1、October 2004 URIC ACID AND CARDIOVASCULAR PROGNOSIS AND THE ACTION OF CARDIOVASCULAR DRUGS ON URIC ACID Ariel J.Reyes Institute of Cardiovascular Theory,Montevideo,Uruguay 尿酸与心血管预后及心血管药物对尿酸的作用1The synthesis of uric acid The antioxidant action/function of uric acid Does uric acid damage the heart and
2、 vessels in man?The renal excretion of uric acid The effects of cardiovascular drugs on uric acid Allopurinol Diuretics Acetylsalicylic acid The purport of the increases in serum uric acid that are caused by cardiovascular drugs in man 尿酸与心血管预后及心血管药物对尿酸的作用2Uric acid is produced in the purine catabol
3、ic chain guanosine inosine hypoxanthine xanthine oxidoreductase xanthine xanthine oxidoreductase uric acid 尿酸与心血管预后及心血管药物对尿酸的作用3Xanthine oxidoreductase system xanthine dehydrogenase low oxygen tension inflammatory cytokines hormones xanthine oxidase Xantine dehydrogenase uses NAD+as an electron acce
4、ptor Xanthine oxidase uses O2 as an electron acceptor Berry CE,Hare JM.J Physiol 2004;555:589606.尿酸与心血管预后及心血管药物对尿酸的作用4Reactive oxygen species are co-generated with xanthine and with uric acid in reactions mediated by xanthine oxidase Hypoxanthine Xanthine +2O2+H2O +2O2+H2O xanthine xanthine oxidase
5、oxidase Xanthine Uric acid +2O-+2H+2O-+2H+Four/two superoxide anion radicals(O-)are formed per each unit of inosine/guanosine catabolised through the action of xanthine oxidase 尿酸与心血管预后及心血管药物对尿酸的作用5The synthesis of uric acid The antioxidant action/function of uric acid Does uric acid damage the hear
6、t and vessels in man?The renal excretion of uric acid The effects of cardiovascular drugs on uric acid Allopurinol Diuretics Acetylsalicylic acid The purport of the increases in serum uric acid that are caused by cardiovascular drugs in man 尿酸与心血管预后及心血管药物对尿酸的作用6Uric acid is an antioxidant:it can/app
7、ears to be able to scavenge several reactive oxygen species:peroxynitrite and peroxyl radicals hydroxyl radical hypochlorous acid nitrogen dioxide,carbonate ion Squadrito GL,Cueto R,Splenser AE,et al.Arch Biochem Biophys 2000;376:3337.Regoli F,Winston GW.Toxicol Appl Pharmacol 1999;156:96105.Whitema
8、n M,Ketsawatsakul U,Halliwell B.Ann N Y Acad Sci 2002;962:242259.Augusto O,Bonini MG,Amanso AM,et al.Free Radic Biol Med 2001;32:841859.尿酸与心血管预后及心血管药物对尿酸的作用7Elevations in serum uric acid entail increases in plasma antioxidant capacity in man Waring WS,Webb DJ,Maxwell SR.J Cardiovasc Pharmacol 2001;3
9、8:365371.Waring WS,Convery A,Mishra V,et al.Clin Sci(Lond)2003;105:425-430.尿酸与心血管预后及心血管药物对尿酸的作用8The synthesis of uric acid The antioxidant action/function of uric acid Does uric acid damage the heart and vessels in man?The renal excretion of uric acid The effects of cardiovascular drugs on uric acid
10、 Allopurinol Diuretics Acetylsalicylic acid The purport of the increases in serum uric acid that are caused by cardiovascular drugs in man 尿酸与心血管预后及心血管药物对尿酸的作用9Acute hyperuricaemia does not impair cardiovascular function in healthy man Local forearm and systemic hyperuricaemia were produced by infus
11、ion of uric acid Basal forearm blood flow was not affected The responses of forearm blood flow to acetylcholine,sodium nitroprusside and L-NMMA were not affected Central haemodynamic variables,baroreflex sensitivity and an index of large artery stiffness were not affected Waring WS,Adwani SH,Breukel
12、s O,et al.Heart 2004;90:155159.尿酸与心血管预后及心血管药物对尿酸的作用10The synthesis of uric acid The antioxidant action/function of uric acid Does uric acid damage the heart and vessels in man?The renal excretion of uric acid The effects of cardiovascular drugs on uric acid Allopurinol Diuretics Acetylsalicylic acid
13、 The purport of the increases in serum uric acid that are caused by cardiovascular drugs in man 尿酸与心血管预后及心血管药物对尿酸的作用11 2/3 of all the uric acid that is produced is excreted by the kidneys in normal man Renal handling of uric acid Total amount filtered:100%Amount secreted into the nephronal proximal
