Hypercapnic Rats Research Articles

Baseline Arterial CO2 Pressure Regulates Acute Intermittent Hypoxia-Induced Phrenic Long-Term Facilitation in Rats.

Moderate acute intermittent hypoxia (mAIH) elicits a progressive increase in phrenic motor output lasting hours post-mAIH, a form of respiratory motor plasticity known as phrenic long-term facilitation (pLTF). mAIH-induced pLTF is initiated by activation of spinally-projecting raphe serotonergic neurons during hypoxia and subsequent serotonin release near phrenic motor neurons. Since raphe serotonergic neurons are also sensitive to pH and CO2, the prevailing arterial CO2 pressure (PaCO2) may modulate their activity (and serotonin release) during hypoxic episodes. Thus, we hypothesized that changes in background PaCO2 directly influence the magnitude of mAIH-induced pLTF. mAIH-induced pLTF was evaluated in anesthetized, vagotomized, paralyzed and ventilated rats, with end-tidal CO2 (i.e., a PaCO2 surrogate) maintained at: (1) ≤39 mmHg (hypocapnia); (2) ∼41 mmHg (normocapnia); or (3) ≥48 mmHg (hypercapnia) throughout experimental protocols. Although baseline phrenic nerve activity tended to be lower in hypocapnia, short-term hypoxic phrenic response, i.e., burst amplitude (Δ = 5.1 ± 1.1 μV) and frequency responses (Δ = 21 ± 4 bpm), was greater than in normocapnic (Δ = 3.6 ± 0.6 μV and 8 ± 4, respectively) or hypercapnic rats (Δ = 2.0 ± 0.6 μV and −2 ± 2, respectively), followed by a progressive increase in phrenic burst amplitude (i.e., pLTF) for at least 60 min post mAIH. pLTF in the hypocapnic group (Δ = 4.9 ± 0.6 μV) was significantly greater than in normocapnic (Δ = 2.8 ± 0.7 μV) or hypercapnic rats (Δ = 1.7 ± 0.4 μV). In contrast, although hypercapnic rats also exhibited significant pLTF, it was attenuated versus hypocapnic rats. When pLTF was expressed as percent change from maximal chemoreflex stimulation, all pairwise comparisons were found to be statistically significant (p < 0.05). We conclude that elevated PaCO2 undermines mAIH-induced pLTF in anesthetized rats. These findings contrast with well-documented effects of PaCO2 on ventilatory LTF in awake humans.

Carbon dioxide removal using low bicarbonate dialysis in rodents.

Extracorporeal carbon dioxide removal may be used to manage hypercapnia, but compared to dialysis, it's not widely available. A recent in vitro study showed that dialysis with low bicarbonate dialysates removes CO2. To show that bicarbonate dialysis removes CO2 in an animal model to validate in-vitro findings and quantify the effect on arterial pH. Male Sprague-Dawley hypercapnic rats were dialyzed with either a conventional dialysate (PrismasolTM) or a bicarbonate-free dialysate (Bicarb0). The effect of dialysis on standard blood gases and electrolytes was measured. Partial pressure of CO2 and bicarbonate concentration in blood decreased significantly after exposure to Bicarb0 compared to PrismasolTM (filter outflow values 12.8 vs 81.1 mmHg; p < 0.01 for CO2 and 3.5 vs 22.0 mmol/L; p < 0.01 for bicarbonate). Total CO2 content of blood was reduced by 459 mL/L during dialysis with Bicarb0 (filter inflow 546 ± 91 vs filter outflow 87 ± 52 mL/L; p < 0.01), but was not significantly reduced with PrismasolTM. Bicarbonate dialysis removes CO2 at rates comparable to existing low-flow ECCO2R.

