Hypertension In Intermittent Hypoxia Research Articles

Pharmacological and genetic inhibition of transient receptor potential melastatin-subfamily member 7 (Trpm7) channel in the carotid body attenuated intermittent hypoxia-induced hypertension

RATIONALE: Obesity causes hypertension and sleep disordered breathing (SDB). Intermittent hypoxia (IH), a cardinal feature of SDB, also causes hypertension contributing to cardiovascular sequelae of obesity. The carotid body plays a role in the IH-induced hypertension. We have previously shown that obesity increases expression of the transient receptor potential melastatin-subfamily member 7 (TRPM7) channel in CB glomus cells and that knockdown of TRPM7 in CB treats hypertension in diet-induced obese mice. Our data in cell culture indicate that hypoxia increases TRPM7 expression. Therefore, we hypothesized that IH increases TRPM7 expression in CB and that pharmacological and genetic inhibition of Trpm7 in CB will treat IH-induced hypertension. Methods: 1) Pharmacological inhibition: We exposed male C57BL/6J mice to IH (n = 9) or air (n = 9) for 5 days and obtained continuous BP telemetry recording prior and after the exposure. Then we applied a long-acting TRPM7 inhibitor FTY720 or placebo to the CB area and repeated BP measurements before and after the 5-day IH or air exposure.2) Genetic inhibition: In another experiment, we knocked out Trpm7 gene expression in CB of male Trpm7 flox/flox mice by administering adenovirus carrying Cre-recombinase to the CB followed by BP recording during the 5-day IH or air exposure. RESULTS: We found that IH induced > 20-fold increase in Trpm7 mRNA expression in CB. IH increased BP from 102.9 ± 1.0 mmHg to 111.7 ± 1.1 mmHg. FTY720 hydrogel abolished the BP increase induced by IH. In Trpm7 flox/flox mice, IH also markedly increased BP prior to the adenoviral treatment from 101.9 ± 1.6 mmHg to 110.2 ± 4.0 mmHg. CB-specific Trpm7 knockout abolished IH-induced hypertension. CONCLUSION: We conclude that IH-induced upregulation of Trpm7 in CB contributes to the development of hypertension in IH and that IH-induced hypertension can be treated by pharmacological and genetic inhibition of Trpm7. 19CDA34700025, R01HL133100, R01HL128970. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Possible Molecular Mechanisms of Hypertension Induced by Sleep Apnea Syndrome/Intermittent Hypoxia.

Intermittent hypoxia (IH) is a central characteristic of sleep apnea syndrome (SAS), and it subjects cells in the body to repetitive apnea, chronic hypoxia, oxygen desaturation, and hypercapnia. Since SAS is linked to various serious cardiovascular complications, especially hypertension, many studies have been conducted to elucidate the mechanism of hypertension induced by SAS/IH. Hypertension in SAS is associated with numerous cardiovascular disorders. As hypertension is the most common complication of SAS, cell and animal models to study SAS/IH have developed and provided lots of hints for elucidating the molecular mechanisms of hypertension induced by IH. However, the detailed mechanisms are obscure and under investigation. This review outlines the molecular mechanisms of hypertension in IH, which include the regulation systems of reactive oxygen species (ROS) that activate the renin-angiotensin system (RAS) and catecholamine biosynthesis in the sympathetic nervous system, resulting in hypertension. And hypoxia-inducible factors (HIFs), Endotheline 1 (ET-1), and inflammatory factors are also mentioned. In addition, we will discuss the influences of SAS/IH in cardiovascular dysfunction and the relationship of microRNA (miRNA)s to regulate the key molecules in each mechanism, which has become more apparent in recent years. These findings provide insight into the pathogenesis of SAS and help in the development of future treatments.

Blockade of Trpm7 in the Carotid Body area attenuated intermittent hypoxia‐induced Hypertension

