Adenosine mediates metabolic and cardiovascular responses to hypoxia in fetal sheep.

Koos, Brian J.; Chau, Andrew; Ogunyemi, Dotun

doi:10.1113/jphysiol.1995.sp021007

Cited by 33 publications

(20 citation statements)

References 18 publications

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“…During hypoxic stress, the fetal carotid body mediates increases in arterial blood pressure and peripheral vascular resistance, a decrease in heart rate and increases in plasma glucose and lactate concentrations (Giussani et al 1993). All of these responses are attenuated by intravenous infusion 8-SPT (Koos et al 1995;Giussani et al 2001) or the selective A 2A antagonist ZM-241385 (Koos & Maeda, 2001). In contrast to these reports, administration of theophylline in the present study did not attenuate any of the above responses.…”

Section: Discussioncontrasting

confidence: 83%

The Role of Adenosine in Regulation of Cerebral Blood Flow During Hypoxia in the Near‐Term Fetal Sheep

Blood

Hunter

Power

2002

The Journal of Physiology

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The aim of this study was to determine in the near-term ovine fetus the role of adenosine in the basal regulation of cerebral blood flow and in the increases in cerebral blood flow in response to acute hypoxic insult. We measured cerebral blood flow in chronically instrumented fetal sheep (127-135 days gestation, term ~145 days) using laser Doppler flowmetry probes implanted in the parietal cortices. Hypoxia was administered for 30 min by lowering the ewe's inspired oxygen to 10-12 % during an infusion of either saline or theophylline, a non-specific adenosine receptor antagonist. The theophylline infusion was begun 30 min prior to and ended 30 min after the completion of the hypoxic insult. The administration of theophylline had no significant effect on cerebral blood flow during the baseline period. During control hypoxic periods, cerebral blood flow increased by ~45 %. During theophylline experiments, however, there was no significant increase in cerebral blood flow during hypoxia. In the control experiments, cerebral blood flow returned to baseline levels during the recovery period, while in the theophylline experiments cerebral blood flow fell below baseline levels. We conclude that, in the near-term ovine fetus, adenosine plays a minimal role in the regulation of basal cerebral blood flow. However, these data are strong evidence for the involvement of adenosine in increased fetal cerebral blood flow during an acute hypoxic insult. Finally, adenosine may also play an important role in the maintenance of fetal cerebral blood flow immediately following hypoxic insult.

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Section: Discussioncontrasting

confidence: 83%

The Role of Adenosine in Regulation of Cerebral Blood Flow During Hypoxia in the Near‐Term Fetal Sheep

Blood

Hunter

Power

2002

The Journal of Physiology

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“…In our previous work, similar rates of adenosine infusion increased fetal plasma epinephrine and norepinephrine concentrations, probably indirectly via stimulation of adenosine A 2A receptors associated with activation of the carotid bodies and subsequent stimulation of adrenergic pathways (24,25,29). Sympathetic activity inhibits fetal insulin release through activation of ␣ 2 -adrenergic receptors that modulate islet cell function (19).…”

Section: Insulinmentioning

confidence: 87%

“…Hypoxia also lowers fetal plasma concentrations of insulin, while it raises levels of glucose and lactate (22,26). Adenosine, via the A 1 receptor, facilitates glycolysis in normoxic adult tissues in vitro (53); thus, adenosine may also be involved in fetal metabolic responses to acute O 2 deficiency (25). This study was designed to test the hypothesis that adenosine (ADO) A 1 and A 2A receptors participate in the regulation of fetal plasma concentrations of insulin, glucose, and lactate under both normoxic and hypoxic conditions.…”