P01.24. Central processing by electroacupuncture of vasodepression and bradycardia reflex responses

Purpose Electroacupuncture (EA) at P5-6 reduces sympathoexcitatory blood pressure (BP) reflex responses. Gammaaminobutyric acid (GABA) receptors in the brainstem region rostral ventral lateral medulla (rVLM) contribute to modulation of sympathoexcitatory visceral reflexes during EA. Gastric distension in hypercapnic acidotic rats, by activating both sympathetic and vagal afferents, decreases BP and heart rate (HR) through a GABAA mechanism in the rVLM. This study investigated the hypothesis that EA modulates gastric induced hemodynamic depressor responses through actions in nuclei that process both sympathetic and parasympathetic outflow. Methods Anesthetized and hypercapnic acidotic induced rats were used to examine the central processing of the actions of EA. An unstressed 2-cm diameter latex balloon attached to a polyurethane tube was inserted into the stomach through the mouth and esophagus to induce gastric distention. Acupuncture needles were placed near the wrist at P5-6 acupoints for 30-min EA (2 Hz, 0.2-0.4 mA, 0.5 ms). Results We observed repeatable decreases in BP and HR with gastric distention every 10 min. Bilateral EA at P5-6 for 30 min reversed the hypotensive response from -26±3 to -6±1 mmHg and the bradycardia from -35±11 to -10 ±3 beats/min for over 70 min. EA’s action on decreased BP and HR, respectively, was inhibited by microinjection of gabazine, a GABAA receptor antagonist, into the caudal–VLM (cVLM) or the nucleus ambiguus (NAmb). Gabazine microinjected into the rVLM reversed EA action on both depressor and bradycardia responses. Conclusion Thus, EA through GABAA receptor mechanisms modulates reflex sympathoinhibition and vagal excitation leading to cardiovascular depression through actions in the rVLM, cVLM and NAmb. These data indicate that EA can normalize elevated and depressed blood pressure.

Sepsis and Therapeutic Hypercapnia

Sepsis and Therapeutic Hypercapnia

Sustained hypercapnic acidosis during pulmonary infection increases bacterial load and worsens lung injury*

Hypercapnic acidosis is commonly permitted in patients with acute respiratory distress syndrome during the use of protective ventilation strategies. Hypercapnic acidosis is also a common complication of multiple lung diseases and is associated with a poor prognosis, although the mechanisms by which it leads to increased mortality is not known. Previous studies using noninfective models of lung injury show that acute (<6 hrs) hypercapnic acidosis reduced lung damage by an anti-inflammatory effect. We hypothesized that this anti-inflammatory effect would be detrimental in vivo in the presence of untreated bacterial infection and sustained hypercapnia (>48 hrs) and, furthermore, that if bacterial reproduction were controlled by antibiotic therapy, then the anti-inflammatory effects of hypercapnic acidosis would no longer prove detrimental. This study was a prospective, randomized animal study. This study was conducted at a university research laboratory. Study subjects were adult male Wistar-Kyoto rats. After intratracheal instillation of Escherichia coli under general anesthesia, rats were housed in normocapnic (21% O2, 0% CO2) or hypercapnic (21% O2, 5% CO2) environments for 2 days. Rats were then reanesthetized for assessment of physiological and quantitative stereologic indices of lung damage, quantitative bacterial counts, and neutrophil phagocytosis. Hypercapnic acidosis was associated with higher lung bacterial colony counts, more structural damage, and lower static lung compliance than normocapnia. Neutrophils isolated from hypercapnic rats demonstrated impaired phagocytosis. In a further separate series of experiments, in which rats were given antibiotic therapy, lung damage was not different between normocapnic and hypercapnic acidosis groups. Prolonged hypercapnic acidosis worsened bacterial infection-induced lung injury. Our findings suggest an immunosuppressive effect of hypercapnic acidosis and have important implications for protective ventilation strategies that permit hypercapnic acidosis in patients with adult respiratory distress syndrome and in the management of hypercapnic acidosis during infective exacerbations of chronic obstructive pulmonary disease and other lung diseases.

