Adenosine A1 and A2A receptors modulate sleep state and breathing in fetal sheep

2001 ◽  
Vol 91 (1) ◽  
pp. 343-350 ◽  
Author(s):  
Brian J. Koos ◽  
Takatsugu Maeda ◽  
Calvin Jan
Keyword(s):  
Low Voltage ◽  
Receptor Subtype ◽  
Respiratory Drive ◽  
Inhibitory Effects ◽  
Sleep State ◽  
Arterial Infusion ◽  
Fetal Sheep ◽  
A2a Receptors ◽  
Fetal Breathing ◽  
Adenosine A1

This study was designed to determine the adenosine (Ado) receptor subtype that mediates the depressant effects of Ado on fetal breathing and rapid eye movements (REM). In chronically catheterized fetal sheep (>0.8 term), intra-arterial infusion of N 6-cyclopentyladenosine (CPA), an Ado A1-receptor agonist, increased the incidence of high-voltage electrocortical (ECoG) activity while virtually abolishing low-voltage activity, REM, and breathing. These effects were blocked by 9-cyclopentyl-1,3-dipropylxanthine (DPCPX), an Ado A1-receptor antagonist. Infusion of DPCPX alone increased breath amplitude but had no significant effect on inspiratory duration, breath interval, incidence of REM, or incidence of low-voltage activity. Ado A2A-receptor blockade with ZM-241385 increased the incidence of low-voltage ECoG activity, REM, and breathing but had no effect on breath amplitude or respiratory cycle. Both DPCPX and ZM-241385 eliminated the inhibitory effects of Ado on REM and breathing. We conclude that 1) Ado A1receptors tonically inhibit fetal respiratory drive, 2) Ado A2A receptors tonically inhibit REM-like behavioral state, and 3) both Ado A1 and A2A receptors mediate the depressant effects of Ado on REM and breathing.

Metabolic and cardiorespiratory responses to hypoxia in fetal sheep: adenosine receptor blockade

1999 ◽  
Vol 276 (6) ◽  
pp. R1805-R1811 ◽  
Author(s):  
Andrew Chau ◽  
Brian J. Koos
Keyword(s):  
Adenosine Receptors ◽  
Low Voltage ◽  
Specific Inhibitor ◽  
Cardiovascular Responses ◽  
Inhibitory Effects ◽  
Fetal Sheep ◽  
Fetal Breathing ◽  
Phasic Rem Sleep ◽  
Transient Bradycardia

8-Phenyltheophylline (PT), a potent and specific inhibitor of adenosine receptors, was infused intra-arterially into unanesthetized fetal sheep to determine the role of adenosine in hypoxic inhibition of fetal breathing. PT in normoxic fetuses increased heart rate and the incidence of low-voltage electrocortical activity, rapid eye movements (REM), and breathing. Mean breath amplitude increased by 44%. Hypoxia (preductal arterial[Formula: see text] = 14 Torr) induced a metabolic acidemia, a transient bradycardia, and hypertension while virtually eliminating REM and breathing. PT administration during hypoxia enhanced the metabolic acidemia, blocked the bradycardia and hypertension, increased the incidence of REM and breathing, and elevated mean breath amplitude. The results indicate that 1) adenosine is involved in fetal glycolytic and cardiovascular responses to hypoxia, 2) activation of central adenosine receptors mediates about one-half the inhibitory effects of hypoxia on REM and breathing, and 3) the depression of breathing may critically depend on a hypoxia-induced reduction in phasic REM sleep.

Fetal breathing, sleep state, and cardiovascular responses to adenosine in sheep

1990 ◽  
Vol 68 (2) ◽  
pp. 489-495 ◽  
Author(s):  
B. J. Koos ◽  
K. Matsuda
Keyword(s):  
Eye Movements ◽  
Low Voltage ◽  
Blood Gases ◽  
Hemoglobin Concentration ◽  
Cardiovascular Responses ◽  
Sleep State ◽  
Fetal Sheep ◽  
Adenosine Receptor Antagonist ◽  
Fetal Breathing ◽  
Arterial Po2

