Angiotensin II receptor blockers (ARBs) may produce a number of molecule-specific effects that appear to be independent of interaction with the angiotensin II type 1 (AT 1)-receptor. These include antagonism of the thromboxane A2 receptor, inhibition of platelet aggregation, induction of peroxisome proliferator-activated receptor gamma (PPARγ) activity, and reduction of serum uric acid levels. However, definitive evidence is lacking that these molecule-specific effects give rise to a therapeutic advantage of one ARB over another. Currently, the possibility of a link between a molecule-specific effect of an ARB and an improvement in clinical outcomes is best illustrated by a reduction in serum uric acid levels with losartan. Data from Losartan Intervention For Endpoint reduction in hypertension (LIFE) study suggest treatment-induced decrease in serum uric acid may contribute to the treatment benefit of a losaran-based versus atenolol-based therapy on the composite endpoint (death, myocardial infarction, or stroke). This finding should prompt further studies to investigate the long-term cardioprotective benefits issue of reducing hyperuricaemia in hypertensive patients.
Ferrario C., Abdelhamed AI, Moore M.AII antagonists in hypertension, heart failure, and diabetic nephropathy: focus on losartan. Curr Med Res Opin2004;20:279-93.
2.
De Gasparo M. , Catt KJ, Inagami T., Wright JW, Unger T.International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev2000;52:415-72.
3.
McKelvie RSThe therapeutic potential of angiotensin II receptor blockers in the treatment of heart failure. Expert Opin Investig Drugs2004;13:245-53.
4.
Ruilope LM, Segura J.Losartan and other angiotensin II antagonists for nephropathy in type 2 diabetes mellitus: a review of the clinical trial evidence. Clin Ther2003;25:3044-64.
5.
Schupp M., Janke J., Clasen R., Unger T., Kintscher U.Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation2004; 109:2054-7.
6.
Li P., Ferrario CM, Brosnihan KBNonpeptide angiotensin II antagonist losartan inhibits thromboxane A2-induced contractions in canine coronary arteries. J Pharmacol Exp Ther1997;281:1065-70.
7.
Li P., Ferrario CM, Brosnihan KBLosartan inhibits thromboxane A2-induced platelet aggregation and vascular constriction in spontaneously hypertensive rats. J Cardiovasc Pharmacol1998;32:198-205.
8.
Fukuhara M., Neves LA, Li P., Diz DI, Ferrario CM, Brosnihan KBThe angiotensin II AT1 receptor antagonist irbesartan prevents thromboxane A2-induced vasoconstriction in the rat hind-limb vascular bed in vivo. J Hypertens2001;19:561-6
9.
Li P., Fukuhara M., Diz DI, Ferrario CM, Brosnihan KBNovel angiotensin II AT(1) receptor antagonist irbesartan prevents thromboxane A(2)-induced vasoconstriction in canine coronary arteries and human platelet aggregation. J Pharmacol Exp Ther2000;292:238-46.
10.
Monton M., Jimenez A., Nunez A. et al. Comparative effects of angiotensin II AT-1-type receptor antagonists in vitro on human platelet activation. J Cardiovasc Pharmacol2000; 35:906-13.
11.
Schwemmer M. , Sommer O., Bassenge E.Angiotensin receptor blocker losartan suppresses platelet activity by interfering with thromboxane signaling. Cardiovasc Drugs Ther2001; 15:301-07.
12.
Fogari R., Derosa G., Mugellini A. et al. Effect of losartan, irbesartan, and candesartan on platelet aggregability and fibrinolysis in type 2 diabetic hypertensive patients. (abstract) . J Hypertens2003;21(suppl 4):S85.
13.
Leu HB, Charng MJ, Ding PYA double blind randomized trial to compare the effects of eprosartan and enalapril on blood pressure, platelets, and endothelium function in patients with essential hypertension.Jpn Heart J2004;45:623-35.
14.
