The cardiovascular system responds to hyperbaric hyperoxia (HBO2) with vasoconstriction, hypertension, bradycardia, and reduced cardiac output (CO). We tested the hypothesis that these responses are linked by a common mechanism-activation of the arterial baroreflex. Baroreflex function in HBO2 was assessed in anesthetized and conscious rats after deafferentation of aortic or carotid baroreceptors or both. Cardiovascular and autonomic responses to HBO2 in these animals were compared with those in intact animals at 2.5 ATA for conscious rats and at 3 ATA for anesthetized rats. During O2 compression, hypertension was greater after aortic or carotid baroreceptor deafferentation and was significantly more severe if these procedures were combined. Similarly, the hyperoxic bradycardia observed in intact animals was diminished after aortic or carotid baroreceptor deafferentation and replaced by a slight tachycardia after complete baroreceptor deafferentation. We found that hypertension, bradycardia, and reduced CO--the initial cardiovascular responses to moderate levels of HBO2--are coordinated through a baroreflex-mediated mechanism initiated by HBO2-induced vasoconstriction. Furthermore, we have shown that baroreceptor activation in HBO2 inhibits sympathetic outflow and can partially reverse an O2-dependent increase in arterial pressure.
The hypothesis that decreases in brain blood flow during respiration of hyperbaric oxygen result from inactivation of nitric oxide (NO) by superoxide anions (O2(-)) is proposed. Changes in brain blood flow were assessed in conscious rats during respiration of atmospheric air or oxygen at a pressure of 4 atm after dismutation of O2(-) with superoxide dismutase or suppression of NO synthesis with the NO synthase inhibitor L-NAME. I.v. administration of superoxide dismutase increased brain blood flow in rats breathing air but was ineffective after previous inhibition of NO synthase. Hyperbaric oxygenation at 4 atm induced decreases in brain blood flow, though prior superoxide dismutase prevented hyperoxic vasoconstriction and increased brain blood flow in rats breathing hyperbaric oxygen. The vasodilatory effect of superoxide dismutase in hyperbaric oxygenation was not seen in animals given prior doses of the NO synthase inhibitor. These results provide evidence that one mechanism for hyperoxic vasoconstriction in the brain consists of inactivation of NO by superoxide anions, decreasing its basal vasorelaxing action.
The physiological role of extracellular superoxide dismutase (SOD3) has received insufficient study. We investigated the hypothesis that SOD3, which neutralizes superoxide anions (O2(-)) in the intercellular space of the brain, prevents the inactivation of nitric oxide (NO) and is thus involved in regulating cerebral vascular tone. Local brain blood flow was measured in the striatum of anesthetized rats during administration of various combinations of a SOD mimetic, a SOD inhibitor, an NO donor, and an NOS inhibitor into the striatum using a Hamilton syringe. In normal conditions, SOD3 was found to minimize O2(-) levels, protecting endogenously produced NO at a sufficient level to maintain cerebral vascular tone and reactivity. SOD3 was found to increase the vasodilatory effect of endogenously produced NO in the brain. SOD3 was found to neutralize superoxide anions produced in the brain during respiration of 100% O2 and to maintain basal NO levels and its vasodilatory potential in normobaric hyperoxia.
Breathing hyperbaric oxygen (HBO₂), particularly at pressures above 3 atmospheres absolute, can cause acute pulmonary injury that is more severe if signs of central nervous system toxicity occur. This is consistent with the activation of an autonomic link between the brain and the lung, leading to acute pulmonary oxygen toxicity. This pulmonary damage is characterized by leakage of fluid, protein, and red blood cells into the alveoli, compatible with hydrostatic injury due to pulmonary hypertension, left atrial hypertension, or both. Until now, however, central hemodynamic parameters and autonomic activity have not been studied concurrently in HBO₂, so any hypothetical connections between the two have remained untested. Therefore, we performed experiments using rats in which cerebral blood flow, electroencephalographic activity, cardiopulmonary hemodynamics, and autonomic traffic were measured in HBO₂ at 5 and 6 atmospheres absolute. In some animals, autonomic pathways were disrupted pharmacologically or surgically. Our findings indicate that pulmonary damage in HBO₂ is caused by an abrupt and significant increase in pulmonary vascular pressure, sufficient to produce barotrauma in capillaries. Specifically, extreme HBO₂ exposures produce massive sympathetic outflow from the central nervous system that depresses left ventricular function, resulting in acute left atrial and pulmonary hypertension. We attribute these effects on the heart and on the pulmonary vasculature to HBO₂-mediated central sympathetic excitation and catecholamine release that disturbs the normal equilibrium between excitatory and inhibitory activity in the autonomic nervous system.
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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