Abstract
We previously reported that ATP-sensitive potassium (KATP) channels regulate ductal constriction in response to oxygen [1]. Diazoxide is a KATP channel opener while the usefulness of diazoxide for hyperinsulinemic hypoglycemia is well established. Yoshida et al. reported DA reopening in very low-birth-weight infants [2]. The objectives of this study were to elucidate the effect of KATP channel openers on the DA in neonatal rats as well as the different effects in preterm and full-term fetal rats [3].
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1 Background
We previously reported that ATP-sensitive potassium (KATP) channels regulate ductal constriction in response to oxygen [1]. Diazoxide is a KATP channel opener while the usefulness of diazoxide for hyperinsulinemic hypoglycemia is well established. Yoshida et al. reported DA reopening in very low-birth-weight infants [2]. The objectives of this study were to elucidate the effect of KATP channel openers on the DA in neonatal rats as well as the different effects in preterm and full-term fetal rats [3].
2 Methods
Near-term rat pups delivered via a cesarean section were housed at 33 °C. After rapid whole-body freezing, the ductus arteriosus (DA) diameter was measured using a microscope and a micrometer. Full-term pregnant rats (gestational day 21) were intraperitoneally injected with diazoxide (10 and 100 mg/kg) 4 h before delivery, and the neonatal DA diameter was measured at 0, 30, or 60 min after birth. The newborn rats were also intraperitoneally injected with diazoxide (10 and 100 mg/kg) at birth or 60 min after birth. DA was measured at 0, 30, or 60 min after injection. In the fetal study, constricted by COX and NOS inhibition the dilating effects of diazoxide was studied by simultaneous administration of indomethacin (10 mg/kg) and l-nitroarginine methyl ester (100 mg/kg) in gestational day 21 and 19.
3 Results
DA closure was delayed in rats exposed to prenatal diazoxide. Both doses of transplacentally administered diazoxide induced significant and dose-dependent inhibitory effect in postnatal DA constriction. Intraperitoneal injection of diazoxide at 60 min after birth induced DA reopening in a dose-dependent manner.
Diazoxide (10 mg/kg) dilatated the fetal DA in both near-term and preterm fetal rats. The effect of diazoxide in dilating the DA at preterm was the same as at full-term fetal rats.
4 Conclusion
KATP channel openers attenuate postnatal DA constriction and dilatate a closing DA in neonatal rats. If the DA is affected in a similar manner in human neonates, then PDA could be warranted for use with KATP channel openers to treat infants with hyperinsulinemic hypoglycemia, especially preterm infants.
References
Nakanishi T, et al. Mechanisms of oxygen-induced contraction of ductus arteriosus isolated from the fetal rabbit. Circ Res. 1993;72(6):1218–28.
Yoshida K, et al. High prevalence of severe circulatory complications with diazoxide in premature infants. Neonatology. 2014;105(3):166–71.
Toyoshima K, et al. Dilatation of the ductus arteriosus by diazoxide in fetal and neonatal rats. Pediatr Int. 2017;59(12):1246–51.
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Toyoshima, K., Momma, K., Ishii, T., Nakanishi, T. (2020). Dilatation of the Ductus Arteriosus by Diazoxide in Fetal and Neonatal Rats. In: Nakanishi, T., Baldwin, H., Fineman, J., Yamagishi, H. (eds) Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension. Springer, Singapore. https://doi.org/10.1007/978-981-15-1185-1_43
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DOI: https://doi.org/10.1007/978-981-15-1185-1_43
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