Serebruany VL, Malinin AI, Lowry DR et al. Effects of valsartan and valeryl 4-hydroxy valsartan on human platelets: a possible additional mechanism for clinical benefits. J Cardiovasc Pharmacol2004;43:677-84.
15.
Burnier M., Pechere-Bertschi A., Nussberger J., Waeber B., Brunner HRStudies of the renal effects of angiotensin II receptor blockade: the confounding factor of acute water loading on the action of vasoactive systems. Am J Kidney Dis1995;26: 108-15.
16.
Hamada T., Hisatome I., Kinugasa Y. et al. Effect of the angiotensin II receptor antagonist losartan on uric acid and oxypurine metabolism in healthy subjects. Intern Med2002;41:793-7.
17.
Minghelli G. , Seydoux C., Goy JJ, Burnier M.Uricosuric effect of the angiotensin II receptor antagonist losartan in heart transplant recipients . Transplantation1998;66:268-71.
18.
Sasaki M., Fujimura A., Harada K., Sunaga K., Ebihara A.Clinical pharmacology of multiple-dose losartan, an angiotensin II receptor antagonist, in patients with essential hypertension. J Clin Pharmacol1996;36:403-08.
19.
Maeso R., Rodrigo E., Munoz-Garcia R. et al. Losartan reduces constrictor responses to endothelin-1 and the thromboxane A2 analogue in aortic rings from spontaneously hypertensive rats: role of nitric oxide. J Hypertens1997;15:1677-84.
20.
Schwemmer M. , Sommer O., Bassenge E.Blockade of angiotensin signaling improves myocardial function in hypercholesterolemia independent of changes in eicosanoid release. Cardiovasc.Drugs Ther2000;14:317-27.
21.
Valentin JP , Jover B., Maffre M., Bertolino F., Bessac AM, John GWLosartan prevents thromboxane A2/prostanoid (TP) receptor mediated increase in microvascular permeability in the rat. Am J Hypertens1997 ;10:1058-63.
22.
Picard P., Chretien L., Couture R.Functional interaction between losartan and central tachykinin NK3 receptors in the conscious rat. Br J Pharmacol1995;114:1563-70.
23.
Li Z., Bosch SM, Smith TL, Diz DIInteractions of nonpeptide angiotensin II receptor antagonists at imidazoline/guanidinium receptor sites in rat forebrain. J Cardiovasc Pharmacol1996;28:425-31.
24.
Ohlstein EH , Brooks DP, Feuerstein GZ, Ruffolo RR, Jr.Inhibition of sympathetic outflow by the angiotensin II receptor antagonist, eprosartan, but not by losartan, valsartan or irbesartan: relationship to differences in prejunctional angiotensin II receptor blockade. Pharmacology1997;55:244-51.
25.
Wagenaar LJ , Voors AA, Buikema H., van Gilst WHAngiotensin receptors in the cardiovascular system. Can J Cardiol2002;18:1331-9.
26.
Liu YH, Yang XP, Sharov VG et al. Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors. J Clin Invest1997;99:1926-35.
27.
Audoly LT, Le TH, Coffman TMWhat can knockout mice contribute to an understanding of hypertension?Curr Hypertens Rep2000;2:192-7.
28.
Reid JLThe sympathetic nervous system and the reninangiotensin system. In: Nicholls MG, Brunner H, Ikram H, Sweet CS , Walker JF (eds.). 100 Years of the Renin-Angiotensin System. Whitehouse Station : Merck & Co., Inc., 1998:163-6.
29.
Reid JLHypertension and the brain. Br Med Bull1994 ; 50:371-80.
30.
Grassi G.Sympathetic deactivation as a goal of nonpharmacologic and pharmacologic antihypertensive treatment: rationale and options. Curr Hypertens Rep2003;5:277-80.
31.
Stroe AF, Gheorghiade M.Carvedilol: beta-blockade and beyond. Rev Cardiovasc Med2004;5(suppl 1):S18-27:S18-S27.
32.
Abraham WT, Iyengar S.Practical considerations for switching beta-blockers in heart failure patients . Rev Cardiovasc Med2004;5(suppl 1):S36-S44.
