Cav 2.2 deficiency or N-type VDCC blockade suppressed Angiotensin II-induced oxidative stress and endothelial dysfunction in mice.
Does inhibition or deletion of N-type voltage-dependent Ca2+ channels prevent angiotensin II-induced endothelial dysfunction and oxidative stress in mice?
N-type voltage-dependent Ca2+ channels in vascular endothelial cells contribute to angiotensin II-induced oxidative stress and endothelial dysfunction, suggesting a potential therapeutic target in hypertension.
N-type voltage-dependent Ca(2+)channels (VDCCs), expressed predominantly in the nervous system, play pivotal roles in sympathetic regulation of the circulatory system. Although N-type VDCCs are also reportedly expressed in the vasculature, their pathophysiological role is obscure. We demonstrated that oxidative stress-related endothelial dysfunction induced by angiotensin (Ang) II is suppressed in mice lacking the N-type VDCC α1B subunit (Cav 2.2). Impairment of endothelium-dependent relaxation of the thoracic aorta observed following Ang II treatment in wild-type (WT) mice was significantly attenuated in the Ang II-treated Cav 2.2-deficient mice, despite the comparable increase of the blood pressure in the two groups of mice. The thoracic aorta of the Cav 2.2-deficient mice showed a smaller positive area of oxidative stress markers as compared to the WT mice. The Ang II-induced endothelial dysfunction was also suppressed by cilnidipine, an L/N-type VDCC blocker, but not by amlodipine, an L-type VDCC blocker; however, this unique effect of cilnidipine was completely abolished in the Cav 2.2-deficient mice. Furthermore, selective inhibition of N-type VDCCs by ω-conotoxin GVIA dramatically suppressed the production of reactive oxygen species (ROS) as well as agonist-induced Ca(2+) influx in the vascular endothelial cells. These results suggest that N-type VDCCs expressed in the vascular endothelial cells contribute to ROS production and endothelial dysfunction observed in Ang II-treated hypertensive mice.
Nishida et al. (2013) studied Angiotensin II-induced oxidative stress-related endothelial dysfunction. Cav 2.2 deficiency and N-type VDCC blockers (cilnidipine, ω-conotoxin GVIA) vs. Wild-type mice and L-type VDCC blocker (amlodipine) was evaluated on Endothelium-dependent relaxation of the thoracic aorta and oxidative stress markers. Cav 2.2 deficiency or N-type VDCC blockade suppressed Angiotensin II-induced oxidative stress and endothelial dysfunction in mice.