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Low-dose flunarizine does not affect short-term fetal circulatory responses to acute asphyxia in sheep near term

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Abstract

Asphyxia is one of the major causes of perinatal brain damage and neuronal cell loss, which may result in psychomotor deficits during later development. It has been shown previously that the immature brain can be protected from ischemic injury by flunarizine, a class IV calcium antagonist. However, cardiovascular side-effects of flunarizine, when applied at the dosages used in those studies, have been reported. Recently, the present authors were able to demonstrate that even by injecting flunarizine at a far lower dosage (1 mg kg-1 estimated bodyweight) neuronal cell damage, caused by occlusion of both carotid arteries for 30 min, can be reduced in fetal sheep near term. The aim of the present study was, therefore, to examine whether low-dose flunarizine affects fetal cardiovascular responses to acute asphyxia in sheep near term. Ten fetal sheep were chronically instrumented at a mean gestational age of 132 +/- 1 days (term is at 147 days). Fetuses from the study group received a bolus injection of flunarizine (1 mg kg-1 estimated fetal weight) 60 min before asphyxia, whereas the solvent was administered to the fetuses from the control group. Organ blood flows, physiological variables and plasma concentrations of catecholamines were measured before, during and after a single occlusion of uterine blood flow for 2 min (i.e. at 0, 1, 2, 3, 4, and 30 min). Before asphyxia, the distribution of combined ventricular output and physiological variables, as well as concentrations of catecholamines, in fetuses from the control group were in the normal range for chronically prepared fetal sheep near term. During acute asphyxia there was a redistribution of cardiac output towards the central organs accompanied by a pronounced bradycardia and a rapid increase in arterial blood pressure. After asphyxia circulatory centralization did not resolve quite as rapidly as it developed, but was almost completely recovered at 30 min after the insult. There were nearly no differences in the time course of physiological and cardiovascular variables measured before, during and after acute intrauterine asphyxia between the control and study groups. From the present study it was concluded that low-dose flunarizine does not affect short-term fetal circulatory responses to acute asphyxia in sheep near term.
... [3,11]. Von den zahlreichen aus diesen pathophysiologischen Erkenntnissen abgeleiteten Therapieregimen, die bisher tierexperimentell überprüft wurden, erscheinen die Applikation von Magnesium [40,53], Calciumantagonisten [6,15] und Sauerstoffradikalfängern [43] sowie die postischämisch induzierte zerebrale Hypothermie [5,20,21,50] für klinische Prüfungen am besten geeignet. ...
... This regimen reduced neuronal cell damage significantly, especially in the parasagittal cortex [49]. Severe drug-related cardiovascular side-effects could be excluded [50]. Thus, flunarizine was neuroprotective without adverse effects on fetal circulatory centralization during acute asphyxia, a crucial mechanism that protects the fetal brain from neuronal injury by increasing cerebral perfusion when oxygen is in short supply. ...
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