mentioning

confidence: 99%

Adenosine A₁ and A_2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep

Maeda¹,

Koos²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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A 1 and A2A receptor subtypes modulate metabolism in adult mammals. This study was designed to determine the role of these receptors in regulating plasma levels of insulin, glucose, and lactate in 20 chronically catheterized fetal sheep (Ͼ0.8 term). In normoxic fetuses (Pa O 2 ϳ24 Torr), systemic blockade of A1 receptors with DPCPX (n ϭ 6) increased plasma concentrations of insulin, glucose, and lactate, but antagonism of A 2A receptors with ZM-241385 (n ϭ 5) had no significant effects. Intravascular administration of adenosine (n ϭ 9) reduced insulin concentrations and elevated glucose and lactate levels. DPCPX (n ϭ 6) augmented the glycemic and lactatemic responses of adenosine. In contrast, ZM241385 (n ϭ 5) virtually abolished adenosine-induced hyperglycemia and hyperlactatemia. Isocapnic hypoxia (Pa O 2 ϳ13 Torr) suppressed insulinemia and enhanced glycemia and lactatemia, but only the hyperglycemia was blunted by blockade of A1 (n ϭ 6) or A2A (n ϭ 6) receptors. We conclude that 1) endogenous adenosine via A1 receptors depresses plasma concentrations of insulin, glucose, and lactate; 2) exogenous adenosine via A2A receptors increases glucose and lactate levels, but these responses are dampened by stimulation of A1 receptors; and 3) hypoxia, which increases endogenous adenosine concentrations, induces hyperglycemia that is partly mediated by activation of A1 and A2A receptors. We predict that adenosine, via A1 receptors, facilitates at least 12% of glucose uptake and utilization in normoxic fetuses. fetus; hypoxia; metabolism; growth; placenta ADENOSINE REGULATES GLUCOSE metabolism in mammals through several mechanisms that include inhibiting insulin secretion by islet cells, altering insulin transduction, and facilitating intracellular glucose transport. Interstitial levels of adenosine increase substantially in hypoxia, hypoglycemia, or heightened cellular metabolism that can occur through intense neuronal activity or skeletal muscle contractions. The physiological effects of adenosine are mediated through activation of G protein-liganded cell surface receptors that are subdivided into four adenosine receptor subtypes: A 1 , A 2A , A 2B , and A 3 (45). These receptors are connected to classical second-messenger pathways that modulate intracellular cAMP production, phospholipase C pathway, and mitogen-activated protein kinases (45,46). With regard to cAMP, stimulation of A 1 receptors, via inhibition of adenylyl cyclase, generally inhibits intracellular cAMP synthesis, while activation of A 2A and A 2B receptors has the opposite effects.Glucose promotes A 1 and A 2A expression in rat cardiac fibroblasts, while insulin suppresses the expression of A 1 and A 2B receptors (11). Insulin also facilitates the equilibrative transcellular movement of adenosine through stimulation of nucleoside transporters in human umbilical vein endothelial cells (37). Adenosine, in turn, inhibits insulin release via activation of islet A 1 receptors (21, 51). Stimulation of A 1 receptors also enhances glucose uptake in tissues thr...

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“…As noted above, this CBF increase appears to be mediated by local vasodilatory agents such as NO [256, 277, 279] and adenosine [306, 308, 309, 567]. In a similar manner, hypoxic-induced redistribution of blood flow to the developing brain has been observed in preterm fetal sheep (0.6 and 0.7 gestational age [568]), as well as in the chick embryo [569], llama [570, 571], and rhesus monkey [572].…”

Section: Developmental Cerebral Blood Flow In Response To Acute Hypoxmentioning

confidence: 99%

Cerebral Artery Signal Transduction Mechanisms: Developmental Changes in Dynamics and Ca<sup>2+</sup> Sensitivity

Longo¹,

Goyal²

2013

CVP

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As compared to the adult, the developing fetus and newborn infant are at much greater risk for dysregulation of cerebral blood flow (CBF), with complications such as intraventricular and germinal matrix hemorrhage with resultant neurologic sequelae. To minimize this dysregulation and its consequences presents a major challenge. Although in many respects the fundamental signal transduction mechanisms that regulate relaxation and contraction pathways, and thus cerebrovascular tone and CBF in the immature organism are similar to those of the adult, the individual elements, pathways, and roles differ greatly. Here, we review aspects of these maturational changes of relaxation/contraction mechanisms in terms of both electro-mechanical and pharmaco-mechanical coupling, their biochemical pathways and signaling networks. In contrast to the adult cerebrovasculature, in addition to attenuated structure with differences in multiple cytoskeletal elements, developing cerebrovasculature of fetus and newborn differs in many respects, such as a strikingly increased sensitivity to [Ca2+]i and requirement for extracellular Ca2+ for contraction. In essence, the immature cerebrovasculature demonstrates both “hyper-relaxation” and “hypo-contraction”. A challenge is to unravel the manner in which these mechanisms are integrated, particularly in terms of both Ca2+-dependent and Ca2+-independent pathways to increase Ca2+ sensitivity. Gaining an appreciation of these significant age-related differences in signal mechanisms also will be critical to understanding more completely the vulnerability of the developing cerebral vasculature to hypoxia and other stresses. Of vital importance, a more complete understanding of these mechanisms promises hope for improved strategies for therapeutic intervention and clinical management of intensive care of the premature newborn.

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Adenosine mediates metabolic and cardiovascular responses to hypoxia in fetal sheep.

Cited by 33 publications

References 18 publications

The Role of Adenosine in Regulation of Cerebral Blood Flow During Hypoxia in the Near‐Term Fetal Sheep

The Role of Adenosine in Regulation of Cerebral Blood Flow During Hypoxia in the Near‐Term Fetal Sheep

Adenosine A₁ and A_2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep

Cerebral Artery Signal Transduction Mechanisms: Developmental Changes in Dynamics and Ca<sup>2+</sup> Sensitivity

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Adenosine mediates metabolic and cardiovascular responses to hypoxia in fetal sheep.

Cited by 33 publications

References 18 publications

The Role of Adenosine in Regulation of Cerebral Blood Flow During Hypoxia in the Near‐Term Fetal Sheep

The Role of Adenosine in Regulation of Cerebral Blood Flow During Hypoxia in the Near‐Term Fetal Sheep

Adenosine A1 and A2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep

Cerebral Artery Signal Transduction Mechanisms: Developmental Changes in Dynamics and Ca<sup>2+</sup> Sensitivity

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Adenosine A₁ and A_2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep