Maturation of Circulatory Responses to Methionine-Enkephalin

Abstract

Summarydescending aorta and inferior vena cava, respectivelv. The fetalThe cardiovascular and respiratory effects of the naturally occurring endogenous opiate, methionine-enkephalin, were studied in 23 fetal sheep, five newborn lambs, 15 pregnant sheep, and four nonpregnant ewes. The opiate peptide produced dose-dependent decreases in heart rate and blood pressure in fetal and neonatal lambs but increased heart rate and blood pressure followed immediately by decreased heart rate and blood pressure in pregnant ewes. The circulatory responses were examined by pharmacologic blockade of receptor activity and by vagotomy. The bradycardia and hypotension in the fetus and tachycardia and hypertension in the adult were shown to be mediated by autonomic efferent nerves. Sinoaortic denervation did not affect the fetal responses to infused enkephalin. Respiration decreased in fetal as well as postnatal animals even at doses of methionine-enkephalin that did not significantly affect heart rate and blood pressure. These data indicate that the cardiovascular effects of infused enkephalins undergo maturational changes and are mediated by the autonomic nervous system.Endorphins and enkephalins are widely distributed throughout the brain, spinal cord, and peripheral autonomic nervous system (13, 37). Opioid receptors are located in these same areas, but are particularly abundant in regions associated with pain perception and pituitary hormone release (10,34,35) and in the medullary nuclei concerned with cardiopulmonary regulation (10,14,34,35). Opiate receptors also increase both in number and in affinity during the latter third of gestation and in the first few weeks after birth in rats (8,9,33). Because endogenous opiates, such as enkephalin, can modify cardiovascular and pulmonary function in adults (2, 5, 25, 36), we wished to assess whether there were developmental changes in circulatory regulation by endogenous opiates.To do this, we chose methionine-enkephalin as an opiate receptor agonist because it has been detected in high concentrations in the adrenal medulla (17, 44), is secreted into the circulation after appropriate stimulation (16,39, 41), and is found widely distributed in autonomic ganglia (19,30,37). In addition, because it is known that the autonomic nervous system matures postnatally (I, 3, 28), and that the enkephalins may function as cotransmitters with acetylcholine and catecholamines in autonomic ganglia and the adrenal medulla (18, 41), it is possible that maturational changes in the enkephalinergic system occur and may be important in modifying the cardiovascular response to stress. MATERIALS AND METHODSSurgery. Surgery was performed in 25 time-dated pregnant ewes at 120-130 days gestation (term is 145 + 5 days). Lower body anesthesia was accomplished by epidural injection of 2% tetracaine hydrochloride (Winthrop Laboratories, CA). The uterus was exposed through a midline incision and fetal hind limbs were delivered through a small hysterotomy. Polyvinyl catheters were inserted into both pedal arteries...

Effect of Endogenous Opioid Blockade on Fetal Cardiovascular and Sympathoadrenal Responses to Hypoxemia Induced by Umbilical Cord Constriction

“…Intravenous administration of methio nine-enkephalin in the fetus has been shown to produce an immediate, profound brady cardia lasting 10-30 s which can be pre vented by opioid receptor blockade with nal oxone or parasympathetic blockade with atropine (muscarinic) and trimethaphan (nic otinic) [17,18]. Thus, it is unlikely that the slight (10%) additional decrease in heart rate observed following naloxone administration in the asphyxiated fetus [11] is the result of opioid receptor blockade alone.…”

Fetal Cardiovascular and Breathing Movement Responses to Endogenous Opiates

“…Mus carinic blockade with atropine and gan glionic blockade with either hexaméthonium or chlorisondamine virtually eliminated the HR changes and suggest that enkephalin acts at either the parasympathetic ganglia or at a central autonomic site. La Gamma et al [ 14] demonstrated similar responses which they believed were compatible with a central site of action. However, the absence of HR slow ing following intracisternal administration of endogenous opioids suggests that the central autonomic centers may not participate in this response in the fetus.…”

“…Recently, developmental changes have been noted in opioid receptor concentration and affinity during the post natal period [12,13]. La Gamma et al [14] have demonstrated depression of heart rate (HR) and blood pressure (BP) following in travenous meth-enkephalin in the sheep fe tus, but tachycardia and hypertension in the adult. The present investigation was under taken to assess the effects of both central ner vous and intravenous administration of meth-enkephalin and P-endorphin on HR, BP and fetal breathing movements (FBM) in the chronically catheterized fetal lamb in utero.…”

Plasma Methionine Enkephalin Levels in the Human Newborn at Birth

“…Both central and peripheral infusions of met-enkephalin in fetal sheep are shown to have significant effects on heart rate, blood pressure and fetal breathing move ments [3,18]. These effects are eliminated by autonomic blockade and blunted by nal oxone.…”