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

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 Nω-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+ (BKCa) and voltage-dependent K+ (Kv) 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 BKCa and Kv channels and neural and endothelial NO. These results help clarify the mechanisms of vasospasm in IMA, as the preferred vessel for coronary bypass.

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