World Sleep Day - March 19, 2021

Emília Monteiro and Sofia Pereira Lab - Translational Pharmacology

Arterial Hypertension (HTN) is the main risk factor with preventive potential for cardiovascular diseases. HTN increases the risk of stroke and myocardial infarction which may be fatal or imply a great loss in mobility and autonomy. Therefore, efforts should be focused in early interventions to prevent irreversible injury of target organs (eg. heart, kidney).
The advent of renin-angiotensin-aldosterone system blockers in 70-80´s constituted a significant improvement in HTN management. However, drug resistant HTN is still a major problem because the umbrella of “essential” HTN covers different mechanisms and vulnerabilities for HTN (phenotypes) under a one-fits-all therapeutic management. Secondary HTN related to obstructive sleep apnea (OSA), while out of the “essential” umbrella of HTN, faces similar challenges, requiring antihypertensive drugs through all life with long-term toxicities. OSA is the most relevant cause of resistant HTN other OSA comorbidities (obesity, kidney disease) might also contribute for it. It is not hard to believe that OSA-HTN might have particular pathways for blood pressure control that justify available drug resistance. The characteristic short ischemia-reperfusion cycles, the associated increases in HIFs, high sympathetic activity and particularly diurnal hypertension despite the exclusive nocturnal trigger, could give some mechanistic-driven rational. Additionally, the multifactorial pathophysiology of OSA (anatomical variables, muscle hypotonicity) precludes an etiological treatment and the standard therapy with continuous positive airway pressure (CPAP), is not patient-friendly, non-adherence rates go up to 50% and effectivity in controlling HTN is controversial and patients maintain antihypertensive drugs plus CPAP use for life.

We have been following the scientific developments on the interaction between environmental factors (pollution, climate), microbiota, lifestyle factors with the individual susceptibility to develop HTN and the impact in antihypertensive drug response. We assume that these factors, combined with particular (epi)genetic/physiological backgrounds, favors increased levels of particular metabolites, increased synthesis and/or decreased elimination, promoting deleterious effects. A parallelism can be made with other secondary causes of HTN (i.e catecholamines and pheochromocytoma, uremic toxins and chronic kidney disease).
That is why AhR protein has attracted our attention: AhR is the hub of a network linking microbiota, environment and metabolic signals that interplays with O2 sensing trough hypoxia inducible factors (HIFs) and is a transcription factor with multitasking that activities (detoxification, immunoregulation, cell proliferation) to deal not only with the complexity of OSA-HTN but also other comorbidities that contribute for that (obesity, chronic kidney disease, insulin resistance). Several genetic studies associated AhR-ARNT-Cyp1A1 with HTN.
We proposed the existence of AhR-related phenotype of HTN, that may contribute to explain why some persons are more sensible to environmental factors than others and /or why the response to anti-hypertensive drugs is so variable among HTN patients, particularly in OSA.
We anticipate that chronic intermittent hypoxia (CIH) increases the production of AhR agonists that dysregulate mechanisms relevant to blood pressure control. From a pharmacological point of view, the collective inhibition of the production of these environmental and internal metabolites would be impossible, so a reasonably option is to block the action of these metabolites. We reported the first proof of concept of AhR antagonists antihypertensive efficacy in CIH-induced HTN, using CH223191 as a model drug.

We are now working to consolidate this evidence and understand the determinants of AhR antagonists’ efficacy, in order to advance in the knowledge that allows its use in humans to treat systemic arterial hypertension.

Learn more: Emília Monteiro & Sofia Pereira Lab