Acute hypoxia does not alter inter-alveolar perfusion distribution in unanesthetized rats

Effects of hypoxic vasoconstriction on inter-alveolar perfusion distribution (< or =1000 alveoli) have not been studied. To address this, we measured inter-alveolar perfusion distribution in the lungs of unanesthetized rats breathing 10% O(2). Perfusion distributions were measured by analyzing the trapping patterns of 4 microm diameter fluorescent latex particles infused into the pulmonary circulation. The trapping patterns were statistically quantified in confocal images of the dried lungs. Trapping patterns were measured in lung volumes that ranged between less than 1 and 1300 alveoli, and were expressed as the log of the dispersion index (logDI). A uniform (statistically random) perfusion distribution corresponds to a logDI value of zero. The more this value exceeds zero, the more the distribution is clustered (non-random). At the largest tissue volume (1300 alveoli) logDI reached a maximum value of 0.68+/-0.42 (mean+/-s.d.) in hypoxic rats (n = 6), 0.50+/-0.38 in hypercapnic rats (n.s.) and 0.48+/-0.25 in air-breathing controls (n.s.). Our results suggest that acute hypoxia did not cause significant changes in inter-alveolar perfusion distribution in unanesthetized, spontaneously breathing rats.

Renal compensation to chronic hypoxic hypercapnia: downregulation of pendrin and adaptation of the proximal tubule

The molecular basis for the renal compensation to respiratory acidosis and specifically the role of pendrin in this condition are unclear. Therefore, we studied the adaptation of the proximal tubule and the collecting duct to respiratory acidosis. Male Wistar-Hannover rats were exposed to either hypercapnia and hypoxia [8% CO(2) and 13% O(2) (hypercapnic, n = 6) or normal air (controls, n = 6)] in an environmental chamber for 10 days and were killed under the same atmosphere. In hypercapnic rats, arterial pH was lower than controls (7.31 +/- 0.01 vs. 7.39 +/- 0.01, P = 0.03), blood HCO(3)(-) concentration was increased (42 +/- 0.9 vs. 32 +/- 0.24 mM, P < 0.001), arterial Pco(2) was increased (10.76 +/- 0.4 vs. 7.20 +/- 0.4 kPa, P < 0.001), and plasma chloride concentration was decreased (92.2 +/- 0.7 vs. 97.2 +/- 0.5 mM, P < 0.001). Plasma aldosterone levels were unchanged. In the proximal tubule, immunoblotting showed an increased expression of sodium/bicarbonate exchanger protein (188 +/- 22 vs. 100 +/- 11%, P = 0.005), confirmed by immunohistochemistry. Total Na/H exchanger protein expression in the cortex was unchanged by immunoblotting (119 +/- 10 vs. 100 +/- 11%, P = 0.27) and immunohistochemistry. In the cortex, the abundance of pendrin was decreased (51 +/- 9 vs. 100 +/- 7%, P = 0.003) by immunoblotting. Immunohistochemistry revealed that this decrease was clear in both cortical collecting ducts (CCDs) and connecting tubules (CNTs). This demonstrates that pendrin expression can be regulated in acidotic animals with no changes in aldosterone levels and no external chloride load. This reduction of pendrin expression may help in redirecting the CNT and CCD toward chloride excretion and bicarbonate reabsorption, contributing to the increased plasma bicarbonate and decreased plasma chloride of chronic respiratory acidosis.

Noninvasive evaluation of acute capillary permeability changes during high-volume ventilation in rats with and without hypercapnic acidosis*

To evaluate whether hypercapnic acidosis attenuates acute alterations of pulmonary capillary permeability due to high lung stretch in rats using a simple, noninvasive, scintigraphic method. Prospective, randomized, controlled animal study. University research laboratory. Male adult Wistar rats weighing 291 +/- 7.5 g. Three groups of rats were studied: controls ventilated with a low (6 mL/kg body weight) tidal volume and rats ventilated with a high (38 mL/kg body weight) tidal volume under normocapnic (Paco(2) = 35.2 +/- 1.65 mm Hg) or hypercapnic (Paco(2) = 102.5 +/- 5.63 mm Hg) conditions. Pulmonary capillary permeability alterations were assessed by monitoring the rate of (111)In-transferrin accumulation in lung tissue. Respiratory system pressure-volume curves were registered and analyzed. High tidal volume ventilation increased In-transferrin plasma to lung flux in such a way that I(111)In-transferrin behaved like a marker of water. The rate of initial (first 30 mins of high tidal volume ventilation) lung transferrin accumulation measured by scintigraphy (standardized lung/heart ratio) was steady, correlated with the percent decrease in respiratory system compliance (a marker of edema progression), and did not differ between normocapnic and hypercapnic groups (18.9 +/- 3.97 vs. 14.2 +/- 2.89%/hr, not significant). However, lung In-tranferrin accumulation rate was highly scattered due to variable interindividual mechanical properties of the respiratory system. This rate was correlated with initial values of volume of the upper inflection point of the pressure-volume curve (r = -.53, p < .001) and end-inspiratory pressure (r = .54, p < .001). Mechanical properties were similar in normocapnic and hypercapnic rats. There was no difference between In-transferrin accumulation rates in these rats when a stringent selection was made based on end-inspiratory pressure (28-32 cm H(2)O) or body weight (330-360 g). Hypercapnic acidosis does not influence in vivo the acute increase in pulmonary capillary permeability due to high-volume ventilation.

