MacLeod K M, Ng D D, Harris K H, Diamond J
Mol Pharmacol. 1987 Jul;32(1):59-64.
Endothelium-derived relaxing factors (EDRFs) have been previously shown to exert an inhibitory influence on the contractile effects of alpha-adrenoceptor agonists in vascular smooth muscle. alpha 2-Adrenoceptor agonists such as clonidine have been reported to be particularly susceptible to this effect, and it has been suggested that clonidine acts on alpha 2 receptors on endothelial cells to stimulate the release of EDRF. EDRF release is known to be accompanied by increased levels of cGMP in many blood vessels, and it is suggested that cGMP exerts an inhibitory influence on the smooth muscle cells, which tends to counteract the contractile effect of the clonidine. This hypothesis was tested in isolated rings of rat aorta and mesenteric artery using the cGMP lowering agent, 6-anilino-5,8-quinolinedione (LY83583). LY83583 markedly decreased resting levels of cGMP in these vascular preparations and completely prevented both the relaxation and the cGMP elevation normally caused by acetylcholine in rat aorta with intact endothelium. These effects of LY83583 are identical to those observed after mechanical disruption of the endothelium. LY83583 also enhanced the contractile responses to norepinephrine and particularly to clonidine in both aorta and mesenteric artery. The effects of LY83583 on contractile responses to both alpha-adrenoceptor agonists were reversed by low concentrations of 8-bromo-cGMP. Clonidine did not increase cGMP levels in vascular preparations with intact endothelia, in the presence or absence of LY83583. Thus, enhanced release of EDRF by clonidine did not appear to be responsible for the inhibition of its contractile effects observed in the presence of intact endothelial cells. Our results suggest instead that this endothelium-dependent inhibition is due to spontaneous release of EDRF, which results in tonic elevation of cGMP in the vascular smooth muscle. This tonic elevation of cGMP exerts a more marked inhibitory effect against contractions induced by the partial agonist, clonidine, than it does against contractions induced by a full agonist, norepinephrine.
内皮源性舒张因子（EDRFs）先前已被证明对血管平滑肌中α-肾上腺素能受体激动剂的收缩作用具有抑制影响。据报道，可乐定等α₂-肾上腺素能受体激动剂对这种作用尤为敏感，并且有人提出可乐定作用于内皮细胞上的α₂受体以刺激EDRF的释放。已知在许多血管中，EDRF的释放伴随着cGMP水平的升高，并且有人提出cGMP对平滑肌细胞具有抑制影响，这倾向于抵消可乐定的收缩作用。使用cGMP降低剂6-苯胺基-5,8-喹啉二酮（LY83583）在大鼠主动脉和肠系膜动脉的离体血管环中对这一假说进行了检验。LY83583显著降低了这些血管标本中的cGMP静息水平，并完全阻止了完整内皮的大鼠主动脉中通常由乙酰胆碱引起的舒张和cGMP升高。LY83583的这些作用与内皮机械性破坏后观察到的作用相同。LY83583还增强了主动脉和肠系膜动脉对去甲肾上腺素尤其是对可乐定的收缩反应。低浓度的8-溴-cGMP可逆转LY83583对两种α-肾上腺素能受体激动剂收缩反应的影响。在存在或不存在LY83583的情况下，可乐定均未增加完整内皮的血管标本中的cGMP水平。因此，可乐定增强EDRF的释放似乎并不是其在完整内皮细胞存在时所观察到的收缩作用受到抑制的原因。相反，我们的结果表明，这种内皮依赖性抑制是由于EDRF的自发释放，这导致血管平滑肌中cGMP的持续性升高。cGMP的这种持续性升高对部分激动剂可乐定诱导的收缩的抑制作用比对完全激动剂去甲肾上腺素诱导的收缩的抑制作用更为明显。
