Adrenoceptor blockade modifies regional cerebral blood flow responses to hyperbaric hyperoxia: protection against CNS oxygen toxicity

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.

CNS function and dysfunction during exposure to hyperbaric oxygen in operational and clinical settings

“…Studies in anesthetized and unanesthetized instrumented animals4 reveal a predictable pattern of physiological changes over the course of the initial latent period and the ensuing bulbo-excitation period that implies increased neural excitability in autonomic and brainstem control centers prior to seizure genesis. Exposure to HBO 2 initially results in a transient parasympathetic response comprised of decreases in heart rate, cardiac output, blood pressure, and sympathetic tone [80,100]. Initially, cerebral blood flow (CBF) is decreased by vasoconstriction and delays a significant increase in brain tissue PO 2 [8,71,72,75,76,79].…”

“…Likewise, minute ventilation decreases initially due to hyperoxic inactivation of peripheral chemoreceptors [69,152]. With extended exposure to HBO 2 , this cardiopulmonary response is overtaken by increased sympathetic outflow resulting in hyperventilation and hypertension [98,100,152]. Part of the mechanism for the shift in autonomic output is compensation for pressure-induced activation of the arterial baroreceptor response [78].…”

“…Having said that, progress has been achieved, which is summarized here. Importantly, CNS-OT seizures resemble convulsions of idiopathic epilepsy [9,89,100]. Accordingly, based on theories borrowed from research on epilepsy under normoxic conditions, plus the results from animal physiology experiments (in vivo and in vitro) that describe the central effects of HBO 2 , we propose that HBO 2 -seizures develop in subcortical regions (oxtox trigger zones) and progressively spread throughout two looping and reverberating-amplifying circuits in the brainstem and cerebral cortex, as outlined in the following section.…”

“…In addition to affecting electrochemical equilibrium and GABA levels in the brain, AEDs may also exhibit antioxidant properties [134,148,149]. Likewise, anti-adrenergic therapy has been shown to be highly efficacious, particularly with non-specific blockade of α 1 /α 2 and β 1 /β 2 receptors [100]. However, treatment with AEDs and anti-adrenergic medications can result in cognitive and physical deficits, with symptoms including drowsiness, dizziness, weakness, nausea, vomiting, and diarrhea [119,137].…”

Rationale for hyperbaric oxygen therapy in traumatic injury and wound care in small animal veterinary practice

“…Improved intracellular oxygen tension maintains mitochondrial and other cellular metabolic functions, which in turn helps maintain integrity of cell membranes and energydependent mechanisms. With HBOT, there is a reduction of the vasogenic and cellular fluid shifts that normally result in edema such as seen in crush injuries, compartmental syndromes, burns, reperfusion injury and reimplantation situations (Dünnwald et al 2018, Gasier et al 2018, Mihaljević et al 2018, Robins & Wyatt 2020. The benefits are the sum effects of vasoconstriction and subsequent tissue increase of NO.…”