Abstract
Preterm infants frequently suffer cardiovascular compromise, with hypotension and/or low systemic blood flow, leading to tissue hypoxia-ischemia (HI). Many preterm infants respond inadequately to inotropic treatments using adrenergic agonists such as dobutamine (DB) or dopamine (DA). This may be because of altered cardiac adrenoceptor expression because of tissue HI or prolonged exposure to adrenergic agonists. We assessed the effects of severe HI with and without DB/DA treatment on cardiac adrenoceptor expression in preterm fetal sheep. Fetal sheep (93–95 days) exposed to sham surgery or severe HI induced by umbilical cord occlusion received intravenous DB or saline for 74 h (HI DB, HI, Sham DB, Sham). The HI groups were also compared with fetal sheep exposed to HI and DA. Fetal hearts were collected to determine -adrenoceptor numbers using [125I]-cyanopindolol binding and mRNA expression of 1-, 2-, 1A-, 2A-, or 2B-adrenoceptors. The HI group had increased -adrenoceptor numbers compared with all other groups in all four heart chambers (P 0.05). This increase in -adrenoceptor numbers in the HI group was significantly reduced by DB infusion in all four heart chambers, but DA infusion in the HI group only reduced -adrenoceptor numbers in the left atria and ventricle. DB alone did not affect -adrenoceptor numbers in the sham animals. Changes in 1-adrenoceptor mRNA levels trended to parallel the binding results. We conclude that HI upregulates preterm fetal cardiac -adrenoceptors, but prolonged exposure to adrenergic agonists downregulates adrenoceptors in the preterm heart exposed to HI and may underpin the frequent failure of inotropic therapy in preterm infants. NEW & NOTEWORTHY This is the first study, to our knowledge, on the effects of hypoxia-ischemia and adrenergic agonists on adrenoceptors in the preterm heart. In fetal sheep, we demonstrate that hypoxia-ischemia increases cardiac -adrenoceptor numbers. However, exposure to both hypoxia-ischemia and adrenergic agonists (dobutamine or dopamine) reduces the increase in -adrenoceptor numbers, which may underpin the inadequate response in human preterm infants to inotropic therapy using adrenergic agonists. Dobutamine alone does not affect the cardiac adrenoceptors in the sham animals.
| Original language | English |
|---|---|
| Pages (from-to) | 1368-1377 |
| Number of pages | 10 |
| Journal | Journal of Applied Physiology |
| Volume | 125 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 1 Nov 2018 |
Keywords
- Cardiac adrenoceptors
- Dobutamine
- Dopamine
- Hypoxia
- Preterm heart
Cite this
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Effects of hypoxia-ischemia and inotropes on expression of cardiac adrenoceptors in the preterm fetal sheep. / Hutchinson, Dana S.; Brew, Nadine; Vu, Teresa; Merlin, Jon; Hale, Nadia; Walker, David W.; Wong, Flora Y.
In: Journal of Applied Physiology, Vol. 125, No. 5, 01.11.2018, p. 1368-1377.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Effects of hypoxia-ischemia and inotropes on expression of cardiac adrenoceptors in the preterm fetal sheep
AU - Hutchinson, Dana S.
AU - Brew, Nadine
AU - Vu, Teresa
AU - Merlin, Jon
AU - Hale, Nadia
AU - Walker, David W.
