Department of Biomedicine, Membranes, University of Aarhus, Aarhus, Denmark.
Department of Biomedical Sciences, University of Copenhagen, Denmark.
J Physiol. 2019 Apr;597(7):1819-1831. doi: 10.1113/JP277368. Epub 2019 Feb 21.
The prevailing dogma about neurogenic regulation of vascular tone consists of major vasodilatation caused by CGRP (and possibly substance P) released from sensory-motor nerves and vasoconstriction caused by noradrenaline, ATP and neuropeptode Y release from sympathetic nerves. Most studies on perivascular nerve-mediated vasodilatation are made in vitro. In the present study, we provide evidence indicating that in vivo electrical perivascular nerve stimulation in rat mesenteric small arteries causes a large β1-adrenoceptor-mediated vasodilatation, which contrasts with a smaller vasodilatation caused by endogenous CGRP that is only visible after inhibition of Y1 NPY receptors.
Mesenteric arteries are densely innervated and the nerves are important regulators of vascular tone and hence blood pressure and blood flow. Perivascular sensory-motor nerves have been shown to cause vasodilatation in vitro. However, less is known about their function in vivo. Male Wistar rats (10-12 weeks old; n = 72) were anaesthetized with ketamine (3 mg kg ) and xylazine (0.75 mg kg ) or pentobarbital (60 mg kg ). After a laparotomy, a section of second-order mesenteric artery was visualized in an organ bath after minimal removal of perivascular adipose tissue. The effects of electrical field stimulation (EFS) and drugs on artery diameter and blood flow were recorded with intravital microscopy and laser speckle imaging. EFS caused vasodilatation in arteries constricted with 1 μm U46619 in the presence of 140 μm suramin and 1 μm prazosin. The vasodilatation was inhibited by 1 μm tetrodotoxin and 5 μm guanethidine, although not by the 1 μm of the CGRP receptor antagonist BIBN4096bs. In the presence of 0.3 μm Y1 receptor antagonist BIBP3226, BIBN4096bs partly inhibited the vasodilatation. Atenolol at a concentration 1 μm inhibited the vasodilatation, whereas 0.1 μm of the β -adrenoceptor selective antagonist ICI-118,551 had no effect. Increasing the extracellular [K ] to 20 mm caused vasodilatation but was converted to vasoconstriction in the presence of 1 μm BIBN4096bs, and constriction to 30 mm potassium was potentiated by BIBN4096bs. Atenolol but not BIBN4096bs increased contraction to EFS in the absence of suramin and prazosin. In mesenteric small arteries of anaesthetized rats, EFS failed to stimulate major dilatation via sensory-motor nerves but induced sympathetic β -adrenoceptor-mediated dilatation.
神经源性血管张力调节的主流观点包括感觉运动神经释放的 CGRP（和可能的 P 物质）引起的主要血管舒张，以及交感神经释放的去甲肾上腺素、ATP 和神经肽 Y 引起的血管收缩。大多数关于血管周围神经介导的血管舒张的研究都是在体外进行的。在本研究中，我们提供的证据表明，在体内电刺激大鼠肠系膜小动脉的血管周围神经会引起大量β 1-肾上腺素能受体介导的血管舒张，这与内源性 CGRP 引起的较小血管舒张形成对比，后者只有在抑制 Y1 NPY 受体后才可见。
肠系膜动脉密布神经，这些神经是血管张力和血压及血流量的重要调节剂。已经证明血管周围感觉运动神经在体外可引起血管舒张。然而，关于它们在体内的功能知之甚少。雄性 Wistar 大鼠（10-12 周龄；n=72）用氯胺酮（3mg/kg）和二甲噻嗪（0.75mg/kg）或戊巴比妥（60mg/kg）麻醉。剖腹手术后，在器官浴中最小程度地去除血管周围脂肪组织后，可视化第二级肠系膜动脉的一段。通过活体显微镜和激光散斑成像记录电刺激（EFS）和药物对动脉直径和血流的影响。在存在 140μm 苏拉明和 1μm 普萘洛尔的情况下，用 1μm U46619 收缩的动脉中，EFS 引起血管舒张。血管舒张被 1μm 河豚毒素和 5μm 胍乙啶抑制，但不受 1μm CGRP 受体拮抗剂 BIBN4096bs 的抑制。在存在 0.3μm Y1 受体拮抗剂 BIBP3226 的情况下，BIBN4096bs 部分抑制了血管舒张。浓度为 1μm 的阿替洛尔抑制血管舒张，而 0.1μm 的β-肾上腺素能受体选择性拮抗剂 ICI-118,551 没有作用。将细胞外[K]增加到 20mm 会引起血管舒张，但在存在 1μm BIBN4096bs 的情况下会转化为血管收缩，而 30mm 钾引起的收缩会被 BIBN4096bs 增强。阿替洛尔但不是 BIBN4096bs 在没有苏拉明和普萘洛尔的情况下增加了对 EFS 的收缩反应。在麻醉大鼠的肠系膜小动脉中，EFS 未能刺激感觉运动神经引起主要的舒张，但诱导了交感神经β-肾上腺素能受体介导的舒张。