33.
Sorrentino MJBeta-blockers for congestive heart failure . Compr Ther2003;29:210-14.
34.
Gavras I., Manolis AJ, Gavras H.The alpha2 -adrenergic receptors in hypertension and heart failure: experimental and clinical studies. J Hypertens2001;19:2115-24.
35.
Majewski H. , Hedler L., Schurr C., Starke K.Modulation of noradrenaline release in the pithed rabbit: a role for angiotensin II. J Cardiovasc Pharmacol1984;6:888-96.
36.
Balt JC, Mathy MJ, Pfaffendorf M., van Zwieten PASympatho-inhibitory properties of various AT1 receptor antagonists . J Hypertens2002;20(suppl 5):S3-S11.
37.
Schiffrin EL , Amiri F., Benkirane K., Iglarz M., Diep QNPeroxisome proliferator-activated receptors: vascular and cardiac effects in hypertension. Hypertension2003;42:664-8.
38.
Issemann I. , Green S.Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature1990;347:645-50.
39.
Dreyer C., Krey G., Keller H., Givel F., Helftenbein G.,Wahli W.Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell1992;68:879-87.
40.
Desvergne B. , Wahli W.Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev1999;20:649-88.
41.
Kersten S., Desvergne B., Wahli W.Roles of PPARs in health and disease. Nature2000;405:421-4.
42.
Fajas L., Auboeuf D., Raspe E. et al. The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem1997;272:18779-89.
43.
Mukherjee R. , Jow L., Croston GE, Paterniti JR, Jr.Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) iso-forms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists. J Biol Chem1997 ;272:8071-6.
44.
Willson TM, Brown PJ, Sternbach DD, Henke BRThe PPARs: from orphan receptors to drug discovery. J Med Chem2000;43:527-50.
45.
Law RE, Goetze S., Xi XP et al. Expression and function of PPARgamma in rat and human vascular smooth muscle cells. Circulation2000;101:1311-18.
46.
Picard F., Auwerx J.PPAR(gamma) and glucose homeostasis. Annu Rev Nutr2002;22:167-97.
47.
Ogihara T., Rakugi H., Ikegami H., Mikami H., Masuo K.Enhancement of insulin sensitivity by troglitazone lowers blood pressure in diabetic hypertensives. Am J Hypertens1995 ;8:316-20.
48.
Sung BH, Izzo JL, Jr., Dandona P., Wilson MFVasodilatory effects of troglitazone improve blood pressure at rest and during mental stress in type 2 diabetes mellitus. Hypertension1999;34:83-8.
49.
Nolan JJ, Ludvik B., Beerdsen P., Joyce M., Olefsky J.Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med1994 ;331:1188-93.
50.
Tack CJ, Ong MK, Lutterman JA, Smits P.Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone. Diabetologia1998;41:569-76.
51.
Yoshioka S., Nishino H., Shiraki T. et al. Antihypertensive effects of CS-045 treatment in obese Zucker rats. Metabolism1993;42:75-80.
52.
Fujimoto M. , Masuzaki H., Tanaka T. et al. An angiotensin II AT1 receptor antagonist, telmisartan augments glucose uptake and GLUT4 protein expression in 3T3-L1 adipocytes.FEBSLett2004;576:492-7.
53.
Lindholm LH , Ibsen H., Borch-Johnsen K. et al. Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study. J Hypertens2002;20:1879-86.
54.
Wu L., Wang R., de Champlain J., Wilson TWBeneficial and deleterious effects of rosiglitazone on hypertension development in spontaneously hypertensive rats. Am J Hypertens2004;17:749-56.
55.
Kermani A., Garg A.Thiazolidinedione-associated congestive heart failure and pulmonary edema . Mayo Clin Proc2003;78:1088-91.
56.
Massberg S. , Schulz C., Gawaz M.Role of platelets in the pathophysiology of acute coronary syndrome. Semin Vasc Med2003 ;3:147-62.
57.