AU - Wong, Flora Y.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - Preterm infants frequently suffer cardiovascular compromise, with hypotension and/or low systemic blood flow, leading to tissue hypoxia-ischemia (HI). Many preterm infants respond inadequately to inotropic treatments using adrenergic agonists such as dobutamine (DB) or dopamine (DA). This may be because of altered cardiac adrenoceptor expression because of tissue HI or prolonged exposure to adrenergic agonists. We assessed the effects of severe HI with and without DB/DA treatment on cardiac adrenoceptor expression in preterm fetal sheep. Fetal sheep (93–95 days) exposed to sham surgery or severe HI induced by umbilical cord occlusion received intravenous DB or saline for 74 h (HI DB, HI, Sham DB, Sham). The HI groups were also compared with fetal sheep exposed to HI and DA. Fetal hearts were collected to determine -adrenoceptor numbers using [125I]-cyanopindolol binding and mRNA expression of 1-, 2-, 1A-, 2A-, or 2B-adrenoceptors. The HI group had increased -adrenoceptor numbers compared with all other groups in all four heart chambers (P 0.05). This increase in -adrenoceptor numbers in the HI group was significantly reduced by DB infusion in all four heart chambers, but DA infusion in the HI group only reduced -adrenoceptor numbers in the left atria and ventricle. DB alone did not affect -adrenoceptor numbers in the sham animals. Changes in 1-adrenoceptor mRNA levels trended to parallel the binding results. We conclude that HI upregulates preterm fetal cardiac -adrenoceptors, but prolonged exposure to adrenergic agonists downregulates adrenoceptors in the preterm heart exposed to HI and may underpin the frequent failure of inotropic therapy in preterm infants. NEW & NOTEWORTHY This is the first study, to our knowledge, on the effects of hypoxia-ischemia and adrenergic agonists on adrenoceptors in the preterm heart. In fetal sheep, we demonstrate that hypoxia-ischemia increases cardiac -adrenoceptor numbers. However, exposure to both hypoxia-ischemia and adrenergic agonists (dobutamine or dopamine) reduces the increase in -adrenoceptor numbers, which may underpin the inadequate response in human preterm infants to inotropic therapy using adrenergic agonists. Dobutamine alone does not affect the cardiac adrenoceptors in the sham animals.
AB - Preterm infants frequently suffer cardiovascular compromise, with hypotension and/or low systemic blood flow, leading to tissue hypoxia-ischemia (HI). Many preterm infants respond inadequately to inotropic treatments using adrenergic agonists such as dobutamine (DB) or dopamine (DA). This may be because of altered cardiac adrenoceptor expression because of tissue HI or prolonged exposure to adrenergic agonists. We assessed the effects of severe HI with and without DB/DA treatment on cardiac adrenoceptor expression in preterm fetal sheep. Fetal sheep (93–95 days) exposed to sham surgery or severe HI induced by umbilical cord occlusion received intravenous DB or saline for 74 h (HI DB, HI, Sham DB, Sham). The HI groups were also compared with fetal sheep exposed to HI and DA. Fetal hearts were collected to determine -adrenoceptor numbers using [125I]-cyanopindolol binding and mRNA expression of 1-, 2-, 1A-, 2A-, or 2B-adrenoceptors. The HI group had increased -adrenoceptor numbers compared with all other groups in all four heart chambers (P 0.05). This increase in -adrenoceptor numbers in the HI group was significantly reduced by DB infusion in all four heart chambers, but DA infusion in the HI group only reduced -adrenoceptor numbers in the left atria and ventricle. DB alone did not affect -adrenoceptor numbers in the sham animals. Changes in 1-adrenoceptor mRNA levels trended to parallel the binding results. We conclude that HI upregulates preterm fetal cardiac -adrenoceptors, but prolonged exposure to adrenergic agonists downregulates adrenoceptors in the preterm heart exposed to HI and may underpin the frequent failure of inotropic therapy in preterm infants. NEW & NOTEWORTHY This is the first study, to our knowledge, on the effects of hypoxia-ischemia and adrenergic agonists on adrenoceptors in the preterm heart. In fetal sheep, we demonstrate that hypoxia-ischemia increases cardiac -adrenoceptor numbers. However, exposure to both hypoxia-ischemia and adrenergic agonists (dobutamine or dopamine) reduces the increase in -adrenoceptor numbers, which may underpin the inadequate response in human preterm infants to inotropic therapy using adrenergic agonists. Dobutamine alone does not affect the cardiac adrenoceptors in the sham animals.
KW - Cardiac adrenoceptors
KW - Dobutamine
KW - Dopamine
KW - Hypoxia
KW - Preterm heart
UR - http://www.scopus.com/inward/record.url?scp=85057394466&partnerID=8YFLogxK
U2 - 10.1152/japplphysiol.00472.2018
DO - 10.1152/japplphysiol.00472.2018
M3 - Article
VL - 125
SP - 1368
EP - 1377
JO - Journal of Applied Physiology
JF - Journal of Applied Physiology
SN - 8750-7587
IS - 5
ER -