RATIONALEObesity leads to high cardiovascular morbidity and mortality via multiple mechanisms including obstructive sleep apnea (OSA) and hypertension. Intermittent hypoxia (IH), a hallmark manifestation of OSA, is an established cause of hypertension. The carotid body (CB) has been implicated in the pathogenesis of hypertension in IH and obesity. We discovered that obesity‐induced hypertension is mediated via the transient receptor potential melastatin 7 (TRPM7) channel in the glomus cells of CB. Here, we investigate the relevance of TRPM7 signaling in CB for the pathogenesis of hypertension by IH. We developed a novel technique allowing continuous sustained release of the TRPM7 inhibitor FTY720 into the CB area using a hydrogel formulation with a single injection abolishing hypertension in obesity for 3 weeks. We hypothesize that IH causes hypertension acting on CB TRPM7.METHODSC57BL/6J male mice (n = 9) were implanted with telemetry in the left femoral artery for continuous blood pressure monitoring and exposed to IH for 5 days. IH was administered by decreasing O2 levels from 21% to 6%, 60 cycles/hr, during the light phase, 9AM ‐9PM. FTY720 hydrogel (n = 5) or control hydrogel (N = 4) were applied locally to the CB region. Blood pressure was recorded at baseline and during IH and the measurement was repeated 2 weeks after hydrogel application.RESULTIH increased mean arterial pressure from 103.8±1.2 mmHg to 114.3±1.4 mmHg on Day 1 of IH and to 113.0±0.6 mmHg on Day 5 of IH respectively. FTY720 hydrogel abolished IH‐induced hypertension by decreasing blood pressure to 106.6±1.6 mmHg (p<0.005) on Day 1 of IH and to 101.5±1.6 mmHg (p<0.001) on Day 5 of IH. In contrast, control hydrogel had no effect on IH‐induced hypertension.CONCLUSIONOur study has shown that inhibition of TRPM7in the carotid bodies abolished IH‐induced hypertension.

Potential Contribution of Carotid Body-Induced Sympathetic and Renin-Angiotensin System Overflow to Pulmonary Hypertension in Intermittent Hypoxia.

Obstructive sleep apnea (OSA), featured by chronic intermittent hypoxia (CIH), is an independent risk for systemic hypertension (HTN) and is associated with pulmonary hypertension (PH). The precise mechanisms underlying pulmonary vascular remodeling and PH in OSA are not fully understood. However, it has been suggested that lung tissue hypoxia, oxidative stress, and pro-inflammatory mediators following CIH exposure may contribute to PH. New evidences obtained in preclinical OSA models support that an enhanced carotid body (CB) chemosensory reactiveness to oxygen elicits sympathetic and renin-angiotensin system (RAS) overflow, which contributes to HTN. Moreover, the ablation of the CBs abolished the sympathetic hyperactivity and HTN in rodents exposed to CIH. Accordingly, it is plausible that the enhanced CB chemosensory reactivity may contribute to the pulmonary vascular remodeling and PH through the overactivation of the sympathetic-RAS axis. This hypothesis is supported by the facts that (i) CB stimulation increases pulmonary arterial pressure, (ii) denervation of sympathetic fibers in pulmonary arteries reduces pulmonary remodeling and pulmonary arterial hypertension (PAH) in humans, and (iii) administration of angiotensin-converting enzyme (ACE) or blockers of Ang II type 1 receptor (ATR1) ameliorates pulmonary remodeling and PH in animal models. In this review, we will discuss the supporting evidence for a plausible contribution of the CB-induced sympathetic-RAS axis overflow on pulmonary vascular remodeling and PH induced by CIH, the main characteristic of OSA.

Angiotensin type 1a receptors in the median preoptic nucleus support intermittent hypoxia-induced hypertension.

Chronic intermittent hypoxia (CIH) is a model of the hypoxemia from sleep apnea that causes a sustained increase in blood pressure. Inhibition of the central renin-angiotensin system or FosB in the median preoptic nucleus (MnPO) prevents the sustained hypertensive response to CIH. We tested the hypothesis that angiotensin type 1a (AT1a) receptors in the MnPO, which are upregulated by CIH, contribute to this hypertension. In preliminary experiments, retrograde tract tracing studies showed AT1a receptor expression in MnPO neurons projecting to the paraventricular nucleus. Adult male rats were exposed to 7 days of intermittent hypoxia (cycling between 21% and 10% O2 every 6 min, 8 h/day during light phase). Seven days of CIH was associated with a FosB-dependent increase in AT1a receptor mRNA without changes in the permeability of the blood-brain barrier in the MnPO. Separate groups of rats were injected in the MnPO with an adeno-associated virus containing short hairpin (sh)RNA against AT1a receptors to test their role in intermittent hypoxia hypertension. Injections of shRNA against AT1a in MnPO blocked the increase in mRNA associated with CIH, prevented the sustained component of the hypertension during normoxia, and reduced circulating advanced oxidation protein products, an indicator of oxidative stress. Rats injected with shRNA against AT1a and exposed to CIH had less FosB staining in MnPO and the rostral ventrolateral medulla after intermittent hypoxia than rats injected with the control vector that were exposed to CIH. Our results indicate AT1a receptors in the MnPO contribute to the sustained blood pressure increase to intermittent hypoxia.

A dual blocker of endothelin A/B receptors mitigates hypertension but not renal dysfunction in a rat model of chronic kidney disease and sleep apnea.