Tan KT, Watson SP, Lip GYThe endothelium and platelets in cardiovascular disease: potential targets for therapeutic intervention. Curr Med Chem Cardiovasc Hematol Agents2004; 2:169-78.
58.
Kramer C., Sunkomat J., Witte J. et al. Angiotensin II receptor-independent antiinflammatory and antiaggregatory properties of losartan: role of the active metabolite EXP3179. Circ Res2002;90:770-6.
59.
Lip GY, Edmunds E., Beevers DGShould patients with hypertension receive antithrombotic therapy?J Intern Med2001;249:205-14.
60.
Sica DA, Schoolwerth ACPart 1. Uric acid and losartan. Curr Opin Nephrol Hypertens2002;11:475-82.
61.
Breckenridge A.Hypertension and hyperuricaemia. Lancet1966;1:15-18.
62.
Tykarski A.Evaluation of renal handling of uric acid in essential hypertension: hyperuricemia related to decreased urate secretion . Nephron1991;59:364-8.
63.
Feig DI, Nakagawa T., Karumanchi SA et al. Hypothesis: Uric acid, nephron number, and the pathogenesis of essential hypertension. Kidney Int2004 ;66:281-7.
64.
Sundstrom J. , Sullivan L., D'Agostino RB, Levy D., Kannel WB,Vasan RSRelations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence (abstract). Hypertension2005;45:28-33.
65.
Johnson RJ, Feig DI, Herrera-Acosta J., Kang DHResurrection of serum uric acid as a causal risk factor in essential hypertension (abstract).Hypertension2005;45:18-20.
66.
Alderman MH , Cohen H., Madhavan S., Kivlighn S.Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension1999;34:144-50.
67.
Alderman MHUric acid and cardiovascular risk. Curr Opin Pharmacol2002;2:126-30.
68.
Bengtsson C. , Lapidus L., Stendahl C., Waldenstrom J.Hyperuricaemia and risk of cardiovascular disease and overall death. A 12-year follow-up of participants in the population study of women in Gothenburg, Sweden. Acta Med Scand1988;224:549-55.
69.
Freedman DS , Williamson DF, Gunter EW, Byers T.Relation of serum uric acid to mortality and ischemic heart disease.The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol1995;141:637-44.
70.
Klein R., Klein BE, Cornoni JC, Maready J., Cassel JC,Tyroler HASerum uric acid. Its relationship to coronary heart disease risk factors and cardiovascular disease, Evans County, Georgia. Arch Intern Med1973;132:401-10.
71.
Moriarity JT , Folsom AR, Iribarren C., Nieto FJ, Rosamond WDSerum uric acid and risk of coronary heart disease: Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol2000;10:136-43.
72.
Verdecchia P., Schillaci G., Reboldi G., Santeusanio F., Porcellati C., Brunetti P.Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study. Hypertension2000;36:1072-8.
73.
Alderman MHSerum uric acid as a cardiovascular risk factor for heart disease. Curr Hypertens Rep2001 ;3:184-9.
74.
Culleton BF , Larson MG, Kannel WB, Levy D.Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study . Ann Intern Med1999;131:7-13.
75.
Puig JG, Mateos F., Buno A., Ortega R., Rodriguez F., Dal Re R.Effect of eprosartan and losartan on uric acid metabolism in patients with essential hypertension. J Hypertens1999 ; 17:1033-9.
76.
Liberopoulos E., Christides D., Elisaf M.Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricemia and gout. J Hypertens2002;20:347.
77.
Manolis AJ, Grossman E., Jelakovic B. et al. Effects of losartan and candesartan monotherapy and losartan/hydrochlorothiazide combination therapy in patients with mild to moderate hypertension. Losartan Trial Investigators. Clin Ther2000;22:1186-203.
78.
SayinT. ,Doven O.,Akyurek O., Dincer I.Neutral effect of valsartan on serum uric acid and renal function tests. J Hum Hypertens2001;15:435-6.
79.