14、tubule:40%Amount reabsorbed from the nephronal proximal tubule:130%Net proximal tubular reabsorption:8894%Renal fractional excretion of uric acid(%of the filtered amount that is excreted in urine):612%尿酸与心血管预后及心血管药物对尿酸的作用12Even the moderate reductions in sodium intake prescribed to patients with hyp
15、ertension or heart failure result in significant increases in serum uric acid concentration Randomised,placebo-controlled,and double-blind crossover study Seventeen hypertensive patients aged 6579 Mean 24-h natriuresis(mmol)304 95 Mean serum uric acid (mol.L-1)277 174 Fotherby MD,Potter JF.J Hum Hyp
16、ertens 1997;11:361366.尿酸与心血管预后及心血管药物对尿酸的作用13The synthesis of uric acid The antioxidant action/function of uric acid Does uric acid damage the heart and vessels in man?The renal excretion of uric acid The effects of cardiovascular drugs on uric acid Allopurinol Diuretics Acetylsalicylic acid The purp
17、ort of the increases in serum uric acid that are caused by cardiovascular drugs in man 尿酸与心血管预后及心血管药物对尿酸的作用14The synthesis of uric acid The antioxidant action/function of uric acid Does uric acid damage the heart and vessels in man?The renal excretion of uric acid The effects of cardiovascular drugs
18、 on uric acid Allopurinol Diuretics Acetylsalicylic acid The purport of the increases in serum uric acid that are caused by cardiovascular drugs in man 尿酸与心血管预后及心血管药物对尿酸的作用15Allopurinol and its metabolite oxypurinol are inhibitors of xanthine oxidase hypoxanthine or xanthine +2O2 +H2O allopurinol xa
19、nthine oxidase oxypurinol xanthine or uric acid +2O2-+2H+尿酸与心血管预后及心血管药物对尿酸的作用16In addition to their action on xanthine oxidase,allopurinol and its metabolite oxypurinol scavenge free radicals directly Moorhouse PC,Grootveld M,Halliwell B,et al.FEBS Lett 1987;213:2328.Das DK,Engelman RM,Clement R,et
20、al.Biochem Biophys Res Commun 1987;148:314319.Hoey BM,Butler J,Halliwell B.Free Radic Res Commun 1988;4:259263.Ricardo SD,Bertram JF,Ryan GB.Exp Nephrol 1995;3:270279.尿酸与心血管预后及心血管药物对尿酸的作用17Relevant actions of allopurinol It improved peripheral vasodilation capacity in heart failure Doehner W,et al.C
21、irculation 2002;105:26192624.Farquharson CA,et al.Circulation 2002;106:221226.It decreased the serum concentration of oxidised LDL autoantibodies in patients with gout,whereas the uricosuric benzbromarone did not Tsutsumi Z,Moriwaki Y,Takahashi S,et al.Clin Chim Acta 2004;339:117122.尿酸与心血管预后及心血管药物对尿
22、酸的作用18The synthesis of uric acid The antioxidant action/function of uric acid Does uric acid damage the heart and vessels in man?The renal excretion of uric acid The effects of cardiovascular drugs on uric acid Allopurinol Diuretics Acetylsalicylic acid The purport of the increases in serum uric aci
23、d that are caused by cardiovascular drugs in man 尿酸与心血管预后及心血管药物对尿酸的作用19All loop diuretics,most thiazide-type diuretics and all potassium-retaining diuretics enhance the reabsorption of uric acid in the proximal tubule of the nephron reduce the renal excretion of uric acid elevate serum uric acid con
24、centration 尿酸与心血管预后及心血管药物对尿酸的作用20The synthesis of uric acid The antioxidant action/function of uric acid Does uric acid damage the heart and vessels in man?The renal excretion of uric acid The effects of cardiovascular drugs on uric acid Allopurinol Diuretics Acetylsalicylic acid The purport of the
25、increases in serum uric acid that are caused by cardiovascular drugs in man 尿酸与心血管预后及心血管药物对尿酸的作用21Acetylsalicylic acid at a daily dose of 500 mg or higher raises uricosuria and reduces serum uric acid Acetylsalicylic acid at 60 or 325 mg once daily reduced the renal fractional excretion of uric acid
