Neonatal glucocorticoid overexposure alters cardiovascular function in young adult horses in a sex-linked manner

Abstract Prenatal glucocorticoid overexposure has been shown to programme adult cardiovascular function in a range of species, but much less is known about the long-term effects of neonatal glucocorticoid overexposure. In horses, prenatal maturation of the hypothalamus–pituitary–adrenal axis and the normal prepartum surge in fetal cortisol occur late in gestation compared to other precocious species. Cortisol levels continue to rise in the hours after birth of full-term foals and increase further in the subsequent days in premature, dysmature and maladapted foals. Thus, this study examined the adult cardiovascular consequences of neonatal cortisol overexposure induced by adrenocorticotropic hormone administration to full-term male and female pony foals. After catheterisation at 2–3 years of age, basal arterial blood pressures (BP) and heart rate were measured together with the responses to phenylephrine (PE) and sodium nitroprusside (SNP). These data were used to assess cardiac baroreflex sensitivity. Neonatal cortisol overexposure reduced both the pressor and bradycardic responses to PE in the young adult males, but not females. It also enhanced the initial hypotensive response to SNP, slowed recovery of BP after infusion and reduced the gain of the cardiac baroreflex in the females, but not males. Basal diastolic pressure and cardiac baroreflex sensitivity also differed with sex, irrespective of neonatal treatment. The results show that there is a window of susceptibility for glucocorticoid programming during the immediate neonatal period that alters cardiovascular function in young adult horses in a sex-linked manner.

[1]  D. De Clercq,et al.  Differences in ultrasound‐derived arterial wall stiffness parameters and noninvasive blood pressure between Friesian horses and Warmblood horses , 2020, Journal of veterinary internal medicine.

[2]  O. Kittnar Selected sex related differences in pathophysiology of cardiovascular system. , 2019, Physiological research.

[3]  A. Fowden,et al.  Physiological development of the equine fetus during late gestation. , 2019, Equine veterinary journal.

[4]  A. Fowden,et al.  Glucocorticoid Maturation of Fetal Cardiovascular Function. , 2019, Trends in molecular medicine.

[5]  D. Giussani,et al.  Combined Antioxidant and Glucocorticoid Therapy for Safer Treatment of Preterm Birth , 2019, Trends in Endocrinology & Metabolism.

[6]  V. Duranthon,et al.  Review: Epigenetics, developmental programming and nutrition in herbivores. , 2018, Animal : an international journal of animal bioscience.

[7]  T. Kuznetsova Sex Differences in Epidemiology of Cardiac and Vascular Disease. , 2018, Advances in experimental medicine and biology.

[8]  J. H. van der Kolk,et al.  Cardiovascular findings in ponies with equine metabolic syndrome. , 2017, Journal of the American Veterinary Medical Association.

[9]  A. Forhead,et al.  Effects of birth weight, sex and neonatal glucocorticoid overexposure on glucose-insulin dynamics in young adult horses. , 2017, Journal of developmental origins of health and disease.

[10]  J. Aschner,et al.  Effect of perinatal glucocorticoids on vascular health and disease , 2017, Pediatric Research.

[11]  J. Jellyman,et al.  Effects of maternal dexamethasone treatment on pancreatic &bgr; cell function in the pregnant mare and post natal foal , 2017, Equine veterinary journal.

[12]  A. Tarrade,et al.  Management of the pregnant mare and long-term consequences on the offspring. , 2016, Theriogenology.

[13]  Y. Tain,et al.  Postnatal dexamethasone-induced programmed hypertension is related to the regulation of melatonin and its receptors , 2016, Steroids.

[14]  A. Fowden,et al.  Glucocorticoids as regulatory signals during intrauterine development , 2015, Experimental physiology.

[15]  A. Fowden,et al.  HORSE SPECIES SYMPOSIUM: Glucocorticoid programming of hypothalamic-pituitary-adrenal axis and metabolic function: Animal studies from mouse to horse. , 2015, Journal of animal science.

[16]  J. Perry,et al.  Puberty timing associated with diabetes, cardiovascular disease and also diverse health outcomes in men and women: the UK Biobank study , 2015, Scientific Reports.

[17]  T. Paravicini,et al.  Developmental Origins of Health and Disease Excess prenatal corticosterone exposure results in albuminuria , sex-specific hypotension , and altered heart rate responses to restraint stress in aged adult mice , 2015 .

[18]  Lubo Zhang,et al.  Dexamethasone Treatment of Newborn Rats Decreases Cardiomyocyte Endowment in the Developing Heart through Epigenetic Modifications , 2015, PloS one.

[19]  C. Hammer,et al.  HORSE SPECIES SYMPOSIUM: Nutritional programming and the impact on mare and foal performance. , 2014, Journal of animal science.

[20]  A. Forhead,et al.  Neonatal glucocorticoid overexposure programs pituitary-adrenal function in ponies. , 2015, Domestic animal endocrinology.

