion molecules and proinflammatory cytokines. J Clin Invest 1995; 96:

glycation end-product-induced angiogenesis by suppressing the 60-85. Gauthier TW, Scalia R, Murohara T, et al. Nitric oxide protects against leukocyte-interaction with their receptors in cultured vascular endothelial

endothelium interactions in the early stages of hypercholesterolemia. Arterios-cells.[67] Such an effect could be important in the treatment of cler Thromb Vasc Biol 1995; 15: 1652-9proliferative diabetic retinopathy. 6. Jeremy JY, Rowe D, Emsley AM, et al. Nitric oxide and the proliferation of

vascular smooth muscle cells. Cardiovasc Res 1999; 43: 580-947. Dubey RK, Jackson EK, Luscher TF. Nitric oxide inhibits angiotensin II-induced

migration of rat aortic smooth muscle cell: role of cyclic-nucleotides and4. Conclusionsangiotensin1 receptors. J Clin Invest 1995; 96: 141-9

8. Galle J, Mulsch A, Busse R, et al. Effects of native and oxidized low densityThe use of ARBs in clinical practice is constantly increasing lipoproteins on formation and inactivation of endothelium-derived relaxing

factor. Arterioscler Thromb 1991; 11: 198-203over time probably due to the additional evidence about their9. Cosentino F, Hishikawa K, Katusic ZS, et al. High glucose increases nitric oxide

beneficial effects on cardiovascular system health. In this context, synthase expression and superoxide anion generation in human aortic endothe-lial cells. Circulation 1997; 96: 25-8the evidence progressively accumulated on olmesartan medoxomil

10. Williams SB, Cusco JA, Roddy MA, et al. Impaired nitric oxide-mediated vasodi-suggests significant protective properties at the vascular wall level.lation in patients with non-insulin-dependent diabetes mellitus. J Am Coll

Indeed, it provides effective vascular protection by favouring Cardiol 1996; 27: 567-7411. Panza JA, Garcia CE, Kilcoyne CM, et al. Impaired endothelium-dependentendothelial function, independently of its strong antihypertensive

vasodilation in patients with essential hypertension: evidence that nitric oxideeffect. This limits oxidative stress, vascular inflammation and cell abnormality is not localized to a single signal transduction pathway. Circulation

1995; 91: 1732-8proliferation leading to the development of atherosclerosis, the12. Michael Pittilo R. Cigarette smoking, endothelial injury and cardiovascular dis-common pathophysiological mechanism of cardiovascular dis-

ease. Int J Exp Pathol 2000; 81: 219-30ease. Furthermore, endothelial dysfunction has been reported to 13. Moslen MT. Reactive oxygen species in normal physiology, cell injury and

phagocytosis. In: Armstrong D, editor. Free radicals in diagnostic medicine.directly correlate with the occurrence of cardiovascular events,New York: Plenum Press, 1994: 17-27

thus representing a strong marker of global cardiovascular risk 14. Gavras H, Brunner HR, Laragh JH. Renin and aldosterone and the pathogenesis ofand, hence, a potential therapeutic target.[68-71] As mentioned in hypertensive vascular damage. Prog Cardiovasc Dis 1974; 17 (1): 39-49


226 Volpe et al.

15. Cosentino F, Savoia C, De Paolis P, et al. Angiotensin II type 2 receptors contribute VIOS study): rationale and baseline characteristics. Am J Cardiovasc Drugsto vascular responses in spontaneously hypertensive rats treated with angioten- 2006; 6 (5): 335-42sin II type 1 receptor antagonists. Am J Hypertens 2005; 18: 493-9 38. Stumpe K. The Multicentre Olmesartan atherosclerosis Regression Study

16. Savoia C, Ebrahimian T, He Y, et al. Angiotensin II/AT2 receptor-induced vasodi- (MORE). Oral presentation at satellite symposium entitled plaque, vascularlation in stroke-prone spontaneously hypertensive rats involves nitric oxide and structure and angiotensin receptor blockade, held at the World Congress ofcGMP-dependent protein kinase. J Hypertens 2006; 24: 2417-22 Cardiology; 2006 Sep 2-6; Barcelona