26、 in healthy subjects Louthrenoo W,Kasitanon N,Wichainun R,et al.J Clin Rheumatol 2002;8:299304.Acetylsalicylic acid at 75 or 100 mg once daily reduced the renal clearance of uric acid and increased uricaemia Caspi D,Lubart E,Graff E,et al.Arthritis Rheum 2000;43:103108.Segal R,Lubart E,Leibovitz A,e
27、t al.Am J Med 2003;115:462466.尿酸与心血管预后及心血管药物对尿酸的作用22 Acetylsalicylic acid 100 mg once daily was found to increase serum antioxidant capacity in healthy subjects Ristimae T,et al.Cardiovasc Drugs Ther 1999;13:485490.尿酸与心血管预后及心血管药物对尿酸的作用23The synthesis of uric acid The antioxidant action/function of u
28、ric acid Does uric acid damage the heart and vessels in man?The renal excretion of uric acid The effects of cardiovascular drugs on uric acid Allopurinol Diuretics Acetylsalicylic acid The purport of the increases in serum uric acid that are caused by cardiovascular drugs in man 尿酸与心血管预后及心血管药物对尿酸的作用
29、24Increases in serum uric acid per se entail increases in total plasma antioxidant capacity and therefore are beneficial to the heart and vessels However,the purport of the increases in serum uric acid that occur in man depends upon definite process(s)and on their combinations 尿酸与心血管预后及心血管药物对尿酸的作用25
30、尿酸与心血管预后及心血管药物对尿酸的作用26尿酸与心血管预后及心血管药物对尿酸的作用27尿酸与心血管预后及心血管药物对尿酸的作用28Institute of Cardiovascular Theory Montevideo,Uruguay 尿酸与心血管预后及心血管药物对尿酸的作用29The published subanalysis of the SHEP results dealing with uric acid lacks cogency 尿酸与心血管预后及心血管药物对尿酸的作用30Introduction Uric acid is an antioxidant.Thus,the inc
31、rease in serum uric acid caused by diuretics is likely to benefit the heart and the vessels 1,2.Chlorthalidone-induced elevations in serum uric acid higher than 0.06 mmol/L(about 1 mg/dL)were found to blunt the positive action of blood pressure reduction with chlorthalidone on the risk of coronary h
32、eart disease in a commercially sponsored subanalysis of the SHEP results that was published in 2000 3.尿酸与心血管预后及心血管药物对尿酸的作用31Objective of the present undertaking To reappraise the question of whether the changes in serum uric acid that were induced by chlorthalidone Had a bearing on cardiovascular pr
33、ognosis in the SHEP.尿酸与心血管预后及心血管药物对尿酸的作用32The Systolic Hypertension in the Elderly Program(SHEP)4327 patients with isolated systolic hypertension were randomly allocated to treatment with placebo chlorthalidone 12.525 mg/day,plus another agent if necessary and observed for 5 years.Chlorthalidone tre
34、atment reduced serum potassium 4;elevated serum uric acid 4.Two subanalyses of the SHEP results were published in 2003:a subanalysis of the relationship between serum uric acid and cardiovascular outcomes 3;a subanalysis of the relationship between hypokalaemia and cardiovascular outcomes 5.尿酸与心血管预后
35、及心血管药物对尿酸的作用33First of the two year-2000 papers on the SHEP:Uric acid and cardiovascular prognosis 3.The risks of cardiovascular events,stroke or coronary heart disease(myocardial infarction,coronary procedures and cardiac death)were lower in chlorthalidone-treated patients.Despite the preceding gen
36、eral finding,elevations in serum uric acid of 0.06 mmol/L(about 1 mg/dL)or higher nullified the decrease in risk of coronary heart disease associated with chlorthalidone treatment.The latter conclusion resulted from a multivariate analysis in which the data were adjusted for several likely confounde
37、rs,but not for serum potassium(Table 1).尿酸与心血管预后及心血管药物对尿酸的作用34Second of the two year-2000 papers on the SHEP:Serum potassium and cardiovascular prognosis 5 Patients who presented hypokalaemia during active treatment presented a mean serum uric acid of 0.41 mmol/L at 1 year(it was 0.37 mmol/L in pati
38、ents without hypokalaemia,P=3.5 n=1951 n=2003 0.32(0.08)0.32(0.08)K=3.5 NS vs K=3.5 1 year K=3.5 n=1951 n=2003 0.37(0.10)0.33(0.09)K 3.5 n=151 n=21 0.41(0.11)0.42(0.09)P=3.5 P=3.5 尿酸与心血管预后及心血管药物对尿酸的作用40Losartan,serum uric acid and serum potassium in LIFE study:an independent undertaking 尿酸与心血管预后及心血管
