title: Altered coronary dilation in deoxycorticosterone acetate-salt hypertension.
abstract: OBJECTIVE
  To compare coronary dilation in uninephrectomized hypertensive deoxycorticosterone acetate (DOCA)-salt rats (HTRs), treated for 2 or 4 weeks, with age-matched uninephrectomized normotensive rats (NTRs). DESIGN AND METHODS Coronary perfusion pressure was recorded in isolated hearts perfused at a constant flow rate to evaluate coronary resistance.
  
  
  RESULTS
  A decreased vasoconstriction due to NG-nitro-Larginine (NNLA, 30 pmol/I) in hearts from HTRs suggested a reduced basal nitric oxide (NO) release. In contrast, coronary vasodilation due to the NO donor, sodium nitroprusside (3 pmol/I), remained unaffected in 2-week HTRs, and was enhanced in 4-week HTRs. Cumulative dose-response curves to bradykinin induced an important vasodilation in NTRs, with a maximal response that remained unaffected in the presence of either NNLA (30 pmol/I), indomethacin (10 pmol/l) or the two combined. In contrast, hearts from HTRs showed a diminished maximal relaxation to bradykinin, suggesting an altered endothelium-dependent relaxation. The presence of NNLA or indomethacin had no effect on the weak relaxation observed in HTRs. However, NNLA and indomethacin combined unmasked an important relaxation due to bradykinin in HTRs. The addition of clotrimazole (1 pmol/I) to NNLA and indomethacin blunted the relaxation due to bradykinin in both NTRs and HTRs. Perfusion with superoxide dismutase (120 IU/ml) restored most of the coronary relaxation due to bradykinin in hearts from HTRs. Bradykinin-induced prostaglandin 12 (PGI2) and E2 (PGE2) production was unaffected by hypertension. No increase in thromboxane A2 (TXA2) due to bradykinin was detected. Finally, reduced reactivity to papaverine and forskolin was observed in hearts from HTRs.
  
  
  CONCLUSIONS
  DOCA-salt hypertension is associated with alterations in coronary reactivity. Basal NO formation appears to be reduced in HTRs, but the intact relaxation to exogenous NO suggests a preserved guanylate cyclase pathway. In addition, alteration in adenylate cyclase activity, and not in prostaglandin production, may explain the blunted cAMP-mediated responses in HTRs. The combined nitric-oxide synthase (NOS) and cyclo-oxygenase (COX) inhibition unmasked an endothelium-derived hyperpolarizing factor (EDHF) involvement in the coronary dilation due to bradykinin in hearts from HTRs, suggesting that endothelial NO and PGI2, although unable to induce coronary smooth-muscle relaxation, can inhibit EDHF production in HTRs. Impairment in the adenylate cyclase pathway and the suppression of NO by free radicals may explain the blunted vasodilation in DOCA-salt hypertension.
authors.affiliation: Groupe de recherche sur le système nerveux autonome, Faculty of Pharmacy, Université de Montréal, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Millette
authors.forename: J
authors.initials: J
authors.lastname: de Champlain
authors.forename: D
authors.initials: D
authors.lastname: Lamontagne
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology*; D003900:Desoxycorticosterone; D015777:Eicosanoids / Q000502:physiology; D004730:Endothelium, Vascular / Q000503:physiopathology; D006162:Guanylate Cyclase / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D019335:Nitroarginine / Q000494:pharmacology; D010208:Papaverine / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D015777:Eicosanoids; D019335:Nitroarginine; D009569:Nitric Oxide; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D010208:Papaverine; D006162:Guanylate Cyclase; D001920:Bradykinin