title: The release of the substrate for xanthine oxidase in hypertensive patients was suppressed by angiotensin converting enzyme inhibitors and alpha1-blockers.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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%).
  
  
  CONCLUSIONS
  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.
authors.affiliation: First Department of Medicine, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Ohtahara
authors.forename: I
authors.initials: I
authors.lastname: Hisatome
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: M
authors.initials: M
authors.lastname: Furuse
authors.forename: K
authors.initials: K
authors.lastname: Sonoyama
authors.forename: Y
authors.initials: Y
authors.lastname: Furuse
authors.forename: T
authors.initials: T
authors.lastname: Hamada
authors.forename: M
authors.initials: M
authors.lastname: Katoh
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: T
authors.initials: T
authors.lastname: Kinugawa
authors.forename: K
authors.initials: K
authors.lastname: Ogino
authors.forename: O
authors.initials: O
authors.lastname: Igawa
authors.forename: T
authors.initials: T
authors.lastname: Shimomura
authors.forename: F
authors.initials: F
authors.lastname: Murakami
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
authors.forename: C
authors.initials: C
authors.lastname: Shigemasa
mesh_terms: D000659:AMP Deaminase / Q000378:metabolism; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism*; D019271:Hypoxanthine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D013379:Substrate Specificity; D014527:Uric Acid / Q000097:blood; D014969:Xanthine Oxidase / Q000378:metabolism*
chemical_list: D000317:Adrenergic alpha-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D014527:Uric Acid; D019271:Hypoxanthine; D014969:Xanthine Oxidase; D000659:AMP Deaminase