Chronic intermittent hypoxia augments chemoreflex control of sympathetic activity: Role of the angiotensin II type 1 receptor

Abstract

Chronic exposure to intermittent hypoxia (CIH) increases carotid sinus nerve activity in normoxia and in response to acute hypoxia. We hypothesized that CIH augments basal and chemoreflex-stimulated sympathetic outflow through an angiotensin receptor-dependent mechanism. Rats were exposed to CIH for 28 days: a subset was treated with losartan. Then, lumbar sympathetic activity was recorded under anesthesia during 20-second apneas, isocapnic hypoxia, and potassium cyanide. We measured carotid body superoxide production and expression of angiotensin II type-1 receptor, neuronal nitric oxide synthase, and NADPH oxidase. Sympathetic activity was higher in CIH vs. control rats at baseline, during apneas and isocapnic hypoxia, but not cyanide. Carotid body superoxide production and expression of angiotensin II type 1 receptor and gp91phox subunit of NADPH oxidase were elevated in CIH rats, whereas expression of neuronal nitric oxide synthase was reduced. None of these differences were evident in animals treated with losartan. CIH-induced augmentation of chemoreflex sensitivity occurs, at least in part, via the renin-angiotensin system.

Oxidative Stress in the Carotid Body: Implications for the Cardioventilatory Alterations Induced by Obstructive Sleep Apnea

“…Since NO at low concentration is an inhibitory modulator of the carotid chemosensory activity (Iturriaga et al, 2000), a reduced NO level may contribute to enhance the carotid body chemosensitivity, as well as to amplify the vasoconstrictor effect of ET-1. This interpretation is supported by the finding that intermittent hypoxia decreases the expression of the neuronal NO synthase in the rat carotid body (Marcus et al, 2010), suggesting that the removal of the inhibitory NO effects may also contribute to enhance the carotid chemosensory responses to hypoxia. Our results also showed that carotid body iNOS immunorreactive levels increased after 21 days of intermittent hypoxic exposure.…”

Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure

“…Fletcher et al (18) demonstrated that systemic administration of the AT1R antagonist (losartan) blocks the increase in MAP associated with CIH. More recent studies have identified at least two different peripheral mechanisms that could account for effects of losartan (28,29) and provided evidence that the brain RAS may also participate in CIH hypertension (9,26). The SFO, a circumventricular organ in the forebrain that lacks blood-brain barrier, serves as a primary target for the central actions of circulating ANG II.…”

“…ANG II has both peripheral and central effects, and subsequent studies have demonstrated that ANG II may have multiple sites of action that contribute to CIH hypertension. ANG II has been shown to have direct effects on chemoreceptors (1), and losartan treatment attenuates the effects of CIH on chemoreflex sensitivity (28). In addition, endothelial dysfunction associated with CIH is also prevented by losartan (29).…”

Contribution of Autonomic Nervous System to the Hypertension Induced by Obstructive Sleep Apnea

“…The enhanced cardiorespiratory responses to acute hypoxia observed in OSA patients has been attributed to a potentiated hypoxic peripheral chemoreflexes [12,58,69,71], suggesting that carotid body chemoreceptors play a main role in the pathological alterations induced by OSA. 26] found that the bilateral carotid body denervation prevented the hypertension in rats exposed to chronic intermittent hypoxia, suggesting that the carotid body contributes to the cardiovascular pathologies induced by OSA.…”

“…OSA patients present enhanced ventilatory, pressor and sympathetic responses to acute hypoxia, attributed to a potentiation of the peripheral hypoxic chemoreflexes [58,100]. Narkiewicz et al [See in 69,71] studied the reflex ventilatory, tachycardic and vasopressor responses to acute hypoxia in untreated normotensive patients with OSA, and found that the hypoxic stimulation produce larger increases in volume-minute ventilation, heart rate and arterial blood pressure in OSA patients than control subjects.…”