Vasodilatory Effect of a Rho Kinase Inhibitor DL0805 on the Rat Basilar Artery and its Potential Mechanisms

[Speaker] Li Li:1
[Co-author] Wendan Lu:1, Yanjia Shen:1, Xiaoping Wu:1, Tianyi Yuan:1, Lianhua Fang:1, Guanhua Du:1
1:National Center for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, China

BACKGROUND DL0805 (5-nitro-1H-indazole-3-carbonitrile) is a new Rho kinase inhibitor discovered by high-throughput screening (HTS) in our previous work, and it was found to have a vasorelaxant effect in rat aortic rings contacted by KCL or angiotensin II. However, whether it has the vasorelaxant effects on isolated rat basilar artery rings and the underlying mechanisms are still not known. METHODS Endothelium-intact and -denuded basilar artery rings were prepared from SD rats, and then stimulated with KCL, 5-hydroxytryptamine (5-HT) and endothelin-1(ET-1). The tension of the basilar artery rings was measured through an isometric force transducer. RESULTS DL0805 exerted vasorelaxation at a dose-dependent manner in endothelium-intact rings contracted by KCL (60 mM), 5-HT (10E-6M) and ET-1 (10E-8M). Preincubation with DL0805 attenuated contractile responses to KCl (10-60 mM), 5-HT (10E-9-10E-5 M) and ET-1 (10E-11-10E-7.5 M) in basilar artery rings. Accordingly, in human brain vascular smooth muscle cells (HBVSMCs), DL0805 was observed to inhibit the ET-1-induced cytoskeletal remodeling. The molecular docking results showed that DL0805 barely interacted with both 5-HT1B receptor (5-HT1BR) and ET1B receptor (ET1BR). Moreover, pre-incubation with pinocembrin dramatically suppressed the high K+-induced extracellular Ca2+ influx and ET-1-induced intracellular Ca2+ release in endothelium-denuded rings. CONCLUSIONS These results demonstrated that DL0805 has a vasorelaxant effect on isolated rat basilar artery rings. It may exert effects by blockade of Ca2+ channels via blocking ET1BR.
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