Cardiovascular and endocrine responses to acute hypoxaemia during and following dexamethasone infusion in the ovine fetus

Fletcher, Andrew; Gardner, David; Edwards, C. M. B.; Fowden, Abigail L.; Giussani, Dino A.

doi:10.1113/jphysiol.2002.036418

Cited by 53 publications

(63 citation statements)

References 70 publications

(94 reference statements)

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“…Results of experiments by Wood and colleagues (25) and later by Wintour and colleagues (6,21) demonstrated that physiological increases in fetal plasma cortisol increase fetal blood pressure. Fletcher and colleagues (8,9) have demonstrated that exogenous glucocorticoids alter baroreflex and chemoreflex responsiveness in the fetal sheep. It is possible that glucocorticoid alters cardiovas- cular reflex control acutely in the fetal sheep by altering the level of expression of iNOS in the fetal brainstem.…”

Section: Discussionmentioning

confidence: 99%

Expression of nitric oxide synthase isoforms is reduced in late-gestation ovine fetal brainstem

Wood¹,

Chen²,

Keller‐Wood³

2005

American Journal of Physiology-Regulatory, Integrative and Comp

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Wood, Charles E., Gin-Fu Chen, and Maureen Keller-Wood. Expression of nitric oxide synthase isoforms is reduced in late-gestation ovine fetal brainstem. Am J Physiol Regul Integr Comp Physiol 289: R613-R619, 2005; doi:10.1152/ajpregu.00722.2004.-Fetal baroreflex responsiveness increases in late gestation. An important modulator of baroreflex activity is the generation of nitric oxide in the brainstem nuclei that integrate afferent and efferent reflex activity. The present study was designed to test the hypothesis that nitric oxide synthase (NOS) isoforms are expressed in the fetal brainstem and that the expression of one or more of these enzymes is reduced in late gestation. Brainstem tissue was rapidly collected from fetal sheep of known gestational ages (80, 100, 120, 130, 145 days gestation and 1 day and 1 wk postnatal). Neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) mRNA was measured using real-time PCR methodology specific for ovine NOS isoforms. The three enzymes were measured at the protein level using Western blot methodology. In tissue prepared for histology separately, the cellular pattern of immunostaining was identified in medullae from late-gestation fetal sheep. Fetal brainstem contained mRNA and protein of all three NOS isoforms, with nNOS the most abundant, followed by iNOS and eNOS, respectively. nNOS and iNOS mRNA abundances were highest at 80 days' gestation, with statistically significant decreases in abundance in more mature fetuses and postnatal animals. nNOS and eNOS protein abundance also decreased as a function of developmental age. nNOS and eNOS were expressed in neurons, iNOS was expressed in glia, and eNOS was expressed in vascular endothelial cells. We conclude that all three isoforms of NOS are constitutively expressed within the fetal brainstem, and the expression of all three forms is reduced with advancing gestation. We speculate that the reduced expression of NOS in this brain region plays a role in the increased fetal baroreflex activity in late gestation. medulla; messenger ribonucleic acid; immunohistochemistry; realtime reverse transcriptase-polymerase chain reaction IN ADDITION TO ITS ROLE as an endothelial cell-derived vascular smooth muscle relaxant, the role of nitric oxide as a neurotransmitter is well established (11). In the medullary nuclei of the adult animal, nitric oxide is synthesized by neurons that express the neuronal form of nitric oxide synthase (nNOS or NOSIII) (3, 23). One of the physiological roles of nNOS in medullary neurons is the local generation of NO that, in turn, acts as an inhibitory neurotransmitter with regard to baroreflex responsiveness (13). Numerous studies in this laboratory have helped to establish the importance of baroreceptor and chemoreceptor reflexes in the minute-to-minute control of blood pressure and umbilical-placental blood flow in the fetus in utero (24,27). Various studies have demonstrated that the reflex mechanisms governing cardiovascular function in the fetus mature as a function of fetal gestational age (18,19...