Size and Composition Changes in Diaphragmatic Fibers in Rats Exposed to Chronic Hypercapnia

To test the hypothesis that chronic hypercapnia changes the composition of the respiratory muscle by continuous augmentation of ventilation. Eighteen male Wistar rats were housed in 10% CO(2) in air for 19 weeks, and their minute ventilation V(E) was measured every 6 weeks. The diaphragm, excited at 19 weeks of exposure, was classified as fiber type I, IIa, or IIb. Cross-sectional areas of individual fibers were measured. Fibers with a target-like appearance on reduced nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR) stain also were counted. The data were compared with those of rats kept in room air. The mean (+/- SD) PaCO(2) after 19 weeks of sustained hypercapnia was 71.0 +/- 4.7 mm Hg. The V(E) remained at a high level until 12 weeks of exposure, and then it significantly decreased at week 18. In a comparison with the control rats, a larger number of type I fibers and a smaller number of type IIb fibers were found in the diaphragm of the chronically hypercapnic rats. In addition, the latter group's cross-sectional area revealed fibers of a significantly smaller diameter. Target-like fibers were observed in 5% of the NADH-TR-stained fibers in the chronically hypercapnic rats but were not seen in the control rats. By increasing the ratio of fatigue-resistant fibers, the diaphragm was able to adapt to a sustained load induced by hypercapnia. However, this adaptive process was accompanied by a degenerative change in the tissue.

Hyperglycemia and Hypercapnia Suppress BDNF Gene Expression in Vulnerable Regions after Transient Forebrain Ischemia in the Rat

Preischemic hyperglycemia or superimposed hypercapnia exaggerates brain damage caused by transient forebrain ischemia. Because high regional levels of brain-derived neurotrophic factor (BDNF) protein correlate with resistance to ischemic damage, we studied the expression of BDNF mRNA using in situ hybridization in rats subjected to 10 minutes of forebrain ischemia under normoglycemic, hyperglycemic, or hypercapnic conditions. Compared with normoglycemic animals, the increase of BDNF mRNA using in situ hybridization in rats subjected to 10 minutes of forebrain ischemia under normoglycemic, or hypercapnic conditions. Compared with normoglycemic animals, the increase of BDNF mRNA in dentate granule cells was attenuated and that in CA3 pyramidal neurons completely prevented in hyperglycemic rats. No ischemia-induced increases of BDNF mRNA levels in the hippocampal formation were detected in hypercapnic animals. Hyperglycemic and hypercapnic rats showed transiently decreased expression of BDNF mRNA levels in the cingulate cortex, which was not observed in normoglycemic animals. The results suggest that suppression of the BDNF gene might contribute to the increased vulnerability of the CA3 region and cingulate cortex in hyperglycemic and hypercapnic animals.

Effect of carbon dioxide on cerebral metabolism during hypoxia-ischemia in the immature rat.

