The Effects of Hypoxia on (Methionine) Enkephalin Peptide and Catecholamine Release in Fetal Sheep

Abstract

ABSTRACT. The effect of hypoxia on plasma met-enkephalin and catecholamine levels was studied in chronically catheterized fetal sheep. Maternal and fetal hypoxia was maintained for 20 min. We found hypoxia significantly increased the plasma levels of large mol wt met-enkephalin containing peptides from 1755 f 229 pg/mL during baseline to 4408 + 1426 pg/mL by 15 minutes of hypoxia. The levels of the met-enkephalin pentapeptide were unchanged during hypoxia from a baseline value of 168 f 56 pg/mL. Norepinephrine and epinephrine levels increased 5-and 10-fold, respectively, by 15 min of hypoxia. These observations suggest cosecretion of the large mol wt met-enkephalin peptides with catecholamines during stress in developing animals. (Pediatr Res 27: 52-55, 1990) Abbreviations MET-ENK, methionine-enkephalin LEU-ENK, leucine enkephalin MET-ENKi, methionine enkephalin immunoreactivity iments to measure the circulating plasma levels of the MET-ENK peptides in fetal sheep in response to hypoxia. MATERIALS AND METHODSSurgical procedures. Date-mated Western mixed-breed ewes (n = 5) with single fetuses were catheterized at 1 16-1 18 d of gestation (term = 150 d). The ewes were sedated preoperatively with ketamine (800 mg) and atropine (1.2 mg) and received a constant infusion of ketamine (8-10 mg/min) during the operation. The fetal hindleg was exteriorized through a uterine incision. After local anesthesia of the fetal leg (1 % lidocaine), polyvinyl catheters were placed in an artery and vein and advanced to the level of the descending aorta and the inferior vena cava, respectively. An additional catheter was placed in the uterus to allow measurement of amniotic fluid pressure. The uterine incision was closed with all catheters tunneled subcutaneously in the maternal flank and stored in a cloth pouch sewn to the skin of the ewe. The ewe also had catheters placed into the femoral vein and artery that were tunneled subcutaneously and stored with the fetal catheters. Oxacillin and gentamycin were given intravenously for 3 d postoperatively to both mother and fetus. Animals were allowed to recover a minimum of 5 d before anv studies were performed. The opiate peptides (endorphins and enke~halins) have been Experimental protocol. Fetal studies were carried out between shown to have significant physiologic effects on autonomic re-122 and 125 d of gestation. On the day of study, the fetal arterial sponses of fetal and neonatal cardiovascular (1) and respiratory catheter and the intrauterine pressure catheters were connected systems (2, 3) in humans and animals. The enke~halin peptides to Statham P23dB pressure transducers that were attached to a are ~ostulated to influence these systems centrally (41, as well as Sensormedics R6 1 1 rectilinear polygraph (Sensormedics Corpo~eri~herally, by inhibitory effects on neurotransmission in sYm-ration, Anaheim, CA). Fetal arterial blood gases and hematocrit pathetic ganglia (5, 6) and on adrenal medullary cat~cholamine were obtained. Arterial blood pressure, heart rate, and amniotic relea...

Plasma Methionine Enkephalin Levels in the Human Newborn at Birth

“…In dogs exposed to hypoglycemia, increased levels of the high-molecularweight peptides are described with no change noted in the pentapeptide levels [10]. In fetal sheep exposed to hypoxia, we have noted a significant elevation of the highmolecular-weight form of circulating met- enkephalin associated with elevated plasma catecholamine levels with no change in the pentapeptide levels [11]. In the present study, we found significantly higher levels of plasma met-enkephalin at birth in neonates when compared to adults.…”

Increased myocardial methionine‐enkephalin with reduced arterial oxygenation in congenital heart disease

“…The present data are the first to indicate that marked levels of myocardial ME are evident in congenital heart disease and that these levels are greater in hypoxia. In light of the previously reported cardioprotective role of enkephalins and opiates, and short half‐life of serum enkephalins in paediatric versus adult subjects, then this hypoxia‐dependent recruitment of augmented ME may constitute an important adaptive response to hypoxia 11,14–16,19,25,31–36 . Thus, the common clinical use of morphine to alleviate severe cyanotic spells may exert benefits beyond effects on myocardial tone.…”

“…The effects of hypoxia on the enkephalin system have been studied in several animal models 17–19 . Fifteen minutes of hypoxia in foetal sheep significantly increased serum levels of large molecular weight ME‐containing peptides as well as norepinephrine, suggesting co‐secretion of enkephalin with catecholamines during hypoxia in foetal sheep 19 . In a piglet study, hypoxia augmented the concentration of ME and leucine–enkephalin in cortical peri‐arachnoid cerebrospinal fluid 17 .…”

“…Cardiac enkephalin content and release during hypoxia has had limited prior investigation 17–19 but has not been previously measured in children with congenital heart disease. We hypothesised that cyanotic attacks occurring as a result of increased sympathetic tone in tetralogy of Fallot may further evoke increases in myocardial ME.…”

Acute Hypoxia Induces Enkephalin Production and Release in an Adrenergic Cell Line Model of Neonatal Chromaffin Cell Responses to Hypoxic Stress

“…To ascertain whether hypoxia induces catecholamine release from MPC cells (as seen for adrenal chromaffin cells [3][4][5][6][7][8][9]37 ), MPC cultures (n ¼ 5 for each interval) were incubated at 10% O 2 in Billups-Rothenberg chambers. At intervals from 0 to 60 minutes, equivalent amounts of HBSS media for each sample were aspirated into HCl (to a final concentration of 0.1 N) for spectrophotometric assay of epinephrine.…”