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Peripheral Chemoreception and Arterial Pressure Responses to Intermittent Hypoxia

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ABSTRACT

Carotid bodies are the principal peripheral chemoreceptors for detecting changes in arterial blood oxygen levels, and the resulting chemoreflex is a potent regulator of blood pressure. Recurrent apnea with intermittent hypoxia (IH) is a major clinical problem in adult humans and infants born preterm. Adult patients with recurrent apnea exhibit heightened sympathetic nerve activity and hypertension. Adults born preterm are predisposed to early onset of hypertension. Available evidence suggests that carotid body chemoreflex contributes to hypertension caused by IH in both adults and neonates. Experimental models of IH provided important insights into cellular and molecular mechanisms underlying carotid body chemoreflex‐mediated hypertension. This article provides a comprehensive appraisal of how IH affects carotid body function, underlying cellular, molecular, and epigenetic mechanisms, and the contribution of chemoreflex to the hypertension. © 2015 American Physiological Society. Compr Physiol 5:561‐577, 2015.

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Figure 1. Figure 1. The ex vivo carotid body responses to acute hypoxia (at black bar in left panels) and to acute intermittent hypoxia (AIH; at arrows in right panels) in control and rats exposed to 10 days of intermittent hypoxia (IH). pO2 = partial pressure of O2 in the medium irrigating the carotid body. Insets: represent superimposed action potentials of “single” fiber from which the data were derived. Note the augmented hypoxic sensory response and long‐lasting increase in baseline activity (sensory LTF) following AIH in IH‐exposed carotid bodies. [From Ref. () with permission.]
Figure 2. Figure 2. Effect of bosentan (50 μmol/L) on mild hypoxia‐evoked chemosensory discharges from a single control (A) and IH‐treated carotid body (B). Summary of the effect of bosentan on chemosensory responses elicited by mild and severe hypoxia in control (C) and IH‐treated carotid bodies (D) (n = 5 in each group). fx, frequency of chemosensory discharges expressed in Hz (A and B) or as percent of hypoxic responses in the absence of bosentan. Open bars represent the effects of hypoxia in the absence of bosentan; hashed and closed bars represent the effects of mild and severe hypoxia in the presence of bosentan, respectively. *P < 0.05; ‡P < 0.001, hypoxic responses following bosentan versus hypoxic responses without bosentan. [From Ref. () with permission.]
Figure 3. Figure 3. Schematic illustration of molecular and cellular mechanisms underlying the effects of intermittent hypoxia (IH) on the carotid body and chemoreflex‐dependent blood pressure changes. Keys: HIF‐1α and HIF‐2α, Hypoxia‐inducible factor 1 and 2α, respectively; Nox2, NADPH oxidase 2; Sod2, Superoxide dismutase 2; ROS, reactive oxygen species; LTF, long‐term facilitation.
Figure 4. Figure 4. Intermittent hypoxia (IH) augments carotid body response to hypoxia in neonatal rats. Examples of carotid body responses to hypoxia in rat pups exposed to 10 days of IH or to normoxia (Control) are shown. Black bars denote the duration of the hypoxic stimulus. Hypoxia: medium pO2 = 33 mmHg. Insets: superimposed action potential from a single unit. imp/s, impulses per second. [Modified from Ref. () with permission].
Figure 5. Figure 5. Schematic illustration of epigenetic mechanisms involving DNA hypermethylation of antioxidant enzymes on neonatal intermittent hypoxia‐induced hypertension in adults.


Figure 1. The ex vivo carotid body responses to acute hypoxia (at black bar in left panels) and to acute intermittent hypoxia (AIH; at arrows in right panels) in control and rats exposed to 10 days of intermittent hypoxia (IH). pO2 = partial pressure of O2 in the medium irrigating the carotid body. Insets: represent superimposed action potentials of “single” fiber from which the data were derived. Note the augmented hypoxic sensory response and long‐lasting increase in baseline activity (sensory LTF) following AIH in IH‐exposed carotid bodies. [From Ref. () with permission.]


Figure 2. Effect of bosentan (50 μmol/L) on mild hypoxia‐evoked chemosensory discharges from a single control (A) and IH‐treated carotid body (B). Summary of the effect of bosentan on chemosensory responses elicited by mild and severe hypoxia in control (C) and IH‐treated carotid bodies (D) (n = 5 in each group). fx, frequency of chemosensory discharges expressed in Hz (A and B) or as percent of hypoxic responses in the absence of bosentan. Open bars represent the effects of hypoxia in the absence of bosentan; hashed and closed bars represent the effects of mild and severe hypoxia in the presence of bosentan, respectively. *P < 0.05; ‡P < 0.001, hypoxic responses following bosentan versus hypoxic responses without bosentan. [From Ref. () with permission.]


Figure 3. Schematic illustration of molecular and cellular mechanisms underlying the effects of intermittent hypoxia (IH) on the carotid body and chemoreflex‐dependent blood pressure changes. Keys: HIF‐1α and HIF‐2α, Hypoxia‐inducible factor 1 and 2α, respectively; Nox2, NADPH oxidase 2; Sod2, Superoxide dismutase 2; ROS, reactive oxygen species; LTF, long‐term facilitation.


Figure 4. Intermittent hypoxia (IH) augments carotid body response to hypoxia in neonatal rats. Examples of carotid body responses to hypoxia in rat pups exposed to 10 days of IH or to normoxia (Control) are shown. Black bars denote the duration of the hypoxic stimulus. Hypoxia: medium pO2 = 33 mmHg. Insets: superimposed action potential from a single unit. imp/s, impulses per second. [Modified from Ref. () with permission].


Figure 5. Schematic illustration of epigenetic mechanisms involving DNA hypermethylation of antioxidant enzymes on neonatal intermittent hypoxia‐induced hypertension in adults.
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Nanduri R. Prabhakar, Ying‐Jie Peng, Ganesh K. Kumar, Jayasri Nanduri. Peripheral Chemoreception and Arterial Pressure Responses to Intermittent Hypoxia. Compr Physiol 2015, 5: 561-577. doi: 10.1002/cphy.c140039