Obstructive sleep apnea is characterized by recurrent episodes of pharyngeal collapse during sleep, resulting in intermittent hypoxia (IH), and is associated with a high incidence of hypertension and accelerated renal failure. In rodents, endothelin (ET)-1 contributes to IH-induced hypertension, and ET-1 levels inversely correlate with glomerular filtration rate in patients with end-stage chronic kidney disease (CKD). Therefore, we hypothesized that a dual ET receptor antagonist, macitentan (Actelion Pharmaceuticals), will attenuate and reverse hypertension and renal dysfunction in a rat model of combined IH and CKD. Male Sprague-Dawley rats received one of three diets (control, 0.2% adenine, and 0.2% adenine + 30 mg·kg-1·day-1 macitentan) for 2 wk followed by 2 wk of recovery diet. Rats were then exposed for 4 wk to air or IH (20 short exposures/h to 5% O2-5% CO2 7 h/day during sleep). Macitentan prevented the increases in mean arterial blood pressure caused by CKD, IH, and the combination of CKD + IH. However, macitentan did not improve kidney function, fibrosis, and inflammation. After CKD was established, rats were exposed to air or IH for 2 wk, and macitentan feeding continued for 2 more wk. Macitentan reversed the hypertension in IH, CKD, and CKD + IH groups without improving renal function. Our data suggest that macitentan could be an effective antihypertensive in patients with CKD and irreversible kidney damage as a way to protect the heart, brain, and eyes from elevated arterial pressure, but it does not reverse toxin-induced tubule atrophy.

Abstract P221: The Mechanism of Salt-Sensitive Hypertension in Intermittent Hypoxia

The mechanism of Salt-sensitive Hypertension in Intermittent Hypoxia (IH) Object: The morbidity of sleep apnea syndrome (SAS) is about 4% of the general population and it has been recognized as an independent risk factor for hypertension as well as other cardiovascular diseases. We established IH condition for rats and mice to investigate the development of salt-sensitive hypertension under IH. Methods: FiO2 was adjusted to cyclically drop to 4-5% every 90 seconds for 8 hours. Male Sprague-Dawley rats at age of 11weeks old and C57B6j mice at age of 8 weeks were kept in IH for 2 weeks with normal salt (0.5%) and high salt (8% NaCl) diet. Blood pressure (BP) and heart rate (HR) were monitored by telemetry. To explore the mechanism of salt sensitivity, Na excretion was measured. At the end of study, we evaluated the activity of sodium-chloride cotransporter (NCC) and epithelial sodium channel (ENaC) by treatment with either hydrochlorothiazide (HCTZ) and Amiloride, respectively. mRNA of WNK4, ACE, ACE-2, Angiotensinogen, 11bHSD-2 were examined. In addition, we analyzed T cell population both by histologically and by FACS analyzer. Results: Only during IH, high salt diet-induced hypertension (+20-30mmHg) and BP decreased after changed to a low-salt diet. In normoxic controls, BP did not change by high salt diet. Natriuresis by HCTZ but not by amiloride was significantly enhanced IH group than normoxic control. There was no significant difference in mRNA level of WNK4, ACE, angiotensinogen, 11bHSD-2. CD3+ T cell was found around the renal tubule cells. Conclusion: The current study revealed that IH induces salt-sensitive hypertension and the enhanced Na+ re-absorption through the NCC may be involved. T-cell inflammation might be one of the reasons for activation of NCC.

Inhibition of FosB in the lamina terminalis (LT) blocks sustained hypertension in intermittent hypoxia (IH)

FosB expression is increased in the LT after IH. To test the role of FosB in IH hypertension, rats were injected in the ventral LT (n = 6) with 400 nl of an adeno‐associated virus (AAV) vector expressing a dominant negative construct for FosB, (AAV‐ JunD) plus GFP, or a control construct expressing only GFP (n=4). All rats were instrumented with radio telemetry transmitters for continuous monitoring of blood pressure and heart rate. After a 7 day control period, rats were exposed to IH (3 min of periods of 21% O2 with 10% O2 for 8 h/day) for 7 days. At the end of IH, rats were anesthetized and perfusion fixed. Their brains were sectioned and processed for GFP fluorescence to verify the location of viral injections and to confirm expression of the AAV transgenes. During the control period, rats injected with the AAV constructs displayed blood pressures and respiratory rates that were comparable to untreated controls. When exposed to IH, both groups showed a normal increase in respiratory rate and blood pressure while being exposed to changes in O2. However, during the dark phase of the light dark cycle while breathing room air, rats injected with the FosB dominant null failed to show the sustained increase in blood pressure as seen in GFP‐construct injected controls. These findings suggest that the LT contributes to IH hypertension and that FosB may mediate changes in gene expression that contribute to IH hypertension. (HL62579 & HL41894)