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

## TL;DR

Norisoboldine relaxes blood vessels and lowers high blood pressure by affecting calcium signaling, reducing inflammation, and improving blood vessel health.

## Contribution

The study identifies new mechanisms by which norisoboldine induces vasorelaxation and reduces hypertension through Ca2+-eNOS signaling and anti-inflammatory effects.

## Key findings

- Norisoboldine's vasodilatory effect is endothelium-dependent and involves multiple signaling pathways.
- Norisoboldine reduces hypertension by increasing NO and cGMP levels and decreasing oxidative stress and inflammation.
- Norisoboldine improves vascular remodeling and reduces aortic wall thickness in hypertensive rats.

## Abstract

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.