Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Biochem Pharmacol. 2012 Apr 1;83(7):882-92. doi: 10.1016/j.bcp.2011.12.038. Epub 2012 Jan 11.
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.
在健康猪的内乳动脉 (IMA) 中，研究了内皮和神经因素作为神经源性和去甲肾上腺素诱导的血管收缩的调节剂的作用。河豚毒素、胍乙啶敏感的电刺激 (EFS) 和去甲肾上腺素引起的收缩被哌唑嗪显著减弱（n=8，P<0.001），而屈洛昔芬的作用较小，表明 IMA 有功能性的 α₁-和 α₂-肾上腺素能神经支配的去甲肾上腺素能神经支配。内皮去除减少了神经源性（n=8，P<0.01）但增强了去甲肾上腺素反应（n=8，P<0.01），表明释放了两种具有相反作用的内皮依赖性因子。在内皮存在的情况下，神经源性和外源性去甲肾上腺素的血管收缩被 L-NOArg（n=7，P<0.05 和 P<0.01）和 ODQ（n=7，两者均 P<0.05）增强；在无内皮的动脉中，用 N（ω）-丙基-L-精氨酸抑制 nNOS 增加了神经源性收缩（n=7，P<0.05）。Western blot 表明存在神经源性和内皮源性的 NO（n=6，P<0.001）。四乙铵（n=9，P<0.001）、伊比替定（n=7，P<0.001）和 4-氨基吡啶（n=8，P<0.01）增强了血管收缩，表明大电导钙激活钾（BK(Ca)) 和电压依赖性钾 (K(v)) 通道在去甲肾上腺素反应中具有调节作用。波生坦预处理（n=8，P<0.05）表明内皮素-1 是推断的收缩性神经源性内皮依赖性因子。吲哚美辛诱导的抑制涉及一种肌肉前列腺素（n=9，P<0.05），功能上和免疫上定位，并来源于环氧合酶 (COX)-1 和 COX-2，如 Western blot 所示（n=5，P=0.1267）。因此，去甲肾上腺素能的 IMA 收缩受收缩性前列腺素的激活和内皮素-1 的释放控制，并通过 BK(Ca) 和 K(v) 通道以及神经和内皮源性的 NO 来抵消。这些结果有助于阐明 IMA 血管痉挛的机制，因为 IMA 是冠状动脉旁路移植的首选血管。
