Fahning Bernah M, Potje Simone R, Paula Tiago D, Grando Marcella D, Bendhack Lusiane M
Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto - University of São Paulo - USP, Brazil.
Department of Medical Sciences, Minas Gerais State University - UEMG, Brazil.
Vasc Biol. 2024 Jun 27;6(1). doi: 10.1530/VB-23-0021. Print 2024 Jan 1.
Renin-angiotensin system plays a critical role in blood pressure control, and the abnormal activation of the AT1 receptor contributes to the development of renovascular hypertension. This study aimed to evaluate the underlying cellular signaling for AT1 receptor activation by Ang II and to compare this mechanism between aortas from 2K-1C and 2K rats. Effects of antagonists and inhibitors were investigated on Ang II-induced contractions in denuded or intact-endothelium aortas. The AT1 receptor antagonist abolished Ang II-induced contraction in 2K-1C and 2K rat aortas, while AT2 and Mas receptors antagonists had no effect. Endothelial nitric oxide synthase inhibition increased the maximal effect (Emax) of Ang II in 2K, which was not changed in 2K-1C aortas. It was associated with lower eNOS mRNA levels in 2K-1C. Endothelium removal increased the Emax of Ang II in 2K-1C and mainly in 2K rat aortas. Nox and COX inhibition did not alter Ang II-induced contraction in 2K and 2K-1C rat aortas. However, AT1 expression was higher in 2K-1C compared to 2K rat aortic rings, whereas expression of phosphorylated (active) IP3 receptors was lower in 2K-1C than in 2K rats. These results demonstrate that endothelium removal impairs Ang II-stimulated contraction in the aorta of 2K-1C rats, which is associated with the reduction of IP3 receptor phosphorylation and activation. In addition, eNOS plays a critical role in Ang II-induced contraction in 2K rat aortas. It is possible that the high Ang II plasma levels could desensitize AT1 receptor in 2K-1C rats, leading to impaired IP3 receptors activation.
肾素 - 血管紧张素系统在血压控制中起关键作用，AT1受体的异常激活有助于肾血管性高血压的发展。本研究旨在评估Ang II激活AT1受体的潜在细胞信号，并比较2K - 1C和2K大鼠主动脉之间的这种机制。研究了拮抗剂和抑制剂对去内皮或完整内皮主动脉中Ang II诱导的收缩的影响。AT1受体拮抗剂消除了2K - 1C和2K大鼠主动脉中Ang II诱导的收缩，而AT2和Mas受体拮抗剂则无作用。内皮型一氧化氮合酶抑制增加了2K大鼠主动脉中Ang II的最大效应（Emax），而在2K - 1C主动脉中未改变。这与2K - 1C中较低的eNOS mRNA水平有关。去除内皮增加了2K - 1C和主要是2K大鼠主动脉中Ang II的Emax。Nox和COX抑制未改变2K和2K - 1C大鼠主动脉中Ang II诱导的收缩。然而，与2K大鼠主动脉环相比，2K - 1C中AT1的表达更高，而2K - 1C中磷酸化（活性）IP3受体的表达低于2K大鼠。这些结果表明，去除内皮会损害2K - 1C大鼠主动脉中Ang II刺激的收缩，这与IP3受体磷酸化和激活的减少有关。此外，eNOS在2K大鼠主动脉中Ang II诱导的收缩中起关键作用。有可能2K - 1C大鼠中高血浆Ang II水平会使AT1受体脱敏，导致IP3受体激活受损。