17. Savoia C, Touyz RM, Volpe M, et al. Angiotensin type 2 receptor in resistance 39. Bahlmann FH, de Groot K, Mueller O, et al. Stimulation of endothelial progenitorarteries of type 2 diabetic hypertensive patients. Hypertension 2007; 49 (2): cells: a new putative therapeutic effect of angiotensin II receptor antagonists.341-6 Hypertension 2005; 45 (4): 526-9

18. Schiffrin EL. Endothelin and endothelin antagonists in hypertension. J Hypertens 40. Yamagishi S, Matsui T, Nakamura K, et al. Pigment-epithelium-derived factor1998; 16: 1891-5 (PEDF) inhibits angiotensin-II-induced vascular endothelial growth factor

(VEGF) expression in MOLT-3 T cells through anti-oxidative properties.19. Hahn AW, Resink TJ, Scott-Burden T, et al. Stimulation of endothelin mRNA andMicrovasc Res 2006; 71 (3): 222-6secretion in rat vascular smooth muscle cells: a novel autocrine function. Cell

Regul 1990; 1: 649-59 41. Takahashi S, Nakamura Y, Nishijima T, et al. Essential roles of angiotensin II invascular endothelial growth factor expression in sleep apnea syndrome. Respir20. Harrison DG, Venema RC, Arnal JF, et al. The endothelial cell nitric oxideMed 2005; 99 (9): 1125-31synthase: is it really constitutively expressed? Agents Actions Suppl 1995; 45:

107-17 42. Koh KK, Ahn JY, Han SH, et al. Pleiotropic effects of angiotensin II receptorblocker in hypertensive patients. J Am Coll Cardiol 2003; 42: 905-1021. Duerrschmidt N, Wippich N, Goettsch W, et al. Endothelin-1induces NAD(P)H

oxidase in human endothelial cells. Biochem Biphys Res Commun 2000; 269: 43. Prasad A, Tupas-Habib T, Schenke WH, et al. Acute and chronic angiotensin-1713-7 receptor antagonism reverses endothelial dysfunction in atherosclerosis. Circu-

lation 2000; 101: 2349-5422. Sedeek MH, Llinas MT, Drummond H, et al. Role of reactive oxygen species inendothelin-induced hypertension. Hypertension 2003; 42: 806-10 44. Hornig B, Landmesser U, Kohler C, et al. Comparative effect of ace inhibition and

angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in23. Li P, Ferrario CM, Brosnihan KB. Losartan inhibits thromboxane A2-inducedpatients with coronary artery disease: role of superoxide dismutase. Circulationplatelet aggregation and vascular constriction in spontaneously hypertensive2001; 103: 799-805rats. J Cardiovasc Pharmacol 1998; 32: 198-205

45. Prasad A, Halcox JP, Waclawiw MA, et al. Angiotensin type 1 receptor antagonism24. Wiemer G, Scholkens BA, Wagner A, et al. The possible role of angiotensin IIreverses abnormal coronary vasomotion in atherosclerosis. J Am Coll Cardiolsubtype AT2 receptors in endothelial cells and isolated ischemic rat hearts. J2001; 38: 1089-95Hypertens Suppl 1993; 11: S234-5

46. Wiecek A, Kokot F, Chudek J, et al. The adipose tissue-a novel endocrine organ of25. Volpe M, Musumeci B, De Paolis P, et al. Angiotensin II AT2 receptor subtype: aninterest to the nephrologist. Nephrol Dial Transplant 2002; 17 (2): 191-5uprising frontier in cardiovascular disease? J Hypertens 2003; 21 (8): 1429-43

47. Pischon T, Girman CJ, Hotamisligil GS, et al. Plasma adiponectin levels and risk of26. Yao L, Kobori H, Rahman M, et al. Olmesartan improves endothelin-inducedmyocardial infarction in men. JAMA 2004; 291 (14): 1730-7hypertension and oxidative stress in rats. Hypertens Res 2004; 27 (7): 493-500

