Postnatal hypoxemia increases angiotensin II sensitivity and up-regulates AT 1a angiotensin receptors in rat carotid body chemoreceptors

Abstract

In the present study, the effects of postnatal hypoxemia on the AT 1 angiotensin receptor-mediated activities in the rat carotid body were studied. Angiotensin II (Ang II) concentration-dependently increased the chemoreceptor afferent activity in the isolated carotid body. Single- or pauci-fiber recording of the sinus nerve revealed that the afferent response to Ang II was enhanced in the postnatally hypoxic carotid body. To determine whether the increased sensitivity to Ang II is mediated by changes in the functional expression of Ang II receptors in the carotid body chemoreceptors, cytosolic calcium ([Ca 2+]i) was measured by spectrofluorimetry in fura-2 acetoxymethyl ester-loaded type I cells dissociated from carotid bodies. Ang II (25-100 nM) concentration-dependently increased [Ca 2+]i in the type I cells. The proportion of clusters of type I cells responsive to Ang II was higher in the postnatally hypoxic group than in the normoxic control (89 vs 66%). In addition, the peak [Ca 2+]i response to Ang II was enhanced 2- to 3-fold in the postnatally hypoxic group. The [Ca 2+]i response to Ang II was abolished by pretreatment with losartan (1 μM), an AT 1 receptor antagonist, but not by PD-123177 (1 μM), an AT 2 antagonist. Double-labeling immunohistochemistry confirmed that an enhanced immunoreactivity for AT 1 receptor was co-localized to the lobules of type I cells in the hypoxic group. In addition, RT-PCR analysis of subtypes of AT 1 receptors showed an up-regulation of AT 1a but a down-regulation of AT 1b receptors, indicating a differential regulation of the expression of AT 1 receptor subtypes by postnatal hypoxia in the carotid body. These data suggest that postnatal hypoxemia is associated with an increased sensitivity of peripheral chemoreceptors in response to Ang II and an up-regulation of AT 1a receptor-mediated [Ca 2+]i activity of the chemoreceptors. This modulation may be important for adaptation of carotid body functions in the hypoxic ventilatory response and in electrolyte and water homeostasis during perinatal and postnatal hypoxia.