The release of the substrate for xanthine oxidase in hypertensive patientswas suppressed by angiotensin converting enzyme inhibitors and alpha(1)-blockers

Objective Hyperuricemia is associated with the vascular injury of hypertens ion, 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, hypox anthine, derived from skeletal muscles, would be oxidized by xanthine oxida se, leading to myogenic hyperuricemia as well as to impaired vascular resis tance caused by oxygen radicals. Methods We investigated the production of hypoxanthione, the precursor of u ric acid and substrate for xanthine oxidase, in hypertensive patients and f ound that skeletal muscles produced hypoxanthine in excess. We used the sem i-ischemic forearm test to examine the release of hypoxanthine (Delta HX), ammonium (Delta Amm) and lactate (Delta LAC) from skeletal muscles in essen tial hypertensive patients before (UHT: n = 88) and after treatment with an tihypertensive agents (THT: n = 37) in comparison to normotensive subjects (NT: n = 14), Results Delta HX, as well as Delta Amm and Delta LAC, were significantly hi gher in UHT and THT (P < 0.01) than in NT, This release of <Delta>HX from e xercising skeletal muscles correlated significantly with the elevation of l actate in NT, UHT and THT (y = 0.209 + 0.031 x; R-2 = 0.222, n = 139: P < 0 .01). Administration of doxazosin (n = 4), bevantolol (n = 5) and alacepll (n = 8) for 1 month significantly suppressed the ratio of percentage change s in <Delta>HX by -38.4 +/- 55.3%, -51.3 +/- 47.3% and -76.3 +/- 52.2%, res pectively (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 increas ed it in <Delta>HX by + 188.2 +/- 331%, + 96.2 +/- 192.2% and + 42.8 +/- 13 7.3%, respectively. The elevation of Delta HX after exercise correlated sig nificantly with the serum concentration of uric acid at rest in untreated h ypertensive patients (y = 0.194 - 0,255x; R-2 = 0.185, n = 30: P < 0.05), T he prevalence of reduction of both <Delta>HX and serum uric acid was signif icantly higher in the patients treated with alacepril, bevantolol and doxaz osin (67%: P < 0.02) than in the patients treated with losartan, atenolol a nd manidipine (12%), Conclusions It is concluded that the skeletal muscles of hypertensive patie nts released <Delta>HX in excess by activation of muscle-type adenosine mon ophosphate (AMP) deaminase, depending on the degree of hypoxia, The modific ation of Delta HX by angiotensin-converting enzyme inhibitors and alpha (1) -blockers influenced the level of serum uric acid, suggesting that the skel etal muscles may be an important source of uric acid as well as of the subs trate of xanthine oxidase in hypertension.