[21]  A. Fowden,et al.  Glucocorticoid programming of hypothalamic-pituitary-adrenal axis and metabolic function : Animal studies from mouse to horse 1 , 2 , 2015 .

[22]  J. Jellyman,et al.  Sex-associated differences in pancreatic β cell function in healthy preweaning pony foals. , 2014, Equine veterinary journal.

[23]  Y. Tain,et al.  Melatonin prevents neonatal dexamethasone induced programmed hypertension: Histone deacetylase inhibition , 2014, The Journal of Steroid Biochemistry and Molecular Biology.

[24]  P. Gluckman,et al.  Early developmental conditioning of later health and disease: physiology or pathophysiology? , 2014, Physiological reviews.

[25]  D. Giussani,et al.  Antioxidant treatment improves neonatal survival and prevents impaired cardiac function at adulthood following neonatal glucocorticoid therapy , 2013, The Journal of physiology.

[26]  E. Camm,et al.  Vitamin C prevents intrauterine programming of in vivo cardiovascular dysfunction in the rat. , 2013, Circulation journal : official journal of the Japanese Circulation Society.

[27]  R. Reynolds Programming effects of glucocorticoids. , 2013, Clinical obstetrics and gynecology.

[28]  A. Fowden,et al.  Hormonal and nutritional drivers of intrauterine growth , 2013, Current opinion in clinical nutrition and metabolic care.

[29]  S. Davidge,et al.  Developmental programming of cardiovascular disease by prenatal hypoxia , 2013, Journal of Developmental Origins of Health and Disease.

[30]  J. Jellyman,et al.  Glucocorticoid overexposure in neonatal life alters pancreatic beta-cell function in newborn foals. , 2013, Journal of animal science.

[31]  J. Joles,et al.  Early determinants of cardiovascular disease. , 2012, Best practice & research. Clinical endocrinology & metabolism.

[32]  B. Khulan,et al.  Glucocorticoids as mediators of developmental programming effects. , 2012, Best practice & research. Clinical endocrinology & metabolism.

[33]  A. Fowden,et al.  Pancreatic endocrine function in newborn pony foals after induced or spontaneous delivery at term. , 2012, Equine veterinary journal. Supplement.

[34]  A. Fowden,et al.  Hypothalamic-pituitary-adrenal axis function in pony foals after neonatal ACTH-induced glucocorticoid overexposure. , 2012, Equine veterinary journal. Supplement.

[35]  H. Shaltout,et al.  Angiotensin-(1-7) Deficiency and Baroreflex Impairment Precede the Antenatal Betamethasone Exposure-Induced Elevation in Blood Pressure , 2012, Hypertension.

[36]  J. Bertram,et al.  Prenatal glucocorticoid exposure in the sheep alters renal development in utero: implications for adult renal function and blood pressure control. , 2011, American journal of physiology. Regulatory, integrative and comparative physiology.

[37]  C. Aurich Reproductive cycles of horses. , 2011, Animal reproduction science.

[38]  P. M. Coan,et al.  Environmental regulation of placental phenotype: implications for fetal growth. , 2011, Reproduction, fertility, and development.

[39]  H. Shaltout,et al.  Acute AT(1)-receptor blockade reverses the hemodynamic and baroreflex impairment in adult sheep exposed to antenatal betamethasone. , 2010, American journal of physiology. Heart and circulatory physiology.

[40]  P. Rossdale Foaling. Part 1: Maternal aspects , 2010 .

[41]  E. Camm,et al.  Investigation of the Use of Antioxidants to Diminish the Adverse Effects of Postnatal Glucocorticoid Treatment on Mortality and Cardiac Development , 2010, Neonatology.

[42]  E. Wintour,et al.  Haemodynamic characteristics of hypertension induced by prenatal cortisol exposure in sheep , 2009, Clinical and experimental pharmacology & physiology.

[43]  M. Faustini,et al.  15-Ketodihydro-PGF2alpha and cortisol plasma concentrations in newborn foals after spontaneous or oxytocin-induced parturition. , 2009, Theriogenology.

[44]  A. Fowden,et al.  The effects of maternal health and body condition on the endocrine responses of neonatal foals. , 2008, Equine veterinary journal.

[45]  J. Karemaker,et al.  Effects of Neonatal Dexamethasone Treatment on the Cardiovascular Stress Response of Children at School Age , 2008, Pediatrics.

[46]  E. E. van der Wall,et al.  Long-term cardiovascular effects of neonatal dexamethasone treatment: hemodynamic follow-up by left ventricular pressure-volume loops in rats. , 2008, Journal of applied physiology.

[47]  H. Teede,et al.  SEX HORMONES AND THE CARDIOVASCULAR SYSTEM: EFFECTS ON ARTERIAL FUNCTION IN WOMEN , 2007, Clinical and experimental pharmacology & physiology.

[48]  P. Kamphuis,et al.  Reduced Life Expectancy in Rats After Neonatal Dexamethasone Treatment , 2007, Pediatric Research.

[49]  V. Pulgar,et al.  Antenatal Betamethasone Administration Has a Dual Effect on Adult Sheep Vascular Reactivity , 2006, Pediatric Research.

