Ohtahara A, Hisatome I, Yamamoto Y, Furuse M, Sonoyama K, Furuse Y, Hamada T, Katoh M, Watanabe M, Kinugawa T, Ogino K, Igawa O, Shimomura T, Murakami F, Yamamoto T, Shigemasa C
First Department of Medicine, Tottori University Faculty of Medicine, Yonago, Japan.
J Hypertens. 2001 Mar;19(3 Pt 2):575-82. doi: 10.1097/00004872-200103001-00009.
Hyperuricemia is associated with the vascular injury of hypertension, and purine oxidation may play a pivotal role in this association, but the pathophysiology is not fully understood. We tested the hypothesis that in hypertensive patients, the excess amount of the purine metabolite, hypoxanthine, derived from skeletal muscles, would be oxidized by xanthine oxidase, leading to myogenic hyperuricemia as well as to impaired vascular resistance caused by oxygen radicals.
We investigated the production of hypoxanthione, the precursor of uric acid and substrate for xanthine oxidase, in hypertensive patients and found that skeletal muscles produced hypoxanthine in excess. We used the semi-ischemic forearm test to examine the release of hypoxanthine (deltaHX), ammonium (deltaAmm) and lactate (deltaLAC) from skeletal muscles in essential hypertensive patients before (UHT: n = 88) and after treatment with antihypertensive agents (THT: n = 37) in comparison to normotensive subjects (NT: n = 14).
deltaHX, as well as deltaAmm and deltaLAC, were significantly higher in UHT and THT (P< 0.01) than in NT. This release of deltaHX from exercising skeletal muscles correlated significantly with the elevation of lactate in NT, UHT and THT (y = 0.209 + 0.031x; R2 = 0.222, n = 139: P < 0.01). Administration of doxazosin (n = 4), bevantolol (n = 5) and alacepil (n = 8) for 1 month significantly suppressed the ratio of percentage changes in deltaHX by -38.4 +/- 55.3%, -51.3 +/- 47.3% and -76.3 +/- 52.2%, respectively (P< 0.05) but losartan (n = 3), atenolol (n = 7) and manidipine (n = 10) did not reduce the ratio of changes; on the contrary, they increased it in deltaHX by +188.2 +/- 331%, +96.2 +/- 192.2% and +42.6 +/- 137.3%, respectively. The elevation of deltaHX after exercise correlated significantly with the serum concentration of uric acid at rest in untreated hypertensive patients (y = 0.194 - 0.255x; R2 = 0.185, n = 30: P < 0.05). The prevalence of reduction of both deltaHX and serum uric acid was significantly higher in the patients treated with alacepril, bevantolol and doxazosin (67%: P < 0.02) than in the patients treated with losartan, atenolol and manidipine (12%).
It is concluded that the skeletal muscles of hypertensive patients released deltaHX in excess by activation of muscle-type adenosine monophosphate (AMP) deaminase, depending on the degree of hypoxia. The modification of deltaHX by angiotensin-converting enzyme inhibitors and alpha1-blockers influenced the level of serum uric acid, suggesting that the skeletal muscles may be an important source of uric acid as well as of the substrate of xanthine oxidase in hypertension.
高尿酸血症与高血压的血管损伤有关，嘌呤氧化可能在这种关联中起关键作用，但病理生理学尚未完全阐明。我们检验了这样一个假设：在高血压患者中，源自骨骼肌的嘌呤代谢产物次黄嘌呤过量，会被黄嘌呤氧化酶氧化，导致肌源性高尿酸血症以及氧自由基引起的血管阻力受损。
我们研究了高血压患者中尿酸前体及黄嘌呤氧化酶底物次黄嘌呤的生成情况，发现骨骼肌产生的次黄嘌呤过量。我们采用半缺血性前臂试验，比较了原发性高血压患者在治疗前（未经治疗的高血压患者：n = 88）和使用抗高血压药物治疗后（治疗后的高血压患者：n = 37）与血压正常者（血压正常受试者：n = 14）骨骼肌中次黄嘌呤（ΔHX）、铵（ΔAmm）和乳酸（ΔLAC）的释放情况。
未经治疗的高血压患者和治疗后的高血压患者的ΔHX以及ΔAmm和ΔLAC均显著高于血压正常受试者（P < 0.01）。运动骨骼肌释放的ΔHX与血压正常受试者、未经治疗的高血压患者和治疗后的高血压患者中乳酸的升高显著相关（y = 0.209 + 0.031x；R2 = 0.222，n = 139：P < 0.01）。给予多沙唑嗪（n = 4）、贝凡洛尔（n = 5）和阿拉普利（n = 8）1个月可分别显著抑制ΔHX变化百分比的比例，降幅分别为-38.4±55.3%、-51.3±47.3%和-76.3±52.2%（P < 0.05），但氯沙坦（n = 3）、阿替洛尔（n = 7）和马尼地平（n = 10）并未降低变化比例；相反，它们使ΔHX的变化比例分别增加了+188.2±331%、+96.2±192.2%和+42.6±137.3%。运动后ΔHX的升高与未经治疗的高血压患者静息时的血尿酸浓度显著相关（y = 0.194 - 0.255x；R2 = 0.185，n = 30：P < 0.05）。接受阿拉普利、贝凡洛尔和多沙唑嗪治疗的患者中，ΔHX和血尿酸均降低的发生率（67%：P < 0.02）显著高于接受氯沙坦、阿替洛尔和马尼地平治疗的患者（12%）。
得出结论，高血压患者的骨骼肌通过激活肌肉型单磷酸腺苷（AMP）脱氨酶，根据缺氧程度过量释放ΔHX。血管紧张素转换酶抑制剂和α1受体阻滞剂对ΔHX的调节影响了血尿酸水平，提示骨骼肌可能是高血压中尿酸以及黄嘌呤氧化酶底物的重要来源。
