Browsing by Author "Zhilyaev, Sergei Yu"

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    Adrenoceptor blockade modifies regional cerebral blood flow responses to hyperbaric hyperoxia: Protection against CNS oxygen toxicity.
    (Journal of applied physiology (Bethesda, Md. : 1985), 2018-07-19) Gasier, Heath G; Demchenko, Ivan T; Zhilyaev, Sergei Yu; Moskvin, Alexander N; Krivchenko, Alexander I; Piantadosi, Claude A
    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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    Baroreceptor afferents modulate brain excitation and influence susceptibility to toxic effects of hyperbaric oxygen.
    (Journal of applied physiology (Bethesda, Md. : 1985), 2014-09) Demchenko, Ivan T; Gasier, Heath G; Zhilyaev, Sergei Yu; Moskvin, Alexander N; Krivchenko, Alexander I; Piantadosi, Claude A; Allen, Barry W
    Unexplained adjustments in baroreflex sensitivity occur in conjunction with exposures to potentially toxic levels of hyperbaric oxygen. To investigate this, we monitored central nervous system, autonomic and cardiovascular responses in conscious and anesthetized rats exposed to hyperbaric oxygen at 5 and 6 atmospheres absolute, respectively. We observed two contrasting phases associated with time-dependent alterations in the functional state of the arterial baroreflex. The first phase, which conferred protection against potentially neurotoxic doses of oxygen, was concurrent with an increase in baroreflex sensitivity and included decreases in cerebral blood flow, heart rate, cardiac output, and sympathetic drive. The second phase was characterized by baroreflex impairment, cerebral hyperemia, spiking on the electroencephalogram, increased sympathetic drive, parasympatholysis, and pulmonary injury. Complete arterial baroreceptor deafferentation abolished the initial protective response, whereas electrical stimulation of intact arterial baroreceptor afferents prolonged it. We concluded that increased afferent traffic attributable to arterial baroreflex activation delays the development of excessive central excitation and seizures. Baroreflex inactivation or impairment removes this protection, and seizures may follow. Finally, electrical stimulation of intact baroreceptor afferents extends the normal delay in seizure development. These findings reveal that the autonomic nervous system is a powerful determinant of susceptibility to sympathetic hyperactivation and seizures in hyperbaric oxygen and the ensuing neurogenic pulmonary injury.
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    Increased Antiseizure Effectiveness with Tiagabine Combined with Sodium Channel Antagonists in Mice Exposed to Hyperbaric Oxygen.
    (Neurotoxicity research, 2019-11) Demchenko, Ivan T; Zhilyaev, Sergei Yu; Alekseeva, Olga S; Krivchenko, Alexander I; Piantadosi, Claude A; Gasier, Heath G
    Hyperbaric oxygen (HBO2) is acutely toxic to the central nervous system, culminating in EEG spikes and tonic-clonic convulsions. GABA enhancers and sodium channel antagonists improve seizure latencies in HBO2 when administered individually, while combining antiepileptic drugs from different functional classes can provide greater seizure latency. We examined the combined effectiveness of GABA enhancers (tiagabine and gabapentin) with sodium channel antagonists (carbamazepine and lamotrigine) in delaying HBO2-induced seizures. A series of experiments in C57BL/6 mice exposed to 100% oxygen at 5 atmospheres absolute (ATA) were performed. We predicted equally effective doses from individual drug-dose response curves, and the combinations of tiagabine + carbamazepine or lamotrigine were tested to determine the maximally effective combined doses to be used in subsequent experiments designed to identify the type of pharmacodynamic interaction for three fixed-ratio combinations (1:3, 1:1, and 3:1) using isobolographic analysis. For both combinations, the maximally effective combined doses increased seizure latency over controls > 5-fold and were determined to interact synergistically for fixed ratios 1:1 and 3:1, additive for 1:3. These results led us to explore whether the benefits of these drug combinations could be extended to the lungs, since a centrally mediated mechanism is believed to mediate hyperoxic-induced cardiogenic lung injury. Indeed, both combinations attenuated bronchoalveolar lavage protein content by ~ 50%. Combining tiagabine with carbamazepine or lamotrigine not only affords greater antiseizure protection in HBO2 but also allows for lower doses to be used, minimizing side effects, and attenuating acute lung injury.