The release of the substrate for xanthine oxidase in hypertensive patients was suppressed by angiotensin converting enzyme inhibitors and α1-blockers

OBJECTIVEHyperuricemia 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. METHODSWe 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 (ΔHX), ammonium (ΔAmm) and lactate (ΔLAC) 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). RESULTSΔHX, as well as ΔAmm and ΔLAC, were significantly higher in UHT and THT (P < 0.01) than in NT. This release of ΔHX from exercising skeletal muscles correlated significantly with the elevation of lactate in NT, UHT and THT (y = 0.209 + 0.031 x;R = 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 ΔHX 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 ΔHX by +188.2 ± 331%, +96.2 ± 192.2% and +42.6 ± 137.3%, respectively. The elevation of ΔHX after exercise correlated significantly with the serum concentration of uric acid at rest in untreated hypertensive patients (y = 0.194 − 0.255x;R = 0.185, n = 30:P < 0.05). The prevalence of reduction of both ΔHX 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%). CONCLUSIONSIt is concluded that the skeletal muscles of hypertensive patients released ΔHX in excess by activation of muscle-type adenosine monophosphate (AMP) deaminase, depending on the degree of hypoxia. The modification of ΔHX by angiotensin-converting enzyme inhibitors and α1-blockers influenced the level of serum uric acid, suggesting