[50]  R. Dampney,et al.  Calculation of threshold and saturation points of sigmoidal baroreflex function curves. , 2006, American journal of physiology. Heart and circulatory physiology.

[51]  T. Scholz,et al.  Early gestation dexamethasone alters baroreflex and vascular responses in newborn lambs before hypertension. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[52]  A. Fowden,et al.  Development of baroreflex function and hind limb vascular reactivity in the horse fetus , 2006, The Journal of physiology.

[53]  A. Fowden,et al.  Intrauterine programming of physiological systems: causes and consequences. , 2006, Physiology.

[54]  D. Weeks,et al.  Prenatal programming of adult blood pressure: role of maternal corticosteroids. , 2005, American journal of physiology. Regulatory, integrative and comparative physiology.

[55]  A. Schatzberg,et al.  Monoamine oxidase and catechol-o-methyltransferase enzyme activity and gene expression in response to sustained glucocorticoids , 2005, Psychoneuroendocrinology.

[56]  A. Fowden,et al.  Development of baroreflex and endocrine responses to hypotensive stress in newborn foals and lambs , 2005, Pflügers Archiv.

[57]  Jeffrey S. Robinson,et al.  Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. , 2005, Physiological reviews.

[58]  C. Saha,et al.  The change in blood pressure during pubertal growth. , 2005, The Journal of clinical endocrinology and metabolism.

[59]  P. Steendijk,et al.  Suppression of physiological cardiomyocyte proliferation in the rat pup after neonatal glucocorticosteroid treatment , 2005, Basic Research in Cardiology.

[60]  T. Scholz,et al.  Early gestation dexamethasone programs enhanced postnatal ovine coronary artery vascular reactivity. , 2005, American journal of physiology. Regulatory, integrative and comparative physiology.

[61]  J. Seckl Prenatal glucocorticoids and long-term programming. , 2004, European journal of endocrinology.

[62]  P. Gluckman,et al.  Developmental Origins of Disease Paradigm: A Mechanistic and Evolutionary Perspective , 2004, Pediatric Research.

[63]  E. Wintour,et al.  Programming the cardiovascular system, kidney and the brain--a review. , 2003, Placenta.

[64]  A. Fowden,et al.  Postnatal cardiovascular function after manipulation of fetal growth by embryo transfer in the horse , 2003, The Journal of physiology.

[65]  P. Rudan,et al.  Increase in cardiac contractility during puberty. , 2003, Collegium antropologicum.

[66]  A. Fowden,et al.  Effects of low dose dexamethasone treatment on basal cardiovascular and endocrine function in fetal sheep during late gestation , 2002, The Journal of physiology.

[67]  P. Kamphuis,et al.  Alterations in Adult Rat Heart after Neonatal Dexamethasone Therapy , 2002, Pediatric Research.

[68]  E. Lumbers,et al.  Effects Of Birth On Baroreceptor‐Mediated Changes In Heart Rate Variability In Lambs And Fetal Sheep , 2002, Clinical and experimental pharmacology & physiology.

[69]  P. Sibbons,et al.  Organogenesis of lung and kidney in Thoroughbreds and ponies. , 2010, Equine veterinary journal.

[70]  C. May,et al.  Altered cardiovascular haemodynamics and baroreceptor-heart rate reflex in adult sheep after prenatal exposure to dexamethasone. , 1999, Clinical science.

[71]  P. Harvey Oestrogen and vascular disease. , 1999, Australian and New Zealand journal of medicine.

[72]  J. Ousey,et al.  Glomerular filtration rate, effective renal plasma flow, blood pressure and pulse rate in the equine neonate during the first 10 days post partum. , 1998, Equine veterinary journal.

[73]  A. Fowden,et al.  Comparative Development of the Pituitary-Adrenal Axis in the Fetal Foal and Lamb , 1995 .

[74]  P. Rossdale Clinical view of disturbances in equine foetal maturation. , 2010, Equine veterinary journal. Supplement.

[75]  M. Manohar Blood flow to the respiratory and limb muscles and to abdominal organs during maximal exertion in ponies. , 1986, The Journal of physiology.

[76]  A. Fowden,et al.  Studies on equine prematurity 2: Post natal adrenocortical activity in relation to plasma adrenocorticotrophic hormone and catecholamine levels in term and premature foals. , 1984, Equine veterinary journal.

[77]  G. Anderson,et al.  Survey of resting blood pressure values in clinically normal horses. , 1984, Equine veterinary journal.

[78]  K. Soliman,et al.  Effect of prenatal exposure to phenobarbital on the development of monoamine oxidase and glucocorticoids. , 1983, General pharmacology.

[79]  B. Slinker,et al.  Arterial baroreflex control of heart rate in the horse, pig, and calf. , 1982, American journal of veterinary research.

[80]  P. Lees,et al.  The rate of rise of intraventricular pressure as an index of myocardial contractility in conscious and anaesthetised ponies. , 1976, Research in veterinary science.