The possibility that adenosine mediates hypoxic inhibition of fetal breathing and eye movements was tested in nine chronically catheterized fetal sheep (0.8 term). Intracarotid infusion of adenosine (0.25 +/- 0.03 mg.min-1.kg-1) for 1 h to the fetus increased heart rate and hemoglobin concentration but did not significantly affect mean arterial pressure or blood gases. As with hypoxia, adenosine decreased the incidence of rapid eye movements by 55% and the incidence of breathing by 77% without significantly affecting the incidence of low-voltage electrocortical activity. However, with longer (9 h) administration, the incidence of breathing and eye movements returned to normal during the adenosine infusion. Intravenous infusion of theophylline, an adenosine receptor antagonist, prevented most of the reduction in the incidence of breathing and eye movements normally seen during severe hypoxia (delta arterial PO2 = -10 Torr). It is concluded that 1) adenosine likely depresses fetal breathing and eye movements during hypoxia and 2) downregulation of adenosine receptors may contribute to the adaptation of breathing and eye movements during prolonged hypoxia.

Fetal breathing, sleep state, and cardiovascular responses to graded hypoxia in sheep

1987 ◽  
Vol 62 (3) ◽  
pp. 1033-1039 ◽  
Author(s):  
B. J. Koos ◽  
H. Sameshima ◽  
G. G. Power
Keyword(s):  
Low Voltage ◽  
Cardiovascular Responses ◽  
Severe Hypoxia ◽  
Sleep State ◽  
Fetal Sheep ◽  
Fetal Bradycardia ◽  
O2 Concentration ◽  
Fetal Breathing ◽  
The Mean ◽  
Mild Hypoxia

Graded isocapnic hypoxemia was produced in unanesthetized fetal sheep by varying the inspired O2 concentration (21, 12, 10.5, and 9%) of the ewe. This produced corresponding mean preductal arterial O2 tension (PaO2) values of 25.2 +/- 1.1 (control), 20.1 +/- 1.0 (mild hypoxia), 17.8 +/- 0.9 (moderate hypoxia), and 16.8 +/- 1.4 Torr (severe hypoxia). These were associated with mean arterial O2 contents (CaO2) of 7.18 +/- 0.44, 5.19 +/- 0.34, 4.24 +/- 0.33, and 3.27 +/- 0.20 ml/dl, respectively. The most severe hypoxia was associated with metabolic acidosis and fetal bradycardia. Hypoxia did not reduce significantly the incidence of low-voltage electrocortical activity. The incidence of breathing and rapid eye movements was not affected by mild hypoxia; however, the incidence of both was significantly reduced during moderate and severe hypoxia. It is concluded that 1) acute reductions in the mean PaO2 of 5.9 +/- 0.6 Torr and CaO2 of 2.00 +/- 0.23 ml/dl are critical in that greater reductions inhibit fetal eye and breathing activity and 2) hypoxia probably inhibits eye and breathing movements by altering sleep state.

Adenosine A2A receptors mediate cardiovascular responses to hypoxia in fetal sheep

2001 ◽  
Vol 280 (1) ◽  
pp. H83-H89 ◽  
Author(s):  
Brian J. Koos ◽  
Takatsugu Maeda
Keyword(s):  
Plasma Volume ◽  
Cardiovascular Responses ◽  
Receptor Subtype ◽  
Gas Mixture ◽  
Adenosine A2a Receptors ◽  
Arterial Infusion ◽  
Fetal Sheep ◽  
A2a Receptors ◽  
Adenosine A2a ◽  
Hypoxic Gas Mixture

