尿酸与心血管预后及心血管药物对尿酸的作用

《尿酸与心血管预后及心血管药物对尿酸的作用》由会员分享，可在线阅读，更多相关《尿酸与心血管预后及心血管药物对尿酸的作用（49页珍藏版）》请在装配图网上搜索。

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 The synthesis of uric acid The antioxidant action/function of uric acid Does uric acid damage the heart and vessels in man? T

2、he 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 Uric acid is produced in the purine catabolic chain guanosine inosine hypoxanthin

3、e xanthine oxidoreductase xanthine xanthine oxidoreductase uric acid Xanthine oxidoreductase system xanthine dehydrogenase low oxygen tension inflammatory cytokines hormones xanthine oxidase Xantine dehydrogenase uses NAD+ as an electron acceptor Xanthine oxidase uses O2 as an electron acceptor Berr

4、y CE, Hare JM. J Physiol 2004; 555:589606. Reactive oxygen species are co-generated with xanthine and with uric acid in reactions mediated by xanthine oxidase Hypoxanthine Xanthine + 2O 2 + H2O + 2O2 + H2O xanthine xanthine oxidase oxidase Xanthine Uric acid + 2O - + 2H+ + 2O- + 2H+ Four/two superox

5、ide anion radicals (O-) are formed per each unit of inosine/guanosine catabolised through the action of xanthine oxidase The 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 cardiov

6、ascular 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 Uric acid is an antioxidant: it can/appears to be able to scavenge several reactive oxygen species: peroxynitrite and peroxyl radicals

7、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. Whiteman M, Ketsawatsakul U, Halliwell B. Ann N Y Acad Sci 2002; 962:242259. Augusto O, Bonin

8、i MG, Amanso AM, et al. Free Radic Biol Med 2001;32:841859. Elevations in serum uric acid entail increases in plasma antioxidant capacity in man Waring WS, Webb DJ, Maxwell SR. J Cardiovasc Pharmacol 2001;38:365371. Waring WS, Convery A, Mishra V, et al. Clin Sci (Lond) 2003;105:425-430. The synthes

9、is 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 acid that are cause

10、d by cardiovascular drugs in man Acute hyperuricaemia does not impair cardiovascular function in healthy man Local forearm and systemic hyperuricaemia were produced by infusion of uric acid Basal forearm blood flow was not affected The responses of forearm blood flow to acetylcholine, sodium nitropr

11、usside 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, Breukels O, et al. Heart 2004;90: 155159. The synthesis of uric acid The antioxidant action/function of uric acid Does uric acid d

12、amage 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 2/3 of all the uric acid that is produced is

13、 excreted by the kidneys in normal man Renal handling of uric acid Total amount filtered: 100% Amount secreted into the nephronal proximal tubule: 40% Amount reabsorbed from the nephronal proximal tubule: 130% Net proximal tubular reabsorption: 8894% Renal fractional excretion of uric acid (% of the

14、 filtered amount that is excreted in urine): 612% Even the moderate reductions in sodium intake prescribed to patients with hypertension or heart failure result in significant increases in serum uric acid concentration Randomised, placebo-controlled, and double-blind crossover study Seventeen hypert

15、ensive 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 Hypertens 1997;11: 361366. The synthesis of uric acid The antioxidant action/function of uric acid Does uric acid damage the heart and vessels in man? The renal excretio

16、n 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 The synthesis of uric acid The antioxidant action/function of uric acid Does uric acid damage the

17、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 Allopurinol and its metabolite oxypurinol are inhibito

18、rs of xanthine oxidase hypoxanthine or xanthine + 2O2 + H2O allopurinol xanthine oxidase oxypurinol xanthine or uric acid + 2O2- + 2H+ In addition to their action on xanthine oxidase, allopurinol and its metabolite oxypurinol scavenge free radicals directly Moorhouse PC, Grootveld M, Halliwell B, et

19、 al. FEBS Lett 1987;213:2328. Das DK, Engelman RM, Clement R, et 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. Relevant actions of allopurinol It improved peripheral vas

20、odilation capacity in heart failure Doehner W, et al. Circulation 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, Tak

21、ahashi S, et al. Clin Chim Acta 2004;339:117122. The 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 Th

22、e purport of the increases in serum uric acid that are caused by cardiovascular drugs in man All 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 elev

23、ate serum uric acid concentration The 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 th

24、e increases in serum uric acid that are caused by cardiovascular drugs in man Acetylsalicylic 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 in healthy subjects

25、 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, et al.

26、Am J Med 2003; 115:462466. 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. The synthesis of uric acid The antioxidant action/function of uric acid Does uric acid damage the heart and

27、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 Increases in serum uric acid per se entail increases in total pl

28、asma 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 Institute of Cardiovascular Theory Montevideo, Uruguay The published subanalysis of th

29、e SHEP results dealing with uric acid lacks cogency Introduction Uric acid is an antioxidant. Thus, the increase 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) wer

30、e found to blunt the positive action of blood pressure reduction with chlorthalidone on the risk of coronary heart disease in a commercially sponsored subanalysis of the SHEP results that was published in 2000 3. Objective of the present undertaking To reappraise the question of whether the changes

31、in serum uric acid that were induced by chlorthalidone Had a bearing on cardiovascular prognosis in the SHEP. The 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

32、 another agent if necessary and observed for 5 years. Chlorthalidone treatment 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

33、the relationship between hypokalaemia and cardiovascular outcomes 5. First 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

34、 in chlorthalidone-treated patients. Despite the preceding general 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 ana

35、lysis in which the data were adjusted for several likely confounders, but not for serum potassium (Table 1). Second 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

36、0.41 mmol/L at 1 year (it was 0.37 mmol/L in patients 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 Losartan, serum uric acid and serum potassiu

37、m in LIFE study: an independent undertaking Introduction 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 o

38、f losartan on serum uric acid to the 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- hypertensiv

39、e therapy for 4 years or until 1 040 patients had a cardiovascular event (death, myocardial infarction or stroke). Results 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

40、serum uric acid increased during treatment 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 sub

41、stantially during treatment in either group 2. End 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)

42、 1 4.141 4.109 -0.032 4.143 4.025 -0.118 2 Uric acid (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 Conclusion by the authors of the LIFE study “The increase in serum uric acid was attenuated by losartan compared with atenolol treatmen

43、t, appearing to explain 29% of the treatment effect 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 fa

44、ct that patients with diuretic-induced hypokalaemia tend to have higher serum uric acid levels than subjects who do not present hypokalaemia 3. Objectives of the present undertaking to evaluate whether the responses of serum potassium to losartan and to atenolol in the LIFE study differed; to discus

45、s the possible bearing of serum uric 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

46、 to their intent-to- treat analysis, 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). Results of th

47、e present undertaking 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 stud

48、y (P 0.0001) evaluated by 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, whil

49、e using the SD values quoted in 1 and assuming that serum potassium at end of study conformed to a Gaussian distribution in both groups. Conclusions Losartan, uric acid and cardiovascular risk in the LIFE study The LIFE study authors ignored serum potassium in their multivariate analysis; this varia

50、ble, which is known to associate negatively with serum uric acid in diuretic-treated patients, was lower in the atenolol than in the losartan group at end of study. The LIFE study authors maintain that the lower levels of serum uric acid in the losartan group entailed an improved cardiovascular prog

51、nosis; this contention is unscientific. Losartan-induced falls in serum uric acid may well detract from the positive cardiovascular actions of this agent, given that uric acid is a powerful antioxidant in man 5. In the absence of further analyses refuting our objections, the LIFE study authors analy

52、sis and conclusion 2 lack cogency. Basis of the old stance on diuretics, uric acid and cardiovascular risk Selected epidemiological studies have disclosed that high levels of serum uric acid impair cardiovascular prognosis The control of high blood pressure with diuretics fails to improve cardiovasc

53、ular prognosis when it elevates serum uric acid markedly The increase in uricosuria and reduction in uricaemia caused by losartan improve cardiovascular prognosis Raised levels of serum uric acid cause renal damage and trigger the development of hypertension in the rat Srinivas TR, Herrera-Acosta J, Feig GI et al. J Hypertens 2004;22:in press.