Effects of L-glutamine supplementation on maternal and fetal hemodynamics in gestating ewes exposed to alcohol

Abstract

Not much is known about effects of gestational alcohol exposure on maternal and fetal cardiovascular adaptations. This study determined whether maternal binge alcohol exposure and L-glutamine supplementation could affect maternal-fetal hemodynamics and fetal regional brain blood flow during the brain growth spurt period. Pregnant sheep were randomly assigned to one of four groups: saline control, alcohol (1.75-2.5 g/kg body weight), glutamine (100 mg/kg body weight) or alcohol + glutamine. A chronic weekend binge drinking paradigm between gestational days (GD) 99 and 115 was utilized. Fetuses were surgically instrumented on GD 117 ± 1 and studied on GD 120 ± 1. Binge alcohol exposure caused maternal acidemia, hypercapnea, and hypoxemia. Fetuses were acidemic and hypercapnic, but not hypoxemic. Alcohol exposure increased fetal mean arterial pressure, whereas fetal heart rate was unaltered. Alcohol exposure resulted in ~40 % reduction in maternal uterine artery blood flow. Labeled microsphere analyses showed that alcohol induced >2-fold increases in fetal whole brain blood flow. The elevation in fetal brain blood flow was region-specific, particularly affecting the developing cerebellum, brain stem, and olfactory bulb. Maternal L-glutamine supplementation attenuated alcohol-induced maternal hypercapnea, fetal acidemia and increases in fetal brain blood flow. L-Glutamine supplementation did not affect uterine blood flow. Collectively, alcohol exposure alters maternal and fetal acid-base balance, decreases uterine blood flow, and alters fetal regional brain blood flow. Importantly, L-glutamine supplementation mitigates alcohol-induced acid-base imbalances and alterations in fetal regional brain blood flow. Further studies are warranted to elucidate mechanisms responsible for alcohol-induced programming of maternal uterine artery and fetal circulation adaptations in pregnancy.

Fig. 1

Model for chronic alcohol binging paradigm. Alcohol or saline infusions were given intravenously over a period of 1 h per day for 3 consecutive days per week between gestational days (GD) 99 and 115 to mimic a weekend binge drinking pattern exhibited by pregnant women. The first four doses of alcohol were 1.75, 2, 2.25 and 2.25 g/kg body weight on GD 99, 100, 101 and 106, respectively. Doses of alcohol were 2.5 g/kg body weight from GD 107. Some ewes received IV infusions of 100 mg L-glutamine/kg body weight three times a day (i.e., 300 mg L-glutamine/kg body weight/day) on three consecutive days per week. Fetuses were surgically instrumented on GD 117 ± 1 and studied on GD 120 ± 1. Full term in sheep is 147 days

Fig. 2

Illustration of surgical catheterization. Catheters were inserted into the maternal femoral artery and vein and they were advanced to the abdominal aorta and inferior vena cava, respectively. For the fetus, catheters were inserted into the cranial-tibial artery and saphenous vein and were advanced to the abdominal aorta and inferior vena cava, respectively. An ultrasonic perivascular flow probe was secured around the primary uterine artery

Fig. 3

Effects of alcohol and L-glutamine supplementation on maternal systemic hemodynamic parameters. Maternal systemic hemodynamic parameters and arterial blood gases were measured at the end of the chronic binge alcohol exposure paradigm on gestational day (GD) 120 ± 1. a, b Maternal mean arterial pressure (MAP) and heart rate (HR) did not differ among groups at the baseline (0 min) or at the end of alcohol infusion (60 min). c Maternal arterial pH was decreased at 60 min in the alcohol and alcohol + glutamine groups compared to the saline control and glutamine groups, as well as compared to their respective baselines. d Maternal arterial partial pressure of carbon dioxide (PCO₂) was increased at 0 min in the alcohol group compared to all other groups and maternal arterial PCO₂ was increased at 60 min in the alcohol and alcohol + glutamine groups compared to the saline control and glutamine groups. e Concentration of maternal arterial bicarbonate (HCO₃) was decreased at 60 min in the alcohol group compared to the saline control and glutamine groups, as well as compared to the baseline. f Maternal arterial partial pressure of oxygen (PO₂) was decreased at 60 min in the alcohol and alcohol + glutamine groups compared to the saline control and glutamine groups, and compared to their respective baselines. a, b, c and d indicate statistically significant differences (P < 0.05), compared to the saline control, alcohol, glutamine and alcohol + glutamine groups, respectively. Single asterisk indicate statistically significant differences (P < 0.05) in the alcohol and/or alcohol + glutamine group, compared to their respective baseline

Fig. 4

Effects of alcohol and L-glutamine supplementation on fetal systemic hemodynamic parameters. Fetal systemic hemodynamic parameters and arterial blood gases were measured at the end of the chronic binge alcohol exposure paradigm on gestational day (GD) 120 ± 1. a Fetal mean arterial pressure (MAP) was elevated in the alcohol group at the baseline (0 min) compared to the saline control group and at the end of alcohol infusion (60 min), compared to the saline control and glutamine groups. b Fetal heart rate (HR) did not differ significantly among groups at 0 min and at 60 min. c Fetal arterial pH was decreased at 60 min in the alcohol and alcohol + glutamine groups, compared to the saline control group, glutamine group and compared to their respective baselines. Fetal arterial pH at 60 min in the alcohol group was significantly lower than the alcohol + glutamine group. d Fetal arterial partial pressure of carbon dioxide (PCO₂) was increased at 60 min in the alcohol and alcohol + glutamine groups, compared to the saline control group, glutamine group and compared to their respective baseline. e, f Fetal arterial bicarbonate (HCO₃) and partial pressure of oxygen (PO₂) did not differ among groups at 0 or 60 min. a, b, c and d indicate statistically significant differences (P <0.05) compared to the saline control, alcohol, glutamine and alcohol + glutamine groups, respectively. Single asterisk indicate statistically significant differences (P < 0.05) in the alcohol and/or alcohol + glutamine group compared to their respective baseline

Fig. 5

Effects of alcohol and L-glutamine supplementation on maternal uterine artery blood flow. Maternal uterine artery blood flow was measured at the end of the chronic binge alcohol exposure paradigm on gestational day (GD) 120 ± 1. Uterine artery blood flow (ml/min) was significantly decreased in the alcohol and alcohol + glutamine groups at the baseline (0 min) and during the period of the entire infusion (0–60 min). a and c indicate statistically significant differences (P < 0.05), compared to the saline control and glutamine groups, respectively

Fig. 6

Effects of alcohol and glutamine supplementation on fetal regional brain blood flow. Fetal regional brain blood flows at the baseline (0 min) and at the end of alcohol infusion (60 min) were measured on the last day of alcohol treatment (GD 120 ± 1). The fold change in fetal cerebellar, olfactory bulb, brain stem and whole-brain blood flow was increased in the alcohol group at the end of 60 min from their respective baselines (0 min) compared to the saline control and glutamine groups. Maternal L-glutamine supplementation mitigated the alcohol-induced alteration in fetal regional brain blood flow