Title

Mechanisms of Sympathoexcitation via Hyper-Acute Intermittent Hypoxia in Humans: Implications for Obstructive Sleep Apnea

Date of Award

5-1-2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

Michael L. Smith

Second Advisor

Robert T. Mallet

Third Advisor

Peter B. Raven

Abstract

Obstructive Sleep Apnea (OSA) is a very prevalent disease that predisposes affected individuals to develop cardiovascular disease, mostly through secondary hypertension, which is independent from co-morbid conditions. Animal and human investigations over the past 25 years have demonstrated that intermittent hypoxia (IH) produces elevations in arterial pressure consistent with what is observed in OSA patients. The generation of this hypertension is dependent on an intact peripheral chemoreflex and an intact sympathetic nervous system. However, the mechanistic link between IH and elevated sympathetic nerve activity (SNA) is not well known. Animal investigations have demonstrated that adaptations in the carotid body, in the central nervous system structures that participate in the chemoreflex arc, and in the adrenal medulla are mechanistically related to the development of hypertension in rodents exposed to chronic IH. These studies have also identified the critical role of reactive oxygen species (ROS) and activation of angiotensin II type 1a receptors (ATR1a) in these maladaptations. Hence, antioxidants and angiotensin receptor blockers (ARBs) may have important treatment potential in OSA patients with hypertension. Both of the projects described in this dissertation will provide the beginning steps of translating animal studies of chronic IH that have uncovered the role of these particular molecular mediators to human patients.

The first project investigates the sympathoexcitatory role of ROS in short-term IH (20 minutes) in humans. Previous investigations in rodents have demonstrated that ROS are generated in the carotid body and in nuclei that participate in the chemoreflex neural arc in response to chronic IH.

Importantly, these studies demonstrate that oral ingestion of antioxidants reduce the production of sympathetically-derived catecholamines from the adrenal medulla, and attenuate the increased acute and sustained carotid body firing in response to chronic IH. Moreover, in animal studies injection of antioxidant substances directly into the cerebral ventricles reduces centrally derived sympathetic outflow. In the present study, young, healthy human subjects ingested either vehicle placebo or the lipid-soluble antioxidant N-acetylcysteine (N-AC), and were then exposed to very short term IH (20 minutes), while direct measurements of SNA via muscle SNA (MSNA) and beat-to-beat arterial pressure were collected in tandem with venous blood samples via intravenous catheter, which was assayed for superoxide with electron paramagnetic spectroscopy (EPR). This experimental design tested the hypothesis that N-AC reduces the MSNA and arterial pressure responses to 20 minutes of IH and reduces the measurements of peripheral venous superoxide. N-AC reduced the sympathetic and arterial pressure response to our paradigm of IH in healthy humans. However, measurements of peripheral superoxide via EPR did not demonstrate any effects of acute IH or N-AC. This indicates that N-AC may be exerting a primarily central effect in the reduction of very short IH-mediated sympathoexcitation, versus modulating peripheral chemoreceptor afferent transmission.

The second project investigated the role of ATR1a activation in our paradigm of acute IH and the subsequent sympathoexcitation in human subjects. Indeed, animal studies have demonstrated that activation of ATR1a mediate, in part, the elevated lumbar SNA (LSNA) in rodents exposed to chronic IH. Furthermore, similar animal studies have identified the role of angiotensin II in mediating the sustained elevation of carotid body discharge after chronic IH. In humans, studies have demonstrated that ingestion of Losartan reduces the arterial pressure response to a single 6 hour exposure of IH. However, it is not clear how Losartan affects the MSNA response to acute IH in humans. Hence, in the second study of this dissertation, human subjects were exposed to acute IH after ingesting Losartan or cellulose placebo while MSNA and arterial pressure were assessed. Furthermore, these measurements were continued into the post-IH recovery period. This experimental design tested the hypothesis that Losartan reduces the immediate and sustained sympathoexcitatory and arterial pressure responses to IH. This results of this study demonstrated that Losartan significantly abrograted the MSNA response to IH and virtually abolished the arterial pressure response, both acutely and during the recovery period. This indicates that activation of ATR1a play an important and substantial role in the sympathetic activation observed after a short-bout of IH in human subjects.

In summary, these studies demonstrate that human IH-mediated sympathoexcitation and hypertension involves generation of oxidative stress (independent of peripheral superoxide) and activation of ATR1a.

Comments

Jouett, Noah, Mechanisms of Sympathoexcitation via Hyper-Acute Intermittent Hypoxia in Humans: Implications for Obstructive Sleep Apnea. Doctor of Philosophy (Biomedical Sciences), September 2016. Available May 2018.

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