Rattan Satish, Fan Ya-Ping, Puri Rajinder N
Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Life Sci. 2002 Mar 22;70(18):2147-64. doi: 10.1016/s0024-3205(01)01527-2.
Studies were performed to compare the actions of Ang II in the internal anal sphincter (IAS) vs. lower esophageal sphincter (LES) smooth muscles in vitro, in opossum and rabbit. Studies also were carried out in isolated smooth muscle cells. In opossum, Ang II produced no discernible effects in the IAS, but did produce a concentration-dependent contraction in the LES. Conversely, in the rabbit, while Ang II caused a modest response in the LES, it caused a significant contraction in the IAS. The contractile responses of Ang II in the opossum LES were mostly resistant to different neurohumoral antagonists but were antagonized by AT1 antagonist losartan. AT2 antagonist PD 123,319, rather than inhibiting, prolonged the contractile action of Ang II. The contractile actions of Ang II in the opossum LES were not modified by the tyrosine kinase inhibitors (genistein and tyrphostin 1 x 10(-6) M) but were partially attenuated by the PKC inhibitor H-7 (1 x 10(-6) M), Ca2+ channel blocker nicardipine (1 x 10(-5) M), Rho kinase inhibitor HA-1077 (1 x 10(-7) M) or p(44/42) MAP kinase inhibitor PD 98059 (5 x 10(-5) M). The combination of HA-1077 and H-7 did not cause an additive attenuation of Ang II responses. Western blot analyses revealed the presence of both AT1 and AT2 receptors. We conclude that Ang lI-induced contraction of sphincteric smooth muscle occurs primarily by the activation of AT1 receptors at the smooth muscle cells and involves multiple pathways, influx of Ca2+, and PKC, Rho kinase and p(44/42) MAP kinase.
开展了多项研究，以比较血管紧张素II（Ang II）在负鼠和家兔体内对肛管内括约肌（IAS）与食管下括约肌（LES）平滑肌的作用。研究还在分离的平滑肌细胞中进行。在负鼠中，Ang II对IAS未产生明显作用，但对LES产生浓度依赖性收缩。相反，在家兔中，虽然Ang II对LES引起适度反应，但对IAS引起显著收缩。Ang II在负鼠LES中的收缩反应大多对不同的神经体液拮抗剂有抗性，但被AT1拮抗剂氯沙坦所拮抗。AT2拮抗剂PD 123,319非但没有抑制，反而延长了Ang II的收缩作用。酪氨酸激酶抑制剂（染料木黄酮和 tyrphostin 1×10⁻⁶ M）未改变Ang II在负鼠LES中的收缩作用，但PKC抑制剂H-7（1×10⁻⁶ M）、钙通道阻滞剂尼卡地平（1×10⁻⁵ M）、Rho激酶抑制剂HA-1077（1×10⁻⁷ M）或p(44/42) MAP激酶抑制剂PD 98059（5×10⁻⁵ M）可部分减弱其收缩作用。HA-1077和H-7联合使用并未导致对Ang II反应的叠加减弱。蛋白质免疫印迹分析显示同时存在AT1和AT2受体。我们得出结论，Ang II诱导的括约肌平滑肌收缩主要通过平滑肌细胞上AT1受体的激活而发生，并且涉及多种途径，包括Ca²⁺内流以及PKC、Rho激酶和p(44/42) MAP激酶。
