TY - JOUR
T1 - Acute cardiac support with intravenous milrinone promotes recovery from early brain injury in a murine model of severe subarachnoid haemorrhage
AU - Mutoh, Tomoko
AU - Mutoh, Tatsushi
AU - Nakamura, Kazuhiro
AU - Yamamoto, Yukiko
AU - Tsuru, Yoshiharu
AU - Tsubone, Hirokazu
AU - Ishikawa, Tatsuya
AU - Taki, Yasuyuki
N1 - Funding Information:
This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (15K10966), Life Science Foundation of Japan, and Cooperative Research Project Program of Joint Usage/Research Center at the IDAC, Tohoku University.
Publisher Copyright:
© 2017 John Wiley & Sons Australia, Ltd
PY - 2017/4/1
Y1 - 2017/4/1
N2 - Early brain injury/ischaemia (EBI) is a serious complication early after subarachnoid haemorrhage (SAH) that contributes to development of delayed cerebral ischaemia (DCI). This study aimed to determine the role of inotropic cardiac support using milrinone (MIL) on restoring acute cerebral hypoperfusion attributable to EBI and improving outcomes after experimental SAH. Forty-three male C57BL/6 mice were assigned to either sham surgery (SAH-sham), SAH induced by endovascular perforation plus postconditioning with 2% isoflurane (Control), or SAH plus isoflurane combined with MIL with and without hypoxia-inducible factor inhibitor (HIF-I) pretreatment. Cardiac output (CO) during intravenous MIL infusion (0.25-0.75 μg/kg/min) between 1.5 and 2.5 hours after SAH induction was monitored with Doppler echocardiography. Magnetic resonance imaging (MRI)-continuous arterial spin labelling was used for quantitative cerebral blood flow (CBF) measurements. Neurobehavioral function was assessed daily by neurological score and open field test. DCI was analyzed 3 days later by determining infarction on MRI. Mild reduction of cardiac output (CO) and global cerebral blood flow (CBF) depression were notable early after SAH. MIL increased CO in a dose-dependent manner (P<.001), which was accompanied by improved hypoperfusion, incidence of DCI and functional recovery than Control (P<.05). The neuroprotective effects afforded by MIL or Control were attenuated by hypoxia-inducible factor (HIF) inhibition (P<.05). These results suggest that MIL improves acute hypoperfusion by its inotropic effect, leading to neurobehavioral improvement in mice after severe SAH, in which HIF may be acting as a critical mediator.
AB - Early brain injury/ischaemia (EBI) is a serious complication early after subarachnoid haemorrhage (SAH) that contributes to development of delayed cerebral ischaemia (DCI). This study aimed to determine the role of inotropic cardiac support using milrinone (MIL) on restoring acute cerebral hypoperfusion attributable to EBI and improving outcomes after experimental SAH. Forty-three male C57BL/6 mice were assigned to either sham surgery (SAH-sham), SAH induced by endovascular perforation plus postconditioning with 2% isoflurane (Control), or SAH plus isoflurane combined with MIL with and without hypoxia-inducible factor inhibitor (HIF-I) pretreatment. Cardiac output (CO) during intravenous MIL infusion (0.25-0.75 μg/kg/min) between 1.5 and 2.5 hours after SAH induction was monitored with Doppler echocardiography. Magnetic resonance imaging (MRI)-continuous arterial spin labelling was used for quantitative cerebral blood flow (CBF) measurements. Neurobehavioral function was assessed daily by neurological score and open field test. DCI was analyzed 3 days later by determining infarction on MRI. Mild reduction of cardiac output (CO) and global cerebral blood flow (CBF) depression were notable early after SAH. MIL increased CO in a dose-dependent manner (P<.001), which was accompanied by improved hypoperfusion, incidence of DCI and functional recovery than Control (P<.05). The neuroprotective effects afforded by MIL or Control were attenuated by hypoxia-inducible factor (HIF) inhibition (P<.05). These results suggest that MIL improves acute hypoperfusion by its inotropic effect, leading to neurobehavioral improvement in mice after severe SAH, in which HIF may be acting as a critical mediator.
KW - cardiac output
KW - cerebral blood flow
KW - delayed cerebral ischaemia
KW - early brain injury
KW - milrione
KW - mouse model
KW - neurobehavioral outcome
KW - subarachnoid haemorrhage
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U2 - 10.1111/1440-1681.12718
DO - 10.1111/1440-1681.12718
M3 - Article
C2 - 28008646
AN - SCOPUS:85016224249
VL - 44
SP - 463
EP - 469
JO - Clinical and Experimental Pharmacology and Physiology
JF - Clinical and Experimental Pharmacology and Physiology
SN - 0305-1870
IS - 4
ER -