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Early ketamine exposure results in cardiac enlargement and heart dysfunction in Xenopus embryos.

Guo R, Liu G, Du M, Shi Y, Jiang P, Liu X, Liu L, Liu J, Xu Y - BMC Anesthesiol (2016)

Bottom Line: However, with the exception of studies about the nervous system, studies about the effect of early ketamine exposure on embryos are rare.Moreover, the heart rate and ventricular shortening fraction were decreased, findings indicative of heart dysfunction.The heart enlargement and decreased VSF may result from the down-regulation of XMLC2 mRNA and protein levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, 400014, PR China.

ABSTRACT

Background: Ketamine is a commonly used clinical anesthetic and a popular recreational drug. However, with the exception of studies about the nervous system, studies about the effect of early ketamine exposure on embryos are rare. Xenopus laevis is a commonly used vertebrate model for assessing teratogenicity. Therefore, we treated Xenopus embryos with ketamine to evaluate its teratogenicity on embryos.

Methods: Xenopus embryos were treated with ketamine from stages 8 to 21. Embryonic and cardiac morphology were analyzed using living embryo imaging and whole-mount RNA in situ hybridization (WMISH). Heart function was measured by heart rate and ventricular shortening fraction (VSF). The mRNA expression levels of several heart development-related genes were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The protein expression levels of XMLC2, phospho-histone H3 (pH3) and histone H3 were determined by western blot.

Results: Ketamine caused concentration-dependent increases in mortality and shortening of body length. At a dose of 0.5 mg/ml, ketamine exposure resulted in cardiac enlargement as the primary manifestation of several malformations: gut defects, a curved axis and shortened body length. Cardiac cells underwent increased proliferation. Moreover, the heart rate and ventricular shortening fraction were decreased, findings indicative of heart dysfunction. XMLC2 expression levels were down-regulated at stages 28, 32/33, 35/36 and 46.

Conclusions: Ketamine exposure during early development has teratogenic effects on Xenopus embryos. The heart enlargement and decreased VSF may result from the down-regulation of XMLC2 mRNA and protein levels. These findings provide new insight into the potential fetal defects induced by ketamine exposure during early pregnancy.

No MeSH data available.


Related in: MedlinePlus

The effect of ketamine on cardiac morphology. a-h Embryos at stage 46. a-b Live embryos. c-h Whole-mount RNA in situ hybridization (WMISH) analysis of the heart-specific gene XNkx2.5 and myocardium-specific genes XTnIc and XMLC2. i The dissected hearts from embryos at stage 46. oft, outflow tract; a, atria; v, ventricle. j-o WMISH analysis of XMLC2 at stage 28, 32/33 and 35/36. Scale bar = 20 μm
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Fig2: The effect of ketamine on cardiac morphology. a-h Embryos at stage 46. a-b Live embryos. c-h Whole-mount RNA in situ hybridization (WMISH) analysis of the heart-specific gene XNkx2.5 and myocardium-specific genes XTnIc and XMLC2. i The dissected hearts from embryos at stage 46. oft, outflow tract; a, atria; v, ventricle. j-o WMISH analysis of XMLC2 at stage 28, 32/33 and 35/36. Scale bar = 20 μm

Mentions: After exposure to 0.5 mg/ml ketamine, no significant differences in mortality were found between the control and ketamine-treated embryos at stage 46 (Table 2). However, it caused heart defects (82.12 %), gut defects (4.64 %), a curved axis (19.87 %) and a shortened body length (8.86 ± 0.86 mm). Therefore, heart defects were the most commonly observed phenotype in the ketamine-treated embryos compared with the controls (82.12 versus 1.84 %), and heart enlargement (76.82 %) was the primary malformation (Table 2). The heart size of the ketamine-treated embryos was increased compared with the control embryos as determined via living embryo imaging, WMISH for the heart and myocardium, and the dissection of the heart tissues at four stages (stage 28, 32/33, 35/36 and 46) from heart tube formation to heart maturity (Fig. 2).Table 2


Early ketamine exposure results in cardiac enlargement and heart dysfunction in Xenopus embryos.

