Abstract
Hypoxia regulates the local expression of angiotensin-generating system in the rat carotid body and the me-tabolite angiotensin IV (Ang IV) may be involved in the modulation of carotid body function. We tested the hypothesis that Ang IV-binding angiotensin AT4 receptors play a role in the adaptive change of the carotid body in hypoxia. The expression and localization of Ang IV-binding sites and AT4 receptors in the rat carotid bodies were studied with histochemistry. Specific fluorescein-labeled Ang IV binding sites and positive staining of AT4 immunoreactivity were mainly found in lobules in the carotid body. Double-labeling study showed the AT4 receptor was localized in glomus cells containing tyrosine hydroxylase, suggesting the expression in the chemosensitive cells. Intriguingly, the Ang IV-binding and AT4 immunoreactivity were more intense in the carotid body of chronically hypoxic (CH) rats (breathing 10% oxygen for 4 weeks) than the normoxic (Nx) control. Also, the protein level of AT4 receptor was doubled in the CH comparing with the Nx group, supporting an upregulation of the expression in hypoxia. To examine if Ang IV induces intracellular Ca2+ response in the carotid body, cytosolic calcium ([Ca2+]i) was measured by spectrofluorimetry in fura-2-loaded glomus cells dissociated from CH and Nx carotid bodies. Exogenous Ang IV elevated [Ca2+]i in the glomus cells and the Ang IV response was significantly greater in the CH than the Nx group. Hence, hypoxia induces an upregulation of the expression of AT4 receptors in the glomus cells of the carotid body with an increase in the Ang IV-induced [Ca2+]i elevation. This may be an additional pathway enhancing the Ang II action for the activation of chemoreflex in the hypoxic response during chronic hypoxia.
Highlights
The carotid body is the major peripheral organ responding to rapid changes in arterial chemical content such as partial pressure of oxygen and carbon dioxide, and plays important roles in the cardiopulmonary responses to hypoxia and hypercapnic acidosis
This is supported by studies with enzyme assay showing an increase in angiotensin-converting enzyme (ACE) activity in the chronically hypoxic rat carotid body comparing with the normoxic control [11]
These findings suggest that chronic hypoxia activates the local components of an intrinsic angiotensin-generating system in the rat carotid body
Summary
The carotid body is the major peripheral organ responding to rapid changes in arterial chemical content such as partial pressure of oxygen and carbon dioxide, and plays important roles in the cardiopulmonary responses to hypoxia and hypercapnic acidosis. Chronic hypoxia causes an upregulation of the expression and localization of AGT mRNA and protein levels in the glomus cells of the rat carotid body [10]. This is supported by studies with enzyme assay showing an increase in ACE activity in the chronically hypoxic rat carotid body comparing with the normoxic control [11].
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