title: Endothelial and neural factors functionally involved in the modulation of noradrenergic vasoconstriction in healthy pig internal mammary artery.
abstract: The role of endothelial and neural factors as modulators of neurogenic- and noradrenaline-induced vasoconstriction was examined in healthy pig internal mammary artery (IMA). Tetrodotoxin-, guanethidine-sensitive electrical field stimulation (EFS)-, and noradrenaline-elicited contractions were significantly diminished by prazosin (n=8, P<0.001) and less so by rauwolscine, indicating functional α₁- and α₂-adrenoceptor-mediated noradrenergic innervation of the IMA. Endothelium removal reduced neurogenic (n=8, P<0.01) but augmented noradrenaline responses (n=8, P<0.01), suggesting the release of two endothelium-dependent factors with opposite effects. In the presence of endothelium, neurogenic and exogenous noradrenaline vasoconstrictions were enhanced by L-NOArg (n=7, P<0.05 and P<0.01 respectively) and ODQ (n=7, both P<0.05); in denuded arteries, nNOS inhibition with N(ω)-propyl-L-arginine increased neurogenic contraction (n=7, P<0.05). Western blotting indicated the presence of neural and endothelial origin NO (n=6, P<0.001). Tetraethylammonium (n=9, P<0.001), iberiotoxin (n=7, P<0.001) and 4-aminopyridine (n=8, P<0.01) enhanced vasoconstrictions revealing a modulatory role of big conductance Ca²⁺-activated K⁺ (BK(Ca)) and voltage-dependent K⁺ (K(v)) channels in noradrenergic responses. Bosentan pretreatment (n=8, P<0.05) suggested endothelin-1 as the inferred contractile neurogenic endothelial-dependent factor. Indomethacin-induced inhibition involved a muscular prostanoid (n=9, P<0.05), functionally and immunologically localized, and derived from cyclooxygenase (COX)-1 and COX-2, as revealed by Western blots (n=5, P=0.1267). Thus, noradrenergic IMA contractions are controlled by contractile prostanoid activation and endothelin-1 release, and offset by BK(Ca) and K(v) channels and neural and endothelial NO. These results help clarify the mechanisms of vasospasm in IMA, as the preferred vessel for coronary bypass.
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
authors.forename: Rosa María
authors.initials: RM
authors.lastname: Pagán
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Martínez
authors.forename: Medardo
authors.initials: M
authors.lastname: Hernández
authors.forename: María Pilar
authors.initials: MP
authors.lastname: Martínez
authors.forename: Albino
authors.initials: A
authors.lastname: García-Sacristán
authors.forename: Carlos
authors.initials: C
authors.lastname: Correa
authors.forename: Susana
authors.initials: S
authors.lastname: Novella
authors.forename: Carlos
authors.initials: C
authors.lastname: Hermenegildo
authors.forename: Dolores
authors.initials: D
authors.lastname: Prieto
authors.forename: Sara
authors.initials: S
authors.lastname: Benedito
mesh_terms: D018674:Adrenergic Antagonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D004558:Electric Stimulation; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism / Q000502:physiology; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D008323:Mammary Arteries / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism / Q000502:physiology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009412:Nerve Fibers / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology* / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D013552:Swine; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
chemical_list: D018674:Adrenergic Antagonists; D045462:Endothelium-Dependent Relaxing Factors; D054086:KATP Channels; D018727:Muscarinic Antagonists; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D011453:Prostaglandins; D009569:Nitric Oxide; D009638:Norepinephrine