We previously have demonstrated that hypocapnia aggravates and hypercapnia protects the immature rat from hypoxic-ischemic brain damage. To ascertain cerebral blood flow (CBF) and metabolic correlates, 7-d postnatal rats were subjected to hypoxia-ischemia during which they were rendered either hypo-(3.5 kPa), normo- (5.1 kPa), or hypercapnic (7.3 kPa) by the inhalation of either 0, 3, or 6% CO2, 8% O2, balance N2. CBF during hypoxia-ischemia was better preserved in the normo- and hypercapnic rat pups; these animals also exhibited a stimulation of cerebral glucose utilization. Brain glucose concentrations were higher and lactate lower in the normo- and hypercapnic animals, indicating that glucose was consumed oxidatively in these groups rather than by anaerobic glycolysis, as apparently occurred in the hypocapnic animals. ATP and phosphocreatine were better preserved in the normo- and hypercapnic rats compared with the hypocapnic animals. Cerebrospinal fluid glutamate, as a reflection of the brain extracellular fluid concentration, was lowest in the hypercapnic rats at 2 h of hypoxia-ischemia. The data indicate that during hypoxia-ischemia in the immature rat, CBF is better preserved during normo- and hypercapnia; the greater oxygen delivery promotes cerebral glucose utilization and oxidative metabolism for optimal maintenance of tissue high energy phosphate reserves. An inhibition of glutamate secretion into the synaptic cleft and its attenuation of N-methyl-D-aspartate receptor activation would further protect the hypercapnic animal from hypoxic-ischemic brain damage.

Tissue Pco2 in Brain Ischemia Related to Lactate Content in Normo- and Hypercapnic Rats

The amount of lactate formed during ischemia determines the rise in tissue PCO2 (PtCO2). Conflicting results exist on the relationship between lactate and PtCO2. The objective of this study was to settle this issue. We varied the preischemic plasma glucose concentration of normo- and hypercapnic rats, assessed tissue lactate and total CO2 contents, and determined the PCO2/lactate relationship over the lactate range 2-40 mmol kg-1. The results showed that whatever the equilibration time, the PCO2/lactate relationship was linear. The results obtained could be reproduced by a theoretical buffer system that mimics the buffering behavior of intracellular fluid. Our results bear on the question of whether compartmentation of H+ occurs during ischemia, with glial cells becoming more acid than neurons. A discontinuous PCO2/lactate relationship, with a constant PCO2 above a certain lactate content, would support this contention. Since our results demonstrate a linear relationship between lactate and PCO2 over the lactate range 2-40 mmol kg-1, they considerably weaken any argument for gross compartmentation of H+.

Extra- and Intracellular pH in the Brain During Ischaemia, Related to Tissue Lactate Content in Normo- and Hypercapnic rats.

The objective of the present study was to assess the relationship between the amount of lactate accumulated during complete ischaemia and the ensuing changes in extra- and intracellular pH (pHe and pHi, respectively). The preischaemic plasma glucose concentration of anaesthetized rats was varied by administration of glucose or insulin, pHe was determined in neocortex with ion-sensitive microelectrodes, and tissue lactate and CO2 contents were measured, tissue CO2 tension being known from separate experiments. The experiments were carried out in both normocapnic [arterial CO2 tension (PaCO2) approximately 40 mm Hg] and hypercapnic (PaCO2 approximately 80 mm Hg) animals. Irrespective of the preischaemic CO2 tension, DeltapHe was linearly related to tissue lactate content. Depending on the preischaemic glucose concentration, DeltapHe varied from <0.4 to >1.4 units. The results thus fail to confirm previous results that the changes in pHe describe two plateau functions (DeltapHe approximately 0.5 and 1.1, respectively), with a transition zone at tissue lactate contents of 17 - 20 mmol kg-1. Changes in pHi given in this study are based on the assumption of a uniform intracellular space. The pHi changed from a normal value of approximately 7.0 to 6.5, 6.1 and 5.8 at tissue lactate contents of 10, 20 and 30 mmol kg-1. The intrinsic (non-bicarbonate) buffer capacity, derived from these figures, was 23 mmol kg-1 pH-1. Some differences in pH and in HCO3- concentration between extra- and intracellular fluids persisted in the ischaemic tissue. These differences were probably caused by a persisting membrane potential in the ischaemic cells.