39、药物对尿酸的作用41Introduction Uric acid is an antioxidant;thus,the uricosuric effect of losartan and the attendant fall in serum uric acid are to be considered detrimental to the heart and vessels.The authors of the LIFE study 1 analysed the contribution of the action of losartan on serum uric acid to the
40、therapeutic effect of this agent and concluded that it was beneficial 2.The LIFE Study 1 Patients:high-risk hypertensives aged 5580.Design:double-masked,randomised,parallel-group study.Patients were assigned to losartan-or atenolol-based anti-hypertensive therapy for 4 years or until 1 040 patients
41、had a cardiovascular event(death,myocardial infarction or stroke).尿酸与心血管预后及心血管药物对尿酸的作用42Results of the LIFE study The primary endpoint(cardiovascular death,stroke and myocardial infarction)was 11.0%in the losartan group,12.8%in the atenolol group(P=0.021)1.Mean serum uric acid increased during treat
42、ment 17.0 mol.L-1 in the losartan group,44.4 mol.L-1 in the atenolol group(P 0.001)2.85 and 86%of patients in the losartan and atenolol groups were also taking hydrochlorothiazide at end of study 2.The authors affirm that serum potassium did not change substantially during treatment in either group
43、2.尿酸与心血管预后及心血管药物对尿酸的作用43End of study biochemical variables as reported in 1 and 2.Mean values(SD).Losartan(n=4605)Atenolol(n=4588)Ref.Baseline Year 4,5 Change Baseline Year 4,5 Change Potassium(mmol/L)4.2 (0.4)4.1(0.4)0.0 (0.4)4.2(0.4)4.1(0.4)-0.1(0.5)1 4.141 4.109-0.032 4.143 4.025-0.118 2 Uric aci
44、d(mol/L)328.2(76.9)347.7(90.0)19.5(72.2)328.8(77.1)375.9(93.1)47.2(76.8)1 17.0(69.8)44.4(72.5)2 尿酸与心血管预后及心血管药物对尿酸的作用44Conclusion by the authors of the LIFE study “The increase in serum uric acid was attenuated by losartan compared with atenolol treatment,appearing to explain 29%of the treatment effe
45、ct on the primary composite endpoint”2.Our main objection to the conclusion by the authors of the LIFE study:Serum potassium was disregarded as a potential confounding factor in the multivariate analysis that grounds this conclusion,despite the fact that patients with diuretic-induced hypokalaemia t
46、end to have higher serum uric acid levels than subjects who do not present hypokalaemia 3.尿酸与心血管预后及心血管药物对尿酸的作用45Objectives of the present undertaking to evaluate whether the responses of serum potassium to losartan and to atenolol in the LIFE study differed;to discuss the possible bearing of serum u
47、ric acid on the differential effect of losartan on the primary outcome.Methods of the present undertaking To compare the responses of serum potassium to losartan and to atenolol,we used the number of patients who took each medication quoted by the authors according to their intent-to-treat analysis,
48、the mean values reported in the subanalysis on uric acid 2 since they are more precise than those reported in 1(see the table above),and the SD values quoted in the prime report 1 since no scatter estimates are reported in 2(see the table above).尿酸与心血管预后及心血管药物对尿酸的作用46Results of the present undertaki
49、ng Serum potassium was higher in the losartan than in the atenolol group at end of study and the incidence of hypokalaemia was higher in the atenolol group Mean serum potassium was higher in the losartan(4.109 mmol.L-1)than in the atenolol group(4.025 mmol.L-1)at end of study (P 0.0001)evaluated by
50、the unpaired t test.6.4%and 9.4%of patients in the losartan and atenolol groups respectively presented hypokalaemia at end of study(P 0.0001)these percentages were evaluated by the integral of the standardised normal curve between minus infinity and 3.499,mmol/L,while using the SD values quoted in 1
