Low glucose sensitivity and polymodal chemosensing in neonatal rat adrenomedullary chromaffin cells

Abstract

Livermore S, Piskuric NA, Buttigieg J, Zhang M, Nurse CA. Low glucose sensitivity and polymodal chemosensing in neonatal rat adrenomedullary chromaffin cells. Am J Physiol Cell Physiol 301: C1104 -C1115, 2011. First published July 20, 2011 doi:10.1152/ajpcell.00170.2011Glucose is the primary metabolic fuel in mammalian fetuses, yet mammals are incapable of endogenous glucose production until several hours after birth. Thus, when the maternal supply of glucose ceases at birth there is a transient hypoglycemia that elicits a counterregulatory surge in circulating catecholamines. Because the innervation of adrenomedullary chromaffin cells (AMCs) is immature at birth, we hypothesized that neonatal AMCs act as direct glucosensors, a property that could complement their previously established roles as hypoxia and acid hypercapnia sensors. During perforated-patch, whole cell recordings, low glucose depolarized and/or excited a subpopulation of neonatal AMCs; in addition, aglycemia (0 mM glucose) caused inhibition of outward K ϩ current, blunted by the simultaneous activation of glibenclamidesensitive K ATP channels. Some cells were excited by each of the three metabolic stimuli, i.e., aglycemia, hypoxia (PO2 ϳ30 mmHg), and isohydric hypercapnia (10% CO2; pH ϭ 7.4). Using carbon fiber amperometry, aglycemia and hypoglycemia (3 mM glucose) induced robust catecholamine secretion that was sensitive to nickel (50 M and 2 mM) and the L-type Ca 2ϩ channel blocker nifedipine (10 M), suggesting involvement of both T-type and L-type voltage-gated Ca 2ϩ channels. Fura-2 measurements of intracellular Ca 2ϩ ([Ca 2ϩ ]i) revealed that ϳ42% of neonatal AMCs responded to aglycemia with a significant rise in [Ca 2ϩ ]i. Approximately 40% of these cells responded to hypoxia, whereas ϳ25% cells responded to both aglycemia and hypoxia. These data suggest that together with hypoxia and acid hypercapnia, low glucose is another important metabolic stimulus that contributes to the vital asphyxia-induced catecholamine surge from AMCs at birth. aglycemia; hypoglycemia; hypoxia; catecholamines; K ϩ current ALTHOUGH GLUCOSE IS THE PRIMARY metabolic fuel in the fetus, glycogenolysis and gluconeogenesis are absent in utero (27). As a result, fetuses are completely dependent on their mothers for the transplacental facilitated diffusion of glucose. During normal birth, this transport ceases, leading to a decrease in blood glucose (hypoglycemia) in the first few hours of life (26,30,39,51,54). In the newborn, hypoglycemia activates a counterregulatory surge in catecholamines and glucagon and a fall in insulin (11). These hormonal changes stabilize blood glucose by initiating glycogenolysis in liver hepatocytes (21,29). Despite this response, over 2% of newborns experience hypoglycemia and require clinical intervention (13), increasing the risk of brain damage (36). Moreover, premature infants, newborns of diabetic mothers, and neonates small-for-gestational age are at increased risk of hypoglycemia, which is one of the primary causes of increased n...

Arterio-venous differences in cord levels of catecholamines, glucose, lactate and blood gases

“…Molecular regulators of carotid body and adrenomedullary catecholamine secretion are oxygen, H + / CO 2 , and glucose, suggesting they are important metabolic mediators in perinatal catecholamine regulation [16,31]; if this is so, regression analyses should show that these regulators have the strongest associations with DA, NE and EPI. However, bivariate associations between levels of cord artery glucose and catecholamines were very weakly negative in the study group as a whole, and also in the subgroup of normoglycemic infants (glucose levels ≥ 2.6 mmol/L).…”

“…In contrast, in correlation analyses, there is no significant relationship between lactate levels and DA, or its immediate metabolites (DOPAC and DA sulfate), but that to NE and EPI is retained. It is not yet clear whether these associations are indicators of a direct regulatory effect of lactate on catecholamine secretion, such as exists for glucose; or whether it is a surrogate effect of pCO 2 /H + on the carotid body and adrenomedullary cells [16,32]. Or indeed, whether it is a surrogate effect of reduced O 2 on adrenomedullary cells, both of which (raised PCO 2 /H + and reduced PO 2 ), occur with relative hypoxia, and all of which are known to stimulate catecholamine secretion [16].…”

“…It is not yet clear whether these associations are indicators of a direct regulatory effect of lactate on catecholamine secretion, such as exists for glucose; or whether it is a surrogate effect of pCO 2 /H + on the carotid body and adrenomedullary cells [16,32]. Or indeed, whether it is a surrogate effect of reduced O 2 on adrenomedullary cells, both of which (raised PCO 2 /H + and reduced PO 2 ), occur with relative hypoxia, and all of which are known to stimulate catecholamine secretion [16]. A possible independent role for lactate in the catecholamine surge is supported by the regression analyses, which shows that levels of lactate, but not PCO 2 or PO 2 (or glucose consistently) are independently associated with NE, EPI and DA levels in cord artery.…”

“…The known molecular regulators of adrenomedullary catecholamine secretion in vitro are oxygen, H + /CO 2 , and glucose, which are proposed as important mediators in perinatal catecholamine regulation [16]. We predicted that levels of these regulators would show the strongest associations, in regression analyses, with dopamine (DA), NE and EPI.…”

Ontogeny of O2 and CO2//H+ chemosensitivity in adrenal chromaffin cells: role of innervation

“…Furthermore, they showed in denervation experiments that removal of the splanchnic innervation in mature or adult animals resulted in a gradual re-appearance of this non-neurogenic mechanism (Slotkin and Seidler, 1988). More recent studies in the rat suggest that adrenal responses to hypercapnia, acidity and hypoglycemia are also suppressed postnatally, in parallel with splanchnic innervation (Livermore et al, 2011;Livermore et al, 2012;Muñoz-Cabello et al, 2005;Rico et al, 2005). Interestingly, in mammals that are born relatively mature (e.g.…”