title: Alpha1D-adrenoceptor-induced relaxation on rat carotid artery is impaired during the endothelial dysfunction evoked in the early stages of hyperhomocysteinemia.
abstract: Hyperhomocysteinemia is a known risk factor for cardiovascular diseases, but the underlying mechanisms of this pathology are complex. We aimed to evaluate the effect of hyperhomocysteinemia in vasorelaxations induced by alpha(1D)-adrenoceptor agonists. Vascular reactivity of rat carotid artery to the alpha-adrenoceptor agonist, phenylephrine, was enhanced in hyperhomocysteinemia. Mechanical removal of endothelium did not modify the carotid responsiveness to phenylephrine, compared to control. Phenylephrine induces endothelium-dependent relaxation, in the presence of 5-methyl urapidil (alpha(1A)-adrenoceptor antagonist). We hypothesised that endothelial-relaxant alpha(1)-adrenoceptors are impaired by hyperhomocysteinemia. Incubation with prazosin (selective alpha(1)-adrenoceptor antagonist) or BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7, 9-dione dihydrochloride) (selective alpha(1D)-adrenoceptor antagonist), similarly inhibited phenylephrine-induced relaxations in both control and hyperhomocysteinemic carotids. Immunohistochemistry showed enhanced immunoreactivity for eNOS and iNOS in hyperhomocysteinemic rats. In carotid arteries from hyperhomocysteinemic rats there was a decrease in superoxide dismutase activity and enhanced superoxide anion production. We conclude that alpha(1D)-adrenoceptors mediate endothelium-dependent relaxation triggered by phenylephrine in rat carotid artery and affect the final tone. Furthermore, the enhanced phenylephrine-induced contraction in carotid artery due to hyperhomocysteinemia is endothelium-dependent and involves a loss of the inhibitory effect of relaxant alpha(1D)-adrenoceptors by reducing NO biodisponibility.
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Claudia Roberta
authors.initials: CR
authors.lastname: de Andrade
authors.forename: Sandra Yasuyo
authors.initials: SY
authors.lastname: Fukada
authors.forename: Vania Claudia
authors.initials: VC
authors.lastname: Olivon
authors.forename: Marcio A F
authors.initials: MA
authors.lastname: de Godoy
authors.forename: Renato
authors.initials: R
authors.lastname: Haddad
authors.forename: Marcos Nogueira
authors.initials: MN
authors.lastname: Eberlin
authors.forename: Fernando Queiroz
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Heraldo Possolo
authors.initials: HP
authors.lastname: de Souza
authors.forename: Francisco R M
authors.initials: FR
authors.lastname: Laurindo
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: de Oliveira
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020138:Hyperhomocysteinemia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
chemical_list: C547721:Adra1d protein, rat; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D004791:Enzyme Inhibitors; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D013481:Superoxides; C057446:5-methylurapidil; D010656:Phenylephrine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; C053428:BMY 7378; D019331:NG-Nitroarginine Methyl Ester; D011224:Prazosin