Nonselective adenosine (ADO) receptor antagonists block hypoxia-induced bradycardia and hypertension in fetal sheep. This study was designed to determine the ADO receptor subtype that is involved in these cardiovascular responses. In chronically catheterized fetal sheep (>0.8 term), fetal hypoxemia was induced by having the ewe breathe a hypoxic gas mixture (9% O2-3% CO2-88% N2) for 1 h. Intra-arterial infusion of ZM-241385, an antagonist highly selective for ADO A2A receptors, to eight fetuses during normoxia significantly increased mean arterial pressure (MAP) from 42.5 ± 2.0 to 46.1 ± 2.0 mmHg without altering heart rate (HR). Infusion of a selective antagonist of ADO A1receptors [1,3-dipropyl-8-cyclopentylxanthine (DPCPX)] elevated MAP and HR only after the infusion was terminated, although administration of the vehicle for ZM-241385 or DPCPX had no effect on MAP or HR. Isocapnic hypoxia with infusion of DPCPX or the vehicle for DPCPX or ZM-241385 produced a transient fall in HR, a rise in MAP, and a decrease in plasma volume. In contrast, ADO A2A receptor blockade abolished the hypoxia-induced bradycardia and hypertension and blunted the decline in plasma volume. We conclude that fetal ADO A2A receptors: 1) modulate AP during normoxia, and 2) mediate cardiovascular responses during acute O2 deficiency.

Specificity of a placental factor inhibiting breathing in fetal sheep

1996 ◽  
Vol 8 (3) ◽  
pp. 423 ◽  
Author(s):  
RE Alvaro ◽  
V Rehan ◽  
Almeida V de ◽  
Z Haider ◽  
M Robertson ◽  
...  
Keyword(s):  
High Voltage ◽  
Low Voltage ◽  
Fetal Liver ◽  
Fetal Life ◽  
Krebs Solution ◽  
Fetal Sheep ◽  
Electrocortical Activity ◽  
Fetal Breathing ◽  
Pregnant Ewe ◽  
Placental Extract

We have found previously that the infusion of a placental extract inhibits breathing induced by 100% O2 plus umbilical cord occlusion in the fetal sheep, suggesting that a placental factor is responsible for the inhibition of fetal breathing. To test whether this factor is specific to the placenta and whether it also inhibits spontaneous fetal breathing (occurring in the absence of cord occlusion), we administered extracts from the placenta, muscle and liver of the pregnant ewe, extracts of fetal liver, and Krebs solution to 16 chronically instrumented fetal sheep at 135 +/- 5 days of gestation. Infusions were made during low-voltage electrocortical activity, 5 to 15 min after a switch from high voltage, when breathing was well established. Within 90 s of the infusion of the placental extract in the carotid artery of the fetus, breathing decreased in 79% (33/42) of the experiments and was completely abolished in 71% (30/42) of them (P < 0.0001 compared with the other infusates). No apnoeas were observed with the Krebs solution (0/19) and the maternal muscle (0/20). Extracts of maternal and fetal liver abolished breathing in only 17% (4/23) and 21% (6/29) of the experiments respectively (NS compared with Krebs solution). There were no significant changes in blood gas tensions, pH, blood pressure and heart rate associated with the infusion of the extracts. The electrocortical activity (ECoG) switched from low to high voltage in 50% of the experiments using placental extract compared with 0% with Krebs solution and maternal muscle, and with 9% and 17% with maternal and fetal liver respectively (P < 0.005). Breathing output (integral of EMGdi x f) during and after the infusions significantly decreased only with the placental extract. These findings indicate the presence of a factor produced by the placenta which inhibits fetal breathing and may be responsible for the normal inhibition of breathing observed in fetal life.

Catecholamine neurons in fetal brain: effects on breathing movements and electrocorticogram

1990 ◽  
Vol 69 (5) ◽  
pp. 1903-1911 ◽  
Author(s):  
S. A. Joseph ◽  
D. W. Walker
Keyword(s):  
Intravenous Infusion ◽  
Low Voltage ◽  
Fetal Brain ◽  
Synaptic Cleft ◽  
Initial Increase ◽  
Fetal Sheep ◽  
Subsequent Decrease ◽  
Fetal Breathing ◽  
Catecholamine Neurons ◽  
6 Hydroxydopamine