Burnier M., Roch-Ramel F., Brunner HRRenal effects of angiotensin II receptor blockade in normotensive subjects . Kidney Int1996;49:1787-90.
80.
Campion EW, Glynn RJ, DeLabry LOAsymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med1987;82:421-6.
81.
Nikas S., Rizos E., Milionis H. et al. The effects of the addition of losartan on uric acid metabolism in patients receiving indapamide. JRAAS2000 ;1:289-91.
82.
Soffer BA, Wright JT, Jr., Pratt JH, Wiens B., Goldberg AI, Sweet CSEffects of losartan on a background of hydrochlorothiazide in patients with hypertension. Hypertension1995;26:112-17.
83.
Weber MA, Byyny RL, Pratt JH et al. Blood pressure effects of the angiotensin II receptor blocker, losartan. Arch Intern Med1995;155:405-11.
84.
Roch-Ramel F., Guisan B., Diezi J.Effects of uricosuric and antiuricosuric agents on urate transport in human brush-border membrane vesicles. J Pharmacol Exp Ther1997; 280:839-45.
85.
Roch-Ramel F., Werner D., Guisan B.Urate transport in brush-border membrane of human kidney. Am J Physiol1994 ;266:F797-F805.
86.
Hoieggen A. , Alderman MH, Kjeldsen SE et al. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int2004 ;65:1041-9.
87.
Timmermans PBPharmacological properties of angiotensin II receptor antagonists. Can J Cardiol1999 ;15 (suppl F):26F-28F.
88.
Silverstein RL, Fenves AZ, Ram CVARBs and target organ protection. Exploring benefits beyond their antihypertensive effects. Postgrad Med2004;116:31-8, 41.
89.
Sada T., Mizuno M.[Pharmacological profiles and clinical effects of olmesartan medoxomil, a novel angiotensin II receptor blocker].NipponYakurigaku Zasshi2004;124:257-69.
90.
Nakashima M. , Uematsu T., Kosuge K., Kanamaru M.Pilot study of the uricosuric effect of DuP-753, a new angiotensin II receptor antagonist, in healthy subjects. Eur J Clin Pharmacol1992;42:333-5.
91.
Smith MC, Barrows S., Meibohm A. et al. The effects of angiotensin II receptor blockade with losartan on systemic blood pressure and renal and extrarenal prostaglandin synthesis in women with essential hypertension. Am J Hypertens1995;8:1177-83.
92.
Fauvel JP, Velon S., Berra N. et al. Effects of losartan on renal function in patients with essential hypertension. J Cardiovasc Pharmacol1996;28:259-63.
93.
Lacourciere Y., Belanger A., Godin C. et al. Long-term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy . Kidney Int2000;58:762-9.
94.
Yamamoto T. , Moriwaki Y., Takahashi S., Tsutsumi Z., Hada T.Effect of losartan potassium, an angiotensin II receptor antagonist, on renal excretion of oxypurinol and purine bases . J Rheumatol2000;27:2232-6.
95.
Schmidt A., Gruber U., Bohmig G., Koller E., Mayer G.The effect of ACE inhibitor and angiotensin II receptor antagonist therapy on serum uric acid levels and potassium homeostasis in hypertensive renal transplant recipients treated with CsA. Nephrol Dial Transplant2001;16:1034-7.
96.
Kamper AL, Nielsen AHUricosuric effect of losartan in patients with renal transplants. Transplantation2001;72:671-4.
97.
Elliott WJ, Calhoun DA, DeLucca PT, Gazdick LP, Kerns DE, Zeldin RKLosartan versus valsartan in the treatment of patients with mild to moderate essential hypertension: data from a multicenter, randomized, double-blind, 12-week trial. Clin Ther2001;23:1166-79.
98.
Wurzner G., Gerster JC, Chiolero A. et al. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. J Hypertens2001;19:1855-60.
99.
Puig JG,Torres R., Ruilope LMAT1 blockers and uric acid metabolism: are there relevant differences? J Hypertens2002;20(suppl 5):S29-S31.