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Section: Discussionmentioning

confidence: 99%

Expression of nitric oxide synthase isoforms is reduced in late-gestation ovine fetal brainstem

Wood¹,

Chen²,

Keller‐Wood³

2005

American Journal of Physiology-Regulatory, Integrative and Comp

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“…An increased incidence of fetal bradycardic responses to fetal stress occurs in women demonstrating high anxiety during pregnancy (20). It is not known whether acidemia and bradycardia occur during labor in fetuses with Cushing's disease; however, in ovine fetuses, exposure to glucocorticoids appears to increase the bradycardia and acidemia during a hypoxic episode (9,11). Despite the apparently normal heart size in the cortisol-treated fetuses at term, we have, in fact, found significant differences in gene expression in the septa collected from the hearts of the cortisol-infused fetuses that were live at the time of euthanasia compared with control fetuses.…”

Section: Perspectives and Significancementioning

confidence: 99%

Elevated maternal cortisol leads to relative maternal hyperglycemia and increased stillbirth in ovine pregnancy

Keller‐Wood

Feng

Wood

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Keller-Wood M, Feng X, Wood CE, Richards E, Anthony RV, Dahl GE, Tao S. Elevated maternal cortisol leads to relative maternal hyperglycemia and increased stillbirth in ovine pregnancy. Am J Physiol Regul Integr Comp Physiol 307: R405-R413, 2014. First published June 11, 2014 doi:10.1152/ajpregu.00530.2013.-In normal pregnancy, cortisol increases; however, further pathological increases in cortisol are associated with maternal and fetal morbidities. These experiments were designed to test the hypothesis that increased maternal cortisol would increase maternal glucose concentrations, suppress fetal growth, and impair neonatal glucose homeostasis. Ewes were infused with cortisol (1 mg·kg Ϫ1 ·day Ϫ1 ) from day 115 of gestation to term; maternal glucose, insulin, ovine placental lactogen, estrone, progesterone, nonesterified free fatty acids (NEFA), ␤-hydroxybutyrate (BHB), and electrolytes were measured. Infusion of cortisol increased maternal glucose concentration and slowed the glucose disappearance after injection of glucose; maternal infusion of cortisol also increased the incidence of fetal death at or near parturition. The design of the study was altered to terminate the study prior to delivery, and post hoc analysis of the data was performed to test the hypothesis that maternal metabolic factors predict the fetal outcome. In cortisol-infused ewes that had stillborn lambs, plasma insulin was increased relative to control ewes or cortisol-infused ewes with live lambs. Maternal cortisol infusion did not alter maternal food intake or plasma NEFA, BHB, estrone, progesterone or placental lactogen concentrations, and it did not alter fetal body weight, ponderal index, or fetal organ weights. Our study suggests that the adverse effect of elevated maternal cortisol on pregnancy outcome may be related to the effects of cortisol on maternal glucose homeostasis, and that chronic maternal stress or adrenal hypersecretion of cortisol may create fetal pathophysiology paralleling some aspects of maternal gestational diabetes. glucose; insulin; cortisol; pregnancy MATERNAL CORTISOL IS INCREASED in normal human pregnancy and is thought to contribute to the increase in maternal glucose concentration, as well as supporting increases in maternal plasma volume and cardiac output. In studies done in our laboratory, we have found that increasing maternal cortisol beyond the normal doubling in ovine pregnancy led to increased uterine blood flow and maternal and fetal glucose and lactate concentrations, whereas decreasing maternal cortisol to concentrations similar to those of nonpregnant ewes resulted in reduced uterine blood flow as gestation advanced (12, 13). Either increased or decreased maternal cortisol concentrations slowed the rate of fetal growth between 115 and 130 days of gestation. In women with Cushing's disease or Cushing's syndrome in pregnancy, there is also an increased incidence of small-for-gestational-age babies, as well as an increased risk of adverse pregnancy outcomes (26, 34). Maternal glucocorticoid treatme...

