Adrenoceptor blockade modifies regional cerebral blood flow responses to hyperbaric hyperoxia: Protection against CNS oxygen toxicity.
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2018-07-19
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Abstract
Exposure to extreme-hyperbaric oxygen (HBO2), > 5-6 atmospheres absolute (ATA), produces baroreflex impairment, sympathetic hyperactivation, hypertension, tachycardia, and cerebral hyperemia, known as Phase II, culminating in seizures. We hypothesized that attenuation of the effects of high sympathetic outflow would preserve regional cerebral blood flow (rCBF) and protect against HBO2-induced seizures. To explore this possibility, we tested four adrenoceptor antagonists in conscious and anesthetized rats exposed to HBO2 at 5 and 6 ATA, respectively: phentolamine (nonselective α1 and 2), prazosin (selective α1), propranolol (nonselective β1 and 2) and atenolol (selective β1). In conscious rats, 4 drug-doses were administered to rats prior to HBO2 exposures, and seizure latencies were recorded. Drug-doses that provided similar protection against seizures were administered before HBO2 exposures in anesthetized rats to determine the effects of adrenoceptor blockade on mean arterial pressure, heart rate, rCBF and EEG spikes. All four drugs modified cardiovascular and rCBF responses in HBO2 that aligned with epileptiform discharges, but only phentolamine and propranolol effectively increased EEG spike latencies by ~20 and 36 min, respectively. When phentolamine and propranolol were delivered during HBO2 at the onset of phase II, only propranolol led to sustained reductions in heart rate and rCBF, preventing the appearance of epileptiform discharges. The enhanced effectiveness of propranolol may extend beyond β-adrenoceptor blockade, i.e. membrane stability and reduced metabolic activity. These results indicate that adrenoceptor drug pre-treatment will minimize the effects of excessive sympathetic outflow on rCBF and extend HBO2 exposure time.
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Gasier, Heath G, Ivan T Demchenko, Sergei Yu Zhilyaev, Alexander N Moskvin, Alexander I Krivchenko and Claude A Piantadosi (2018). Adrenoceptor blockade modifies regional cerebral blood flow responses to hyperbaric hyperoxia: Protection against CNS oxygen toxicity. Journal of applied physiology (Bethesda, Md. : 1985), 125(4). pp. 1296–1304. 10.1152/japplphysiol.00540.2018 Retrieved from https://hdl.handle.net/10161/24103.
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Scholars@Duke
Heath Gasier
Dr. Gasier is a physiologist and nutritionist. His research is focused on understanding how breathing altered PO2 impacts cell physiology in the lung, brain, and skeletal muscle. Emphasis is placed on mitochondrial quality control (dynamics, mitophagy, and biogenesis) and bioenergetics. He uses in vivo and in vitro models, and employs an array of methods (e.g., confocal and electron microscopy, Seahorse respiration, immunoblotting, RT-qPCR, ELISA’s, isotope tracers, and 10X genomics) for hypothesis testing. The goal of his research is to improve the operational capacity of divers and safety of hyperoxia in hyperbaric and critical care medicine. Dr. Gasier believes in a hands-on mentoring approach and individualized training plans based on mentee’s aspirations. He is committed to lifetime learning and contributing to knowledge advancement.
Claude Anthony Piantadosi
Dr. Piantadosi's laboratory has special expertise in the pathogenic mechanisms of acute organ failure, particularly acute lung injury (ALI), with an emphasis on the molecular regulatory roles of the physiological gases— oxygen, carbon monoxide, and nitric oxide— as they relate to the damage responses to acute inflammation. The basic science focuses on oxidative processes and redox-regulation, especially the molecular mechanisms by which reactive oxygen and nitrogen species transmit biological signals involved in the maintenance of energy metabolism and mitochondrial health, but also contribute to pathogenesis and to the resolution of tissue injury.
Clinically, ALI and the related syndrome of multiple organ failure has a high mortality, which is related to the host inflammatory response, but is not well understood scientifically; thus, the laboratory is devoted to understanding these mechanisms in the context of the host response to relevant but well-controlled experimental manipulations including hyperoxia, bacterial infections, toxic drugs, and cytokine/chemokine signals. The approach relies on animal models, mainly transgenic and knockout mice, and cell models, especially lung and heart cells to evaluate and understand the physiology, pathology, and cell and molecular biology of the injury responses, to test independent and integrated mechanisms, and to devise interventions to prevent damage.
Apart from the lung, significant work is devoted to understanding damage to the heart, brain, liver, and kidney caused by these immune mechanisms, specifically emphasizing the role of mitochondria, key targets and sources of oxidative damage. This damage compromises their ability to support energy homeostasis and advanced cellular functions, and impacts on the important roles these organelles play in cell death by apoptosis and necrosis as well as in the resolution of cellular damage and inflammation.
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