title: Evidence for a causal role of the renin-angiotensin system in nitrate tolerance.
abstract: BACKGROUND
  We have previously shown that nitroglycerin (NTG) therapy increases vascular expression of endothelin 1 (ET-1) and stimulates vascular superoxide (O2.-) production via activation of NADH/NADPH oxidases. Both phenomena are stimulated by angiotensin II in vitro, and the renin-angiotensin system is activated during early nitrate therapy. We hypothesized that either angiotensin II or ET-1 may increase vascular O2.- production during nitrate therapy.
  
  
  RESULTS
  In New Zealand White rabbits, 3 days of treatment with NTG patches increased plasma renin activity for the entire treatment period. After 24 hours of NTG treatment, angiotensin II type 1 (AT1) receptor expression and vascular ACE activity were significantly decreased. At this time, constrictions to angiotensin I and II were depressed, but there was no loss of NTG vasodilator potency. Within 3 days of continuous NTG treatment, relaxations to NTG were markedly blunted. This was associated with an increase in AT1 receptor mRNA expression, a return of ACE activity back to baseline, and a marked increase in constrictions to angiotensin I and II despite continuously increased plasma renin activity. Tolerance was associated with a 2-fold increase in vascular O2.-, as estimated by lucigenin-enhanced chemiluminescence. Concomitant treatment with the AT1 receptor antagonist losartan (5 to 25 mg. kg-1. d-1) dose-dependently normalized vascular O2.- and prevented tolerance to NTG and cross-tolerance to endogenous nitric oxide released by acetylcholine. The nonselective ET-1 receptor blocker bosentan (100 mg. kg-1. d-1) had similar but less pronounced effects.
  
  
  CONCLUSIONS
  The positive effects of AT1 and ET-1 receptor blockade on tolerance and O2.- production imply a pathophysiological role for angiotensin II and to some extent for ET-1 in the development of nitrate tolerance.
authors.affiliation: Department of Medicine, Emory University School of Medicine, Veterans Administration Hospital, Atlanta, GA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kurz
authors.forename: U
authors.initials: U
authors.lastname: Hink
authors.forename: G
authors.initials: G
authors.lastname: Nickenig
authors.forename: A B
authors.initials: AB
authors.lastname: Borthayre
authors.forename: D G
authors.initials: DG
authors.lastname: Harrison
authors.forename: T
authors.initials: T
authors.lastname: Münzel
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000077300:Bosentan; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D019808:Losartan / Q000494:pharmacology; D008163:Luminescent Measurements; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D005996:Nitroglycerin / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D009097:Multienzyme Complexes; D009566:Nitrates; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013449:Sulfonamides; D014665:Vasodilator Agents; D013481:Superoxides; D000804:Angiotensin II; D009569:Nitric Oxide; D000803:Angiotensin I; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D005996:Nitroglycerin; D019808:Losartan; D000077300:Bosentan