Physiology Group, Department of Basic Medical Sciences, Ghent University, UZ blok B, De Pintelaan 185, 9000, Ghent, Belgium.
Pflugers Arch. 2012 Apr;463(5):669-77. doi: 10.1007/s00424-012-1083-1. Epub 2012 Mar 14.
Cannabinoids have potent vasodilatory actions in a variety of vascular preparations. Their mechanism of action, however, is complex. Apart from acting on vascular smooth muscle or endothelial cannabinoid receptors, several studies point to the activation of type 1 vanilloid (TRPV1) receptors on primary afferent perivascular nerves, stimulating the release of calcitonin gene-related peptide (CGRP). In the present study, the direct influence of the cannabinoid methanandamide and the neuropeptide CGRP on the membrane potassium ion (K(+)) currents of rat mesenteric myocytes was explored. Methanandamide (10 μM) decreased outward K(+) currents, an effect similar to that observed in smooth muscle cells from the rat aorta. Conversely, CGRP (10 nM) significantly increased whole-cell K(+) currents and this effect was abolished by preexposure to tetraethylammonium chloride (1 mM) or iberiotoxin (100 nM), inhibitors of large-conductance calcium-dependent K (BK(Ca)) channels but not by glibenclamide (10 μM), an inhibitor of ATP-dependent K channels. In the presence of the CGRP receptor antagonist CGRP(8-37) (100 nM), the adenylyl cyclase inhibitor SQ22536 (100 μM), or the protein kinase A inhibitor Rp-cAMPS (10 μM), CGRP had no effect. These findings show that methanandamide does not increase membrane K(+) currents in smooth muscle cells of small mesenteric arteries, supporting an indirect mechanism for the reported hyperpolarizing influence in this vessel. Moreover, CGRP acts directly on these smooth muscle cells by increasing BK(Ca) channel activity in a CGRP receptor and cyclic adenosine monophosphate-dependent way. Collectively, these data indicate that methanandamide relaxes and hyperpolarizes intact mesenteric vessels by releasing CGRP from perivascular nerves.
大麻素在各种血管制剂中具有强大的血管舒张作用。然而，其作用机制很复杂。除了作用于血管平滑肌或内皮大麻素受体外，几项研究还指出，初级传入血管周围神经上的 1 型香草素（TRPV1）受体被激活，刺激降钙素基因相关肽（CGRP）的释放。在本研究中，探索了大麻素甲酰胺和神经肽 CGRP 对大鼠肠系膜心肌细胞膜钾离子（K+）电流的直接影响。甲酰胺（10 μM）减少外向 K+电流，其作用类似于在大鼠主动脉平滑肌细胞中观察到的作用。相反，CGRP（10 nM）显著增加全细胞 K+电流，该作用被四乙铵氯化物（1 mM）或 Iberiotoxin（100 nM）预先暴露所消除，后者是大电导钙依赖性 K（BK（Ca））通道的抑制剂，但不是格列本脲（10 μM），它是 ATP 依赖性 K 通道的抑制剂。在 CGRP 受体拮抗剂 CGRP（8-37）（100 nM）、腺苷酸环化酶抑制剂 SQ22536（100 μM）或蛋白激酶 A 抑制剂 Rp-cAMPS（10 μM）存在的情况下，CGRP 没有作用。这些发现表明，甲酰胺不会增加肠系膜小动脉平滑肌细胞中的膜 K+电流，支持在该血管中报告的超极化作用的间接机制。此外，CGRP 通过以 CGRP 受体和环磷酸腺苷依赖性方式增加 BK（Ca）通道活性，直接作用于这些平滑肌细胞。总的来说，这些数据表明，甲酰胺通过从血管周围神经释放 CGRP 来松弛和超极化完整的肠系膜血管。
