Abstract
BackgroundDespite its clinical importance, a dearth of information exists on the cellular and molecular mechanisms that underpin brain stem death. A suitable neural substrate for mechanistic delineation on brain stem death resides in the rostral ventrolateral medulla (RVLM) because it is the origin of a life-and-death signal that sequentially increases (pro-life) and decreases (pro-death) to reflect the advancing central cardiovascular regulatory dysfunction during the progression towards brain stem death in critically ill patients. The present study evaluated the hypothesis that heme oxygnase-1 (HO-1) may play a pro-life role as an interposing signal between hypoxia-inducible factor-1 (HIF-1) and nitric oxide synthase I (NOS I)/protein kinase G (PKG) cascade in RVLM, which sustains central cardiovascular regulatory functions during brain stem death.MethodsWe performed cardiovascular, pharmacological, biochemical and confocal microscopy experiments in conjunction with an experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos (Mev; 10 nmol) bilaterally into RVLM of adult male Sprague-Dawley rats.ResultsWestern blot analysis coupled with laser scanning confocal microscopy revealed that augmented HO-1 expression that was confined to the cytoplasm of RVLM neurons occurred preferentially during the pro-life phase of experimental brain stem death and was antagonized by immunoneutralization of HIF-1α or HIF-1β in RVLM. On the other hand, the cytoplasmic presence of HO-2 in RVLM neurons manifested insignificant changes during both phases. Furthermore, immunoneutralization of HO-1 or knockdown of ho-1 gene in RVLM blunted the augmented life-and-death signals exhibited during the pro-life phase. Those pretreatments also blocked the upregulated pro-life NOS I/PKG signaling without affecting the pro-death NOS II/peroxynitrite cascade in RVLM.ConclusionsWe conclude that transcriptional upregulation of HO-1 on activation by HIF-1 in RVLM plays a preferential pro-life role by sustaining central cardiovascular regulatory functions during brain stem death via upregulation of NOS I/PKG signaling pathway. Our results further showed that the pro-dead NOS II/peroxynitrite cascade in RVLM is not included in this repertoire of cellular events.
Highlights
Despite its clinical importance, a dearth of information exists on the cellular and molecular mechanisms that underpin brain stem death
A logical neural substrate for this delineation resides in the rostral ventrolateral medulla (RVLM), which is longknown to be responsible for the maintenance of sympathetic vasomotor tone and stable systemic arterial pressure (SAP) [10] and is the origin of the LF component [11] that presents itself as the life-and-death signal that disappears before brain stem death [12]
Activation of heme oxygnase-1 (HO-1) leads to phasic upregulation of nitric oxide synthase I (NOS I)/protein kinase G (PKG) signaling in RVLM We demonstrated previously [13,14,16,17] that whereas NOS I/PKG signaling in RVLM is responsible for the pro-life phase, NOS II/peroxynitrite signaling underlies the pro-death phase of Mev intoxication
Summary
A dearth of information exists on the cellular and molecular mechanisms that underpin brain stem death. Component, which reflects dysfunction of central circulatory control, consistently occurs before brain stem death ensues It follows that delineation of the cellular and molecular mechanisms that underpin the impending impairment of brain stem cardiovascular regulatory machinery should enrich the dearth of mechanistic information currently available on brain stem death. The distinct phases of an augmentation followed by a reduction of the LF power manifested during Mev intoxication resemble those exhibited by patients died of organophosphate poisoning during the progression towards brain stem death [9] As such, they can be designated the pro-life and pro-death phase of cardiovascular regulation in this model of brain stem death [12]. NOS III in RVLM is not engaged in either the pro-life or pro-death phase of the Mev intoxication model of brain stem death [16]
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