We investigated the effect of increasing the synaptic concentration of catecholamines released from central pathways on breathing movements and electrocortical (ECoG) activity in fetal sheep in utero. In 11 trials (9 fetuses) intravenous infusion of the noradrenergic uptake inhibitor desipramine (DMI) resulted in an initial increase in the incidence of breathing movements from 47.8 +/- 2.2%/h to a maximum of 77.9 +/- 5.5%/h (P less than 0.05) followed by a subsequent decrease to 18.8 +/- 2.7%/h (P less than 0.05), which was associated with a decrease in the incidence of low-voltage ECoG activity. Mean breath amplitude also increased after DMI infusion from 5.8 +/- 0.2 mmHg to a peak of 8.9 +/- 0.9 mmHg (P less than 0.05). In five fetuses, intravenous injection of the alpha 1-receptor antagonist prazosin 30 min after the start of the DMI infusion blocked the increase of breath amplitude observed when DMI was given alone. Intracisternal infusion of 6-hydroxydopamine (6-OHDA, which causes an initial displacement of transmitter stores followed by a neurotoxic action) in six fetuses caused an increase in mean breath amplitude from 6.6 +/- 0.3 mmHg (control) to 22.3 +/- 5.5 mmHg (P less than 0.05) and a prolonged episode of breathing movements (168.5 +/- 47.2 min). The incidence of low-voltage ECoG activity was also increased significantly. A second infusion of 6-OHDA, 2 days after the first, had no effect on breathing movements or ECoG activities. The two treatments with 6-OHDA also resulted in a significant reduction in the response to intravenous infusion of DMI, indicating that endogenous release of norepinephrine had been reduced by the neurotoxin. These results suggest that 1) there is normally some tonic release of norepinephrine from central pathways, but this release is insufficient to stimulate sustained fetal breathing, and 2) accumulation in the synaptic cleft of catecholamines from central neurons is able to stimulate fetal breathing and promote low-voltage ECoG activity. Possible mechanisms that normally limit the activity of central catecholamine pathways before birth are discussed.

Effect of mild hypocapnia on fetal breathing and behavior in unanesthetized normoxic fetal lambs

1994 ◽  
Vol 76 (4) ◽  
pp. 1476-1480 ◽  
Author(s):  
I. M. Kuipers ◽  
W. J. Maertzdorf ◽  
D. S. De Jong ◽  
M. A. Hanson ◽  
C. E. Blanco
Keyword(s):  
Low Voltage ◽  
Blood Gases ◽  
Electromyographic Activity ◽  
Fetal Life ◽  
Fetal Sheep ◽  
Arterial Ph ◽  
Fetal Breathing ◽  
The Mean ◽  
And Behavior ◽  
Arterial Po2

We hypothesized that the level of arterial PCO2 (PaCO2) affects the incidence of fetal breathing movements and electrocorticographic (ECoG) states in chronically instrumented fetal sheep. Six fetuses of 128–132 days gestational age were instrumented for recording fetal behavior and for later connection to an extracorporeal membrane oxygenation (ECMO) system to change fetal blood gases. Before ECMO fetal arterial pH and blood gases were pH 7.40 +/- 0.01, PaCO2 42.9 +/- 1.5 Torr, and arterial PO2 (PaCO2) 19.2 +/- 1.7 Torr; during ECMO in normocapnia they were pH 7.37 +/- 0.01, PaCO2 46.1 +/- 0.7 Torr, and PaCO2 27.6 +/- 3.0 Torr; and during ECMO in mild hypocapnia they were pH 7.47 +/- 0.01, PaCO2 35.3 +/- 1.7 Torr, and PaCO2 26.6 +/- 1.7 Torr. The overall incidence of breathing movements, the incidence of breathing movements during low-voltage (LV) ECoG activity, and the mean duration of periods of breathing decreased significantly during hypocapnia. Fetal ECoG activity showed normal cycling during the periods of mild hypocapnia, and the mean duration of LV ECoG periods did not change. During mild hypocapnia, eye movements remained associated with LV ECoG activity and nuchal electromyographic activity remained associated with high-voltage ECoG activity. These results suggest that the presence of breathing movements in fetal life is not only dependent on the behavioral state but also on the level of fetal PaCO2.