48. Miyata T, van Ypersele de Strihou C, Ueda Y, et al. Angiotensin II receptor27. Yamamoto T, Kajikuri J, Watanabe Y, et al. Chronic nitroglycerine administrationantagonists and angiotensin-converting enzyme inhibitors lower in vitro thereduces endothelial nitric oxide production in rabbit mesenteric resistanceformation of advanced glycation end products: biochemical mechanisms. J Amartery. Br J Pharmacol 2005; 146 (4): 534-42Soc Nephrol 2002; 13: 2478-8728. Sonta T, Inoguchi T, Matsumoto S, et al. In vivo imaging of oxidative stress in the

49. Mervaala EM, Muller DN, Park JK, et al. Monocyte infiltration and adhesionkidney of diabetic mice and its normalization by angiotensin II type 1 receptormolecules in a rat model of high human renin hypertension. Hypertension 1999;blocker. Biochem Biophys Res Commun 2005; 330 (2): 415-2233 (1 Pt 2): 389-9529. Fliser D, Wagner KK, Loos A, et al. Chronic angiotensin II receptor blockade

50. Brasier AR, Recinos A, Eledrisi MS. Vascular inflammation and the renin-reduces (intra)renal vascular resistance in patients with type 2 diabetes. J Amangiotensin system. Arterioscler Thromb Vasc Biol 2002; 22 (8): 1257-66Soc Nephrol 2005; 16 (4): 1135-40

51. Takai S, Miyazaki M. Effect of olmesartan medoxomil on atherosclerosis: clinical30. Kadowaki D, Anraku M, Tasaki Y, et al. Effect of olmesartan on oxidative stress inimplications of the emerging evidence. Am J Cardiovasc Drugs 2006; 6 (6):hemodialysis patients. Hypertens Res 2007; 30: 395-402363-631. Kanematsu Y, Tsuchiya K, Ohnishi H, et al. Effects of angiotensin II receptor

52. Verma S, Wang CH, Li SH, et al. A self-fulfilling prophecy: C-reactive proteinblockade on the systemic blood nitric oxide dynamics in Nω-nitro-L-arginineattenuates nitric oxide production and inhibits angiogenesis. Circulation 2002;methyl ester treated rats. Hypertens Res 2006; 29: 369-74106 (8): 913-932. Fliser D, Buchholz K, Haller H. Antiinflammatory effects of angiotensin II subtype

53. Venugopal SK, Devaraj S, Yuhanna I, et al. Demonstration that C-reactive protein1 receptor blockade in hypertensive patients with microinflammation. Circula-decreases eNOS expression and bioactivity in human aortic endothelial cells.tion 2004; 110 (9): 1103-7Circulation 2002; 106 (12): 1439-4133. de Vinuesa SG, Goicoechea M, Kanter J, et al. Insulin resistance, inflammatory

biomarkers, and adipokines in patients with chronic kidney disease: effects of 54. Vane JR, Anggard EE, Botting RM. Regulatory functions of the vascular endothe-angiotensin II blockade. J Am Soc Nephrol 2006; 17: S206-12 lium. N Engl J Med 1990; 323 (1): 27-36

34. Kurata A, Nishizawa H, Kihara S, et al. Blockade of angiotensin II type-1 receptor 55. Bevilacqua MP. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol.reduces oxidative stress in adipose tissue and ameliorates adipocytokine dys- 1993; 11: 767-804regulation. Kidney Int 2006; 70 (10): 1717-24 56. Pedrinelli R, Giampietro O, Carmassi F, et al. Microalbuminuria and endothelial

35. Takai S, Jin D, Sakaguchi M, et al. The regressive effect of an angiotensin II dysfunction in essential hypertension. Lancet 1994; 344 (8914): 14-8receptor blocker on formed fatty streaks in monkeys fed a high-cholesterol diet. 57. Arishiro K, Hoshiga M, Negoro N, et al. Angiotensin receptor-1 blocker inhibitsJ Hypertens 2005; 23 (10): 1879-86 atherosclerotic changes and endothelial disruption of the aortic valve in