Guo R, Liu G, Du M, Shi Y, Jiang P, Liu X, Liu L, Liu J, Xu Y - BMC Anesthesiol (2016)

The effect of ketamine on cardiac morphology. a-h Embryos at stage 46. a-b Live embryos. c-h Whole-mount RNA in situ hybridization (WMISH) analysis of the heart-specific gene XNkx2.5 and myocardium-specific genes XTnIc and XMLC2. i The dissected hearts from embryos at stage 46. oft, outflow tract; a, atria; v, ventricle. j-o WMISH analysis of XMLC2 at stage 28, 32/33 and 35/36. Scale bar = 20 μm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4836076&req=5

Fig2: The effect of ketamine on cardiac morphology. a-h Embryos at stage 46. a-b Live embryos. c-h Whole-mount RNA in situ hybridization (WMISH) analysis of the heart-specific gene XNkx2.5 and myocardium-specific genes XTnIc and XMLC2. i The dissected hearts from embryos at stage 46. oft, outflow tract; a, atria; v, ventricle. j-o WMISH analysis of XMLC2 at stage 28, 32/33 and 35/36. Scale bar = 20 μm
Mentions: After exposure to 0.5 mg/ml ketamine, no significant differences in mortality were found between the control and ketamine-treated embryos at stage 46 (Table 2). However, it caused heart defects (82.12 %), gut defects (4.64 %), a curved axis (19.87 %) and a shortened body length (8.86 ± 0.86 mm). Therefore, heart defects were the most commonly observed phenotype in the ketamine-treated embryos compared with the controls (82.12 versus 1.84 %), and heart enlargement (76.82 %) was the primary malformation (Table 2). The heart size of the ketamine-treated embryos was increased compared with the control embryos as determined via living embryo imaging, WMISH for the heart and myocardium, and the dissection of the heart tissues at four stages (stage 28, 32/33, 35/36 and 46) from heart tube formation to heart maturity (Fig. 2).Table 2

Bottom Line: However, with the exception of studies about the nervous system, studies about the effect of early ketamine exposure on embryos are rare.Moreover, the heart rate and ventricular shortening fraction were decreased, findings indicative of heart dysfunction.The heart enlargement and decreased VSF may result from the down-regulation of XMLC2 mRNA and protein levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, 400014, PR China.

ABSTRACT

Background: Ketamine is a commonly used clinical anesthetic and a popular recreational drug. However, with the exception of studies about the nervous system, studies about the effect of early ketamine exposure on embryos are rare. Xenopus laevis is a commonly used vertebrate model for assessing teratogenicity. Therefore, we treated Xenopus embryos with ketamine to evaluate its teratogenicity on embryos.

Methods: Xenopus embryos were treated with ketamine from stages 8 to 21. Embryonic and cardiac morphology were analyzed using living embryo imaging and whole-mount RNA in situ hybridization (WMISH). Heart function was measured by heart rate and ventricular shortening fraction (VSF). The mRNA expression levels of several heart development-related genes were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The protein expression levels of XMLC2, phospho-histone H3 (pH3) and histone H3 were determined by western blot.

Results: Ketamine caused concentration-dependent increases in mortality and shortening of body length. At a dose of 0.5 mg/ml, ketamine exposure resulted in cardiac enlargement as the primary manifestation of several malformations: gut defects, a curved axis and shortened body length. Cardiac cells underwent increased proliferation. Moreover, the heart rate and ventricular shortening fraction were decreased, findings indicative of heart dysfunction. XMLC2 expression levels were down-regulated at stages 28, 32/33, 35/36 and 46.

Conclusions: Ketamine exposure during early development has teratogenic effects on Xenopus embryos. The heart enlargement and decreased VSF may result from the down-regulation of XMLC2 mRNA and protein levels. These findings provide new insight into the potential fetal defects induced by ketamine exposure during early pregnancy.

No MeSH data available.


Related in: MedlinePlus