oa Role of Inositol 1,4,5-Triphosphate Receptors in Hypertension

Background: Chronic hypertension is a deadly disease that affects nearly 30–36% of the adult population in Qatar and the regional. Inositol 1,4,5-triphosphate receptors (IP3R) are intracellular calcium (Ca²⁺) channels that mediate the release of Ca2+ from sarcoplasmic reticulum in response to IP3 binding. A rise in cytoplasmic Ca²⁺ mediated by voltage-dependent L-type Ca²⁺ (CaL) channels and IP3-dependent Ca²⁺ release can enhance vascular smooth muscle cells (VSMC) contractility and determine peripheral vascular resistance.

Objective: The goal of this study is to elucidate the role of IP3R in hypertension.

Methods: Two rat models of hypertension and the A7r5 rat embryonic aortic cells are used in this project. Proteins for western blot were isolated from small mesenteric arteries (SMA) from hypertensive rats and A7r5 cells. Contraction measurements were performed in isolated arterial rings mounted for tension-recording assays. Contraction was induced with KCl and the phospholipase C (PLC) activator m-3M3FBS. The modulation of the vasoconstrictor responsiveness of SMA by IP3R and nitric oxide (NO) was depicted in a pressurized SMA incubated in the presence or absence of 2-APB (IP3R blocker) and L-NAME (NO synthase inhibitor). A7r5 basal Ca²⁺ levels were assessed using a fluorescence Ca²⁺ imaging system.

Results: Our preliminary results show that IP3R is up regulated in SMA from two different hypertensive rat models and following membrane depolarization in A7r5 cells. This up regulation is associated with an enhanced myogenic tone in response to activation of the PLC-IP3 pathway in SMA and with an increased basal Ca²⁺ levels in A7r5 cells. In contrast, pharmacological inhibition of IP3R alters the vasoconstriction response of pressurized vessels. Furthermore, IP3R upregulation and basal Ca²⁺ increase are lost in A7r5 cells treated with Nifedipine (CaL channels blocker) and drugs that block the Calcineurin-NFAT pathway before depolarization with KCl.

Conclusions: These findings improve our basic understanding of the etiology of hypertension by defining the abnormalities of IP3-dependent Ca²⁺ signaling in VSMC. This may provide novel insights into the pathogenesis of hypertension and set the groundwork for developing novel therapeutic targets for the treatment of hypertension.