Organismal Responses to Hypoxemic Challenges.

As a counterpoint to the volumes of beautiful work exploring how the carotid bodies (CBs) sense and transduce stimuli into neural traffic, this study explored one organismal reflex response to such stimulation. We challenged the anesthetized, paralyzed, artificially ventilated cat with two forms of acute hypoxemia: 10 % O(2)/balance N(2) (hypoxic hypoxia [HH] and carbon monoxide hypoxia [COH]). HH stimulates both CBs and aortic bodies (ABs), whereas COH stimulates only the ABs. Our design was to stimulate both with HH (HHint), then to stimulate only the ABs with COH (COHint); then, after aortic depressor nerve transaction, only the CBs with HH (HHabr), and finally neither with COH (COHabr). We recorded whole animal responses from Group 1 cats (e.g., cardiac output, arterial blood pressure, pulmonary arterial pressure/and vascular resistance) before and after sectioning the aortic depressor nerves. From Group 2 cats (intact) and Group 3 cats (aortic body resected) we recorded the vascular resistance in several organs (e.g., brain, heart, spleen, stomach, pancreas, adrenal glands, eyes). The HHint challenge was the most effective at keeping perfusion pressures adequate to maintain homeostasis in the face of a systemic wide hypoxemia with locally mediated vasodilation. The spleen and pancreas, however, showed a vasoconstrictive response. The adrenals and eyes showed a CB-mediated vasodilation. The ABs appeared to have a significant impact on the pulmonary vasculature as well as the stomach. Chemoreceptors via the sympathetic nervous system play the major role in this organism's response to hypoxemia.

Effects of hypercapnia and NO synthase inhibition in sustained hypoxic pulmonary vasoconstriction.

BACKGROUND: Acute respiratory disorders may lead to sustained alveolar hypoxia with hypercapnia resulting in impaired pulmonary gas exchange. Hypoxic pulmonary vasoconstriction (HPV) optimizes gas exchange during local acute (0-30 min), as well as sustained (> 30 min) hypoxia by matching blood perfusion to alveolar ventilation. Hypercapnia with acidosis improves pulmonary gas exchange in repetitive conditions of acute hypoxia by potentiating HPV and preventing pulmonary endothelial dysfunction. This study investigated, if the beneficial effects of hypercapnia with acidosis are preserved during sustained hypoxia as it occurs, e.g in permissive hypercapnic ventilation in intensive care units. Furthermore, the effects of NO synthase inhibitors under such conditions were examined. METHOD: We employed isolated perfused and ventilated rabbit lungs to determine the influence of hypercapnia with or without acidosis (pH corrected with sodium bicarbonate), and inhibitors of endothelial as well as inducible NO synthase on acute or sustained HPV (180 min) and endothelial permeability. RESULTS: In hypercapnic acidosis, HPV was intensified in sustained hypoxia, in contrast to hypercapnia without acidosis when HPV was amplified during both phases. L-NG-Nitroarginine (L-NNA), a non-selective NO synthase inhibitor, enhanced acute as well as sustained HPV under all conditions, however, the amplification of sustained HPV induced by hypercapnia with or without acidosis compared to normocapnia disappeared. In contrast 1400 W, a selective inhibitor of inducible NO synthase (iNOS), decreased HPV in normocapnia and hypercapnia without acidosis at late time points of sustained HPV and selectively reversed the amplification of sustained HPV during hypercapnia without acidosis. Hypoxic hypercapnia without acidosis increased capillary filtration coefficient (Kfc). This increase disappeared after administration of 1400 W. CONCLUSION: Hypercapnia with and without acidosis increased HPV during conditions of sustained hypoxia. The increase of sustained HPV and endothelial permeability in hypoxic hypercapnia without acidosis was iNOS dependent.

Effects of hypercapnia with and without acidosis on hypoxic pulmonary vasoconstriction.

Acute respiratory disorders and permissive hypercapnic strategy may lead to alveolar hypoxia and hypercapnic acidosis. However, the effects of hypercapnia with or without acidosis on hypoxic pulmonary vasoconstriction (HPV) and oxygen diffusion capacity of the lung are controversial. We investigated the effects of hypercapnic acidosis and hypercapnia with normal pH (pH corrected with sodium bicarbonate) on HPV, capillary permeability, gas exchange, and ventilation-perfusion matching in the isolated ventilated-perfused rabbit lung. No alteration in vascular tone was noted during normoxic hypercapnia with or without acidosis compared with normoxic normocapnia. Hypercapnia with normal pH resulted in a transient increase in HPV during the course of consecutive ventilation maneuvers, whereas hypercapnic acidosis increased HPV over time. Hypercapnic acidosis decreased exhaled NO during hypoxia more than hypercapnia with normal pH and normocapnia, whereas intravascular NO release was unchanged. However, inhibition of NO synthesis by nitro-L-arginine (L-NNA) resulted in a loss of the increased HPV caused by hypercapnic acidosis but not that caused by hypercapnia with normal pH. Furthermore, capillary permeability increased during hypoxic hypercapnia with normal pH but not hypoxic hypercapnic acidosis. This effect was NO-dependent because it disappeared during L-NNA administration. Ventilation-perfusion matching and arterial PO2 were improved according to the strength of HPV in hypercapnia compared with normocapnia during Tween nebulization-induced lung injury. In conclusion, the increased HPV during hypercapnic acidosis is beneficial to lung gas exchange by improving ventilation-perfusion matching and preserving the capillary barrier function. These effects seem to be linked to NO-mediated pathways.

Contribution of nitric oxide synthase (NOS) in blood-brain barrier disruption during acute focal cerebral ischemia in normal rat.

Endogenous level of nitric oxide (NO) is increased in the brain following the stroke, and deactivation of NO synthase has been shown to attenuate its destructive actions in animal stroke models using middle cerebral artery occlusion (MCAO) procedures. However, little is known about the effects of NO in cerebral vascular integrity and edema during acute cerebral ischemia. Here we investigated whether NO plays any role in the progression of blood-brain barrier (BBB) disruption and edema formation in ischemia/reperfusion injury. Intraperitoneal administration of NO substrate l-arginine (300mg/kg), or NOS inhibitor (l-NAME, 1mg/kg), was done in normal rats at 20min before a 60-min MCAO. Mean arterial blood pressures (MAP) and regional cerebral blood flow (rCBF) were continuously recorded during experiment. Neurological deficit score (NDS) was evaluated 12h after termination of MCAO followed with evaluations of cerebral infarction volume (CIV), edema formation and cerebral vascular permeability (CVP), as determined by the Evans blue dye extravasations (EBE) technique. No significant changes were observed in the values of MAP and rCBF with l-arginine or l-NAME during ischemia or reperfusion periods. There was a 75-85% reduction in rCBF in during MCAO which returned back to its pre-occlusion level during reperfusion. Acute cerebral ischemia with or without l-arginine augmented NDS (4.00±0.44 and 3.00±0.30), in conjunction with increased CIV (518±57mm(3) and 461±65mm(3)), provoked edema (3.09±0.45% and 3.30±0.49%), and elevated EBE (8.28±2.04µg/g and 5.09±1.41µg/g). Inhibition of NO production by l-NAME significantly improved NDS (1.50±0.22), diminished CIV (248±56mm(3)), edema (1.18±0.58%) and EBE (1.37±0.12µg/g). This study reconfirms the cerebroprotective properties of reduced tissue NO during acute ischemic stroke, and it also validates the deleterious actions of increased NOS activity on the disruption of cerebral microvascular integrity and edema formation of ischemia/reperfusion injuries in normal rat, without changing arterial blood pressure or blood flows to ischemic regions.