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

2009 ◽  
Vol 296 (3) ◽  
pp. R693-R701 ◽  
Author(s):  
Takatsugu Maeda ◽  
Brian J. Koos
Keyword(s):  
Plasma Concentrations ◽  
Receptor Subtypes ◽  
Fetal Sheep ◽  
A2a Receptors ◽  
Endogenous Adenosine ◽  
Adenosine A1 ◽  
Elevated Glucose ◽  
Lactate Levels ◽  
Stimulation Of

Adenosine A1 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 (>0.8 term). In normoxic fetuses (PaO2 ∼24 Torr), systemic blockade of A1 receptors with DPCPX ( n = 6) increased plasma concentrations of insulin, glucose, and lactate, but antagonism of A2A receptors with ZM-241385 ( n = 5) had no significant effects. Intravascular administration of adenosine ( n = 9) reduced insulin concentrations and elevated glucose and lactate levels. DPCPX ( n = 6) augmented the glycemic and lactatemic responses of adenosine. In contrast, ZM241385 ( n = 5) virtually abolished adenosine-induced hyperglycemia and hyperlactatemia. Isocapnic hypoxia (PaO2 ∼13 Torr) suppressed insulinemia and enhanced glycemia and lactatemia, but only the hyperglycemia was blunted by blockade of A1 ( n = 6) or A2A ( n = 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.

Effects of various concentrations of O2 and umbilical cord occlusion on fetal breathing and behavior

1990 ◽  
Vol 68 (4) ◽  
pp. 1597-1604 ◽  
Author(s):  
R. J. Baier ◽  
S. U. Hasan ◽  
D. B. Cates ◽  
D. Hooper ◽  
B. Nowaczyk ◽  
...  
Keyword(s):  
Umbilical Cord ◽  
High Voltage ◽  
Airway Pressure ◽  
Low Voltage ◽  
Fetal Lung ◽  
Mean Airway Pressure ◽  
Fetal Sheep ◽  
Arterial Pco2 ◽  
Fetal Breathing ◽  
And Behavior

To test the hypothesis that continuous fetal breathing could be induced by hyperoxemia alone or by hyperoxemia and umbilical cord occlusion, even in the absence of a rise in arterial PCO2 (PaCO2), we studied 18 chronically instrumented fetal sheep on 34 occasions using our window model (18). After a resting cycle (1 low-voltage followed by 1 high-voltage electrocortical activity epoch), the fetal lung was distended via an endotracheal tube using mean airway pressure of approximately cmH2O. Inspired N2, 17% O2, and 100% O2 were given to the fetus during one cycle each. While 100% O2 was given, the umbilical cord was occluded (balloon cuff).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of meclofenamate on breathing movements in fetal sheep before delivery

1988 ◽  
Vol 64 (2) ◽  
pp. 759-766 ◽  
Author(s):  
L. D. Wallen ◽  
D. T. Murai ◽  
R. I. Clyman ◽  
C. H. Lee ◽  
F. E. Mauray ◽  
...  
Keyword(s):  
Low Voltage ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Electrocortical Activity ◽  
Fetal Plasma ◽  
Prostaglandin Synthase ◽  
Fetal Breathing ◽  
Fetal Breathing Movements ◽  
Synthase Inhibitor ◽  
Control Infusion

There is evidence that prostaglandins (PG), specifically PGE2, participate in the regulation of fetal breathing movements (FBM). During late gestation, when FBM occur intermittently and primarily during low-voltage electrocortical activity, the concentration of PGE2 in fetal plasma ([PGE2]) is high. During the days before delivery [PGE2] increases and FBM decrease. To determine whether the increase in [PGE2] is responsible for the concurrent decrease in FBM, we infused the prostaglandin synthase inhibitor, meclofenamate (0.7 mg.kg-1.h-1), into eight fetal sheep continuously for 5-–13 days before delivery; five control fetuses received a continuous infusion of the solvent for 5–11 days before delivery. Compared with control infusion, meclofenamate caused a significant decrease in [PGE 2] until the day of delivery and a significant increase in FBM [overall and during high-voltage electrocortical activity (HVA)] until 2 days before delivery. Although there were significant correlations between [PGE2] and FBM (overall and during HVA), both groups showed similar decreases in FBM during the 2 days before delivery. We conclude that the decrease in FBM before delivery is not dependent on the concurrent increase in [PGE2].

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