Norisoboldine Induces Endothelium-Dependent Vasorelaxation and Attenuates Hypertension by Modulating Ca2+-eNOS Signaling, Oxidative Stress, and Inflammation

Vascular function is a direct factor affecting blood pressure, and it is a primary strategy for clinically controlling hypertension by regulating the constriction/relaxation of blood vessels. This study evaluates the vasodilatory and anti-hypertensive effects of norisoboldine (NOR), an isoquinoline alkaloid in Ayurvedic medicine. The rat thoracic aorta was isolated to investigate the vasodilatory effect, and L-NAME-induced hypertensive rats were established, respectively. In the isolated vascular ring, removal of the endothelium resulted in a significant decrease in the vasodilatory effect. Pretreatment with L-NAME, ODQ, KT5823, WT, Tri, Dilt, calcium-free solution, TG, Gd³⁺, 2-APB, Indo, 4-AP, Gli, and BaCl₂ inhibited the vasodilatory effect of NOR. In vascular endothelial cells, NOR promoted eNOS phosphorylation and inhibited TNF-α-induced expression of ICAM-1 and VCAM-1. SBP and DBP were significantly decreased after administration of different doses of NOR in the femoral vein of rats. In addition, NOR significantly reduced the blood pressure of L-NAME-induced hypertensive rats, up-regulated the serum levels of NO, cGMP, and CAT, and down-regulated MDA, IL-6, and TNF-α in hypertensive rats. NOR administration improved pathological changes in the thoracic aorta by regulating the arrangement of thoracic aortic smooth muscle cells, decreasing the thickness of the thoracic aortic wall, and reducing the degree of collagen deposition and fibrosis. In conclusion, the vasodilatory mechanisms of NOR were related to the Ca²⁺-eNOS signaling pathway, including the PGI₂ and various K⁺/Ca²⁺ channels, the inositol triphosphate receptor (IP₃R) calcium release, and the α-adrenergic receptor pathway. The anti-hypertensive mechanism of NOR may be related to increased NO and cGMP bioavailability, inhibition of oxidative stress and inflammatory responses, and improved vascular remodeling.