title: Calcitonin gene-related peptide antagonism attenuates the haemodynamic and glycaemic responses to acute hypoxaemia in the late gestation sheep fetus.
abstract: The fetal defence to acute hypoxaemia involves cardiovascular and metabolic responses, which include peripheral vasoconstriction and hyperglycaemia. Both these responses are mediated via neuroendocrine mechanisms, which require the stimulation of the sympathetic nervous system. In the adult, accumulating evidence supports a role for calcitonin gene-related peptide (CGRP) in the activation of sympathetic outflow. However, the role of CGRP in stimulated cardiovascular and metabolic functions before birth is completely unknown. This study tested the hypothesis that CGRP plays a role in the fetal cardiovascular and metabolic defence responses to acute hypoxaemia by affecting sympathetic outflow. Under anaesthesia, five sheep fetuses at 0.8 of gestation were surgically instrumented with catheters and a femoral arterial Transonic flow-probe. Five days later, fetuses were subjected to 0.5 h hypoxaemia during either i.v. saline or a selective CGRP antagonist in randomised order. Treatment started 30 min before hypoxaemia and ran continuously until the end of the challenge. Arterial samples were taken for blood gases, metabolic status and hormone analyses. CGRP antagonism did not alter basal arterial blood gas, metabolic, cardiovascular or endocrine status. During hypoxaemia, similar falls in Pa,O2 occurred in all fetuses. During saline infusion, hypoxaemia induced hypertension, bradycardia, femoral vasoconstriction, hyperglycaemia and an increase in haemoglobin, catecholamines and neuropeptide Y (NPY). In contrast, CGRP antagonism markedly diminished the femoral vasoconstrictor and glycaemic responses to hypoxaemia, and attenuated the increases in haemoglobin, catecholamines and NPY. Combined, these results strongly support the hypothesis that CGRP plays a role in the fetal cardiovascular and metabolic defence to hypoxaemia by affecting sympathetic outflow.
authors.affiliation: Department of Physiology, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: A S
authors.initials: AS
authors.lastname: Thakor
authors.forename: M R
authors.initials: MR
authors.lastname: Bloomfield
authors.forename: M
authors.initials: M
authors.lastname: Patterson
authors.forename: D A
authors.initials: DA
authors.lastname: Giussani
mesh_terms: D000136:Acid-Base Equilibrium / Q000502:physiology; D000818:Animals; D001784:Blood Gas Analysis; D001786:Blood Glucose / Q000378:metabolism*; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002395:Catecholamines / Q000378:metabolism; D005260:Female; D005311:Fetal Hypoxia / Q000378:metabolism*; D005333:Fetus / Q000098:blood supply / Q000502:physiology; D005865:Gestational Age; D006439:Hemodynamics / Q000187:drug effects*; D000860:Hypoxia / Q000378:metabolism*; D009478:Neuropeptide Y / Q000097:blood; D010446:Peptide Fragments / Q000494:pharmacology; D011247:Pregnancy; D012756:Sheep; D013564:Sympathetic Nervous System / Q000502:physiology
chemical_list: D001786:Blood Glucose; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002395:Catecholamines; D009478:Neuropeptide Y; D010446:Peptide Fragments; C058636:calcitonin gene-related peptide (8-37); D015740:Calcitonin Gene-Related Peptide