ARYL HYDROCARBON RECEPTOR ANTAGONISTS - A NEW ENTRY IN ANTIHYPERTENSIVE ARMAMENTARIUM OF OBSTRUCTIVE SLEEP APNEA?

Abstract

Objective: To investigate aryl hydrocarbon receptor (AhR) metabolic circuitry as a druggable target in chronic intermittent hypoxia (CIH) induced hypertension (HTA). Design and method: This study was approved by Nova Medical School's Ethics Committee and followed national and international regulations. We used a rat model of CIH-induced HTA to disclose the hypothesis that the aryl hydrocarbon receptor (AHR) is activated by IH, once it shares the same binding partner of HIF-1alpha and promotes pro-oxidant, pro-inflammatory (NF-kB) and pro-fibrotic events in common with CIH. AhR activation was measured by the mRNA and protein levels of its hallmark target gene Cyp1a1. Blood pressure, heart rate and locomotor activity were measured daily by radiotelemetry. A CIH paradigm of 21% to 5% of O2, 5.6 cycles/h, 10.5 h/day was used in their inactive/sleep period. Results: Upon established hypertension (21 days exposure to IH), we observed an increase in Cyp1a1 mRNA (hallmark of AhR activation) in kidney cortex (6-fold), kidney medulla (3-fold) and liver (3-fold), but not in other tissues. Increased renal expression of Ahr and markers of inflammation (Rela), epithelial to mesenchymal transition markers, the rate-controlling step of gluconeogenesis, Pepck1, and members of HIF-pathway, namely, Hif-3alpha were also observed. The ratio kynurenin/tryptophan (inflammatory index) was also increased in the kidney. The chronicity of IH increased the protein levels of cyp1a1 protein (western blot). Daily administration (14 days) of AHR antagonist, CH-223191 (5 mg.kg-1.day-1, gavage), simultaneously to CIH prevented the increase in systolic blood pressure (SBP) by 53 ± 12% and in diastolic blood pressure (DBP) by 44 ± 16%. Moreover, this AhR antagonist administration upon already established HTN reversed the increase in SBP by 52 ± 12%. Despite the antihypertensive effect seen in the rats’ active phase, in the inactive period, CH22319 did not revert the non-dipping blood pressure profile associated to CIH. Conclusions: CIH caused an activation of AHR signaling particularly in the kidney and its pharmacological blockade had a significant impact reverting already established HTN. This first evidence inspires innovative research opportunities for the understanding and treatment of this particular type of HTN.