36. Kato M, Sada T, Chuma H, et al. Severity of hyperlipidemia does not affect hypercholesterolemic rabbits. J Am Coll Cardiol 2007; 49 (13): 1482-9antiatherosclerotic effect of an angiotensin II receptor antagonist in apoli- 58. Zeiher AM, Schachlinger V, Hohnloser SH, et al. Coronary atherosclerotic wallpoprotein E-deficient mice. J Cardiovasc Pharmacol 2006; 47 (6): 764-9 thickening and vascular reactivity in humans: elevated high-density lipoprotein

37. Smith RD, Yokoyama H, Averill DB, et al. The protective effects of angiotensin II levels ameliorate abnormal vasoconstriction in early atherosclerosis. Circula-blockade with olmesartan medoxomil on resistance vessel remodeling (the tion 1994; 89 (6): 2525-32



59. Yuhanna IS, Zhu Y, Cox BE, et al. High-density lipoprotein binding to scavenger 68. Suwaidi JA, Hamasaki S, Higano ST, et al. Long-term follow-up of patients withreceptor-BI activates endothelial nitric oxide synthase. Nat Med 2001; 7 (7): mild coronary artery disease and endothelial dysfunction. Circulation 2000;853-7

101: 948-5460. Yu X, Murao K, Imachi H, et al. Regulation of scavenger receptor class BI gene

69. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilatorexpression by angiotensin II in vascular endothelial cells. Hypertension 2007;49 (6): 1378-84 dysfunction on adverse long-term outcome of coronary heart disease. Circula-

61. Smith R, Yokoyama H, Averill D, et al. The relative effects of renin angiotensin tion 2000; 101: 1899-906system and the adrenergic system on vascular remodelling [abstract]. J

70. Neunteufl T, Heher S, Katzenschlager R, et al. Late prognostic value of flow-Hypertens 2005; 23 Suppl. 2: S15

mediated dilation in the brachial artery of patients with chest pain. Am J Cardiol62. Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells,2000; 86: 207-10vascular function, and cardiovascular risk. N Engl J Med 2003; 348: 593–600

63. Takahashi T, Kalka C, Masuda H, et al. Ischemia- and cytokine-induced mobiliza- 71. Halcox JP, Schenke WH, Zalos G, et al. Prognostic value of coronary vasculartion of bone marrow-derived endothelial progenitor cells for neovasculariza-

endothelial dysfunction. Circulation 2002; 106: 653-8tion. Nat Med 1999; 5 (4): 434-8

72. Kanamori H, Takemura G, Li Y, et al. Inhibition of Fas-associated apoptosis in64. Asahara T, Masuda H, Takahashi T, et al. Bone marrow origin of endothelialprogenitor cells responsible for postnatal vasculogenesis in physiological and granulation tissue cells accompanies attenuation of postinfarction left ventricu-pathological neovascularization. Circ Res 1999; 85: 221-8 lar remodeling by olmesartan. Am J Physiol Heart Circ Physiol 2007; 292 (5):

65. Rehman J, Li J, Orschell CM, et al. Peripheral blood ‘endothelial progenitor cells’H2184-94

are derived from monocyte/macrophages and secrete angiogenic growth fac-tors. Circulation 2003; 107: 1164-9

66. Urbich C, Heeschen C, Aicher A, et al. Relevance of monocytic features forCorrespondence: Prof. Massimo Volpe, Sant’Andrea Hospital, II Faculty ofneovascularization capacity of circulating endothelial progenitor cells. Circula-

tion 2003; 108: 2511-6 Medicine, University of Rome “La Sapienza”, Via di Grottarossa 1035,67. Yamagishi SI, Matsui T, Nakamura K, et al. Olmesartan blocks advanced glycation

00189 Rome, Italy.end products (AGEs)-induced angiogenesis in vitro by suppressing receptor forE-mail: [email protected] (RAGE) expression. Microvasc Res. Epub 2007 May 18


Effects of Olmesartan on Endothelial Function

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