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    • The present findings demonstrate for the first

    2021-10-27

    The present findings demonstrate for the first time in immature rats that hippocampal infusion of ET-1 results in a rapid and long-lasting decrease in regional cerebral blood flow (rCBF) and oxygen saturation (pO2). These data are in accord with the results of studies and adult animals, which have shown that after injection of ET-1 there was development of cerebral ischemia in the territory of the middle cerebral artery (Bogaert et al., 2000) or in the AT9283 mg parenchyma (Fuxe et al., 1997). Our results indicate that in immature rats decreased rCBF in the hippocampus is more severe compared to the other groups if the ETB receptors are blocked by the selective antagonist, BQ788. On the other hand, there are only mild changes in rCBF after activation of ETB receptors by the selective agonist, 4-Ala-ET-1, or by infusion of the selective antagonist of ETA receptors, BQ123, in combination with ET-1. These findings strongly suggest that activation of ETA receptors by the intrahippocampal infusion of ET-1 is crucial for the observed changes in rCBF and focal ischemia; whereas, ETB receptors probably mediate only mild modulatory effects. Further confirmation of these receptor subtype actions could be achieved by the application of a selective agonist for ETA receptors, but unfortunately, such a drug is currently not available commercially. As expected, the reduction in rCBF after injection of ET-1 was accompanied by a decrease in pO2. The time course of decreased pO2, however, was different from that of rCBF. While rCBF was persistently decreased (Fig. 1A), pO2 showed a stepwise recovery (see Fig. 2A). One explanation for this discrepancy may be that in our studies, pO2 was measured in animals under isoflurane anesthesia. Clinical data obtained in patients under long-lasting anesthesia have shown that pO2 increases over time, most likely due to a decline in oxygen consumption (Lee et al., 2012). A similar phenomenon may have occurred in our anesthetized rats. In addition to decreased rCBF and pO2, the intra-hippocampal infusion of ET-1 produced hippocampal damage in P12 rats. This result confirms our previous findings in immature rats (Tsenov et al., 2007) and those of Fuxe et al., 1992, Fuxe et al., 1997 in adult animals. The latter authors also pointed out the correlation of ET-1 induced damage with reduced rCBF and demonstrated that the formation of a lesion following ET-1 injection can be prevented by local pretreatment with dihydralazine, a powerful vasodilator (Fuxe et al., 1992). Thus, previous data in adult animals in our data in immature animals strongly suggest that tissue damage induced by ET-1 is a consequence of focal ischemia. Furthermore, our present data demonstrated that the correlation in experimental groups between ischemia and tissue damage extends to ET receptor subtypes. Infusion of ET-1+ETB antagonist produced both evidence of ischemia (decreased CBF and decreased pO2) and significant hippocampal damage. By contrast, treatments that did not produce significant ischemia (ETB agonist or ET-1+ETA receptor antagonist) did not produce major tissue damage, although some FJB positive cells were observed in the hippocampi of animals receiving the latter treatment. The reason for the appearance of some tissue damage in the ET-1+ETA antagonist group needs to be explored further. One explanation might be incomplete ETA receptor blockade. In unanesthetized freely moving animals, intracerebral administration of ET-1 has been shown to result in the development of epileptic seizures in both adult and immature rats (Mateffyova et al., 2006, Nagasaka et al., 1999, Tsenov et al., 2007). Furthermore, using co-administration of ET-1 and the specific antagonists of ET receptors in the ET-1 model, Nagasaka et al. (1999) concluded that activation of ETA receptors was critical for development of clinical seizures, while activation of ETB receptors did not lead to convulsive behavior. In these studies, however, EEG recording was not performed and the evaluation of seizures was restricted to behavioral phenomena.