title: Arterial function in nitric oxide-deficient hypertension: influence of long-term angiotensin II receptor antagonism.
abstract: OBJECTIVE
  Since the effects of angiotensin II receptor antagonism on arterial function in nitric oxide (NO)-deficient hypertension are unknown, we investigated the influence of losartan therapy (20 mg kg-1 day-1) on the control of arterial tone in NG-nitro-L-arginine methyl ester (L-NAME; 20 mg kg-1 day-1)-induced hypertension.
  
  
  METHODS
  Forty Wistar rats were divided into four groups: control, losartan, L-NAME, and losartan + L-NAME. The responses of isolated mesenteric arterial rings were examined in standard organ chambers after 8 treatment weeks.
  
  
  RESULTS
  Losartan therapy prevented the development of L-NAME-induced hypertension and the associated impairments of endothelium-independent relaxations to nitroprusside, isoprenaline, and cromakalim, vasodilators acting via the formation of NO, activation of beta-adrenoceptors and opening of K+ channels, respectively. In addition, endothelium-dependent relaxations of noradrenaline-precontracted rings to acetylcholine during NO synthase inhibition in vitro were decreased in L-NAME rats, and clearly improved by losartan therapy. The inhibition of cyclooxygenase by diclofenac improved the responses to acetylcholine more effectively in L-NAME than losartan + L-NAME rats, but the relaxations remained decreased in L-NAME rats when compared with losartan + L-NAME rats. When hyperpolarization of smooth muscle was prevented by precontractions induced by high concentration of KCl, the responses to acetylcholine during combined NO synthase and cyclooxygenase inhibition were similar and almost abolished in all groups. Furthermore, superoxide dismutase, a scavenger of superoxide anions, enhanced the acetylcholine-induced relaxations more effectively in L-NAME than losartan + L-NAME rats, although plasma antioxidant capacity was similar in all study groups.
  
  
  CONCLUSIONS
  Chronic L-NAME-induced hypertension was associated with attenuated arterial relaxation via endothelium-dependent and -independent mechanisms, both of which were improved by the losartan treatment. The mechanisms whereby losartan enhanced arterial relaxation in this model of experimental hypertension may have included enhanced hyperpolarization and increased sensitivity to NO in smooth muscle, and decreased vascular production of superoxide and vasoconstrictor prostanoids.
authors.affiliation: University of Tampere Medical School, Department of Pharmacological Sciences, Finland. jarkko.kalliovalkama@uta.fi
authors.forename: J
authors.initials: J
authors.lastname: Kalliovalkama
authors.forename: P
authors.initials: P
authors.lastname: Jolma
authors.forename: J P
authors.initials: JP
authors.lastname: Tolvanen
authors.forename: M
authors.initials: M
authors.lastname: Kähönen
authors.forename: N
authors.initials: N
authors.lastname: Hutri-Kähönen
authors.forename: X
authors.initials: X
authors.lastname: Wu
authors.forename: P
authors.initials: P
authors.lastname: Holm
authors.forename: I
authors.initials: I
authors.lastname: Pörsti
mesh_terms: D000804:Angiotensin II; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D019806:Cromakalim / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D008638:Mesenteric Arteries; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology*; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D016861:Cyclooxygenase Inhibitors; D014665:Vasodilator Agents; D019806:Cromakalim; D000804:Angiotensin II; D004008:Diclofenac; D009599:Nitroprusside; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019808:Losartan; D007545:Isoproterenol; D019331:NG-Nitroarginine Methyl Ester