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“…The rate-pressure product, an index of myocardial work (18,40), was calculated as FBP ϫ FHR (mmHg ⅐ beats ⅐ min Ϫ1 ). Fetal femoral vascular resistance (FVR) was calculated using Ohm's principle by dividing FBP, corrected for amniotic pressure, by mean FBF (22).…”

Section: Measurements and Calculationsmentioning

confidence: 99%

Development of the ovine fetal cardiovascular defense to hypoxemia towards full term

Fletcher¹,

Gardner²,

Edwards³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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. Development of the ovine fetal cardiovascular defense to hypoxemia towards full term. Am J Physiol Heart Circ Physiol 291: H3023-H3034, 2006. First published July 21, 2006 doi:10.1152/ajpheart.00504.2006.-We tested the hypothesis that fetal cardiovascular responses to hypoxemia change close to full term in relation to the prepartum increase in fetal basal cortisol and investigated, in vivo, the neural and endocrine mechanisms underlying these changes. Fetal heart rate and peripheral hemodynamic responses to 1 h of hypoxemia were studied in 25 chronically instrumented sheep within three narrow gestational age ranges: 125-130 (n ϭ 13), 135-140 (n ϭ 6), and Ͼ140 (n ϭ 6) days (full term ϳ145 days). Chemoreflex function and plasma concentrations of vasoconstrictor hormones were measured. Reductions in fetal arterial PO2 during hypoxemia were similar at all ages. At 125-130 days, hypoxemia elicited transient bradycardia, femoral vasoconstriction, and increases in plasma concentrations of catecholamines, neuropeptide Y (NPY), AVP, ACTH, and cortisol. Close to full term, in association with the prepartum increase in fetal basal cortisol, there was a developmental increase in the magnitude and persistence of fetal bradycardia and in the magnitude of the femoral constrictor response to hypoxemia. The mechanisms mediating these changes close to full term included increases in the gain of chemoreflex function and in the magnitudes of the fetal NPY and AVP responses to hypoxemia. Data combined irrespective of gestational age revealed significant correlations between fetal basal cortisol and fetal bradycardia, femoral resistance, chemoreflex function, and plasma AVP concentrations. The data show that the fetal cardiovascular defense to hypoxemia changes in pattern and magnitude just before full term because of alterations in the gain of the neural and endocrine mechanisms mediating them, in parallel with the prepartum increase in fetal basal cortisol.fetus; prepartum cortisol surge; glucocorticoid IN ALL MAMMALIAN SPECIES studied to date, fetal basal cortisol concentration increases immediately before full term (23). In the ovine fetus, this increase in plasma cortisol begins in the last 15 days of gestation, at ϳ130 days (full term ϳ145 days) (3, 43), and increases most dramatically within the last 5 days before delivery, between 140 and 145 days. The prepartum cortisol surge is known to be an important factor in the developmental maturation of fetal tissues and physiological systems in preparation for the transition to neonatal life (23). For example, the prepartum maturation of basal cardiovascular function in the fetus is influenced by cortisol. The developmental increase in ovine fetal mean arterial blood pressure (FBP) and fall in fetal heart rate (FHR) are prevented by fetal adrenalectomy and restored to normal by cortisol replacement (63). Similarly, the prepartum cortisol surge has been associated with developmental changes in the basal activity of many fetal endocrine vasoconstrictor mechanisms, such as the norad...

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Cardiovascular and endocrine responses to acute hypoxaemia during and following dexamethasone infusion in the ovine fetus

Cited by 53 publications

References 70 publications

Expression of nitric oxide synthase isoforms is reduced in late-gestation ovine fetal brainstem

Expression of nitric oxide synthase isoforms is reduced in late-gestation ovine fetal brainstem

Elevated maternal cortisol leads to relative maternal hyperglycemia and increased stillbirth in ovine pregnancy

Development of the ovine fetal cardiovascular defense to hypoxemia towards full term

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