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Pagán RM, Martínez AC, Hernández M, Martínez MP, García-Sacristán A, Correa C, Novella S, Hermenegildo C, Prieto D, Benedito S

Endothelial and neural factors functionally involved in the modulation of noradrenergic vasoconstriction in healthy pig internal mammary artery.

Biochem. Pharmacol.. 2012 Apr;83(7):882-92, PMID: 22260985

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.

PHARMACOLOGY & PHARMACY

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