Extracellular pH, [K+], and synaptic transmission in the dorsal horn of the spinal cord of hypercapnic rats

Extracellular pH, [K+], and synaptic transmission in the dorsal horn of the spinal cord of hypercapnic rats

Vascular responses of choroid plexus during hypercapnia in rats.

The response of blood flow to choroid plexus (CPBF) during hypercapnia is controversial. The goal of this study was to determine the effect of hypercapnia on CPBF in unanesthetized rats. Rats breathed air or a mixture of 5-8% CO2 in air, and CPBF was measured with [14C]isopropyliodoamphetamine and quantitative autoradiography. In hypercapnic rats [arterial PCO2 61.6 +/- 1.6 (SE) mmHg; n = 7] CPBF was similar to that of normocapnic control rats (525 +/- 39 ml.min-1.100 g-1; arterial PCO2 42.7 +/- 0.6 mmHg; n = 5). In contrast, blood flow to cerebral cortex increased 67% during hypercapnia. CPBF in normocapnic rats that were treated with phentolamine was similar to untreated normocapnic and hypercapnic rat CPBF. However, during hypercapnia, CPBF in phentolamine-treated rats increased 29%. Responses were similar in blood flow to choroid plexus of lateral, third, and fourth ventricles. Our findings indicate that hypercapnia has no effect on CPBF when alpha-adrenergic receptors are intact. In contrast, after blockade of alpha-adrenergic receptors, hypercapnia increases CPBF. These findings suggest that, during hypercapnia, levels of sympathetic activity or blood-borne catecholamines are increased that prevent increases in CPBF.

CO2 reactivity and heterogeneity of cerebral blood flow in ischemic, border zone, and normal cortex

Regional arterial CO2 tension (PaCO2) reactivity of cerebral blood flow (CBF) and the effect of PaCO2 on the spatial and temporal heterogeneity of CBF were investigated by using autoradiographically determined CBF in the rat middle cerebral artery occlusion model after a 2-h period under pentobarbital anesthesia to clarify the relation between PaCO2 reactivity, CBF heterogeneity, and the temporal cycling of CBF. PaCO2 was adjusted to one of four levels. CBF was determined in four cortical areas and white matter using the tissue fractionation of [14C]iodoantipyrine [( 14C]IAP) in combination with vessel mapping using in vivo 4% thioflavine S. Specific PaCO2 reactivity and CBF were normal in the nonischemic cortex, normal, although slightly depressed, in the border zone far from the ischemic core area, and depressed in the border zone adjacent to the ischemic core area (P less than 0.001) and the ischemic core (P less than 0.001). In normocapnic and hypocapnic animals, CBF heterogeneity in the form of regularly spaced CBF columns perpendicular to the cortical surface was observed in the nonischemic hemisphere but was absent in the ischemic core area. In hypercapnic rats, flow columns were present in the ischemic core areas and border zones but were absent on the nonischemic side. There was a highly significant interaction (P less than 0.0001) in observer-determined heterogeneity grades between PaCO2 level and each of three areas, normal, border zone, and ischemic core. In normal cortex, comparison of the thioflavine S-stained vessels with the flow columns provided evidence supporting the concept of capillary recruitment and cycling as a mode of normal cerebral blood flow control. The presence of flow columns in severely ischemic areas in hypercapnic animals indicates that a short period of high PaCO2 transiently augments microregional flow and could enhance the delivery of a therapeutic agent to these microregions of the ischemic core. The regional analysis of PaCO2 reactivity suggests an index of future tissue viability.

Role of hyperventilation in hypoxia on lung growth in rats

This study was conducted in an attempt to differentiate the contribution of hyperventilation, if any, from that of low PO2 on adaptive lung growth in response to hypoxia. Male albino rats were exposed to one of the following: (1) Room air for 7 days, as control; (2) 10% O2 in N2 for 7 days; (3) 10% O2 for 6h, 1 day or 2 days and air for the remaining of 7 days; (4) 10% O2 for 2 days and 7% CO2 in air for 5 days; (5) air for 2 days and 7% CO2 for 5 days; or (6) 7% CO2 in air for 7 days. Lung growth was assessed by measuring the lung weight, lung air volume, lung DNA content and rate of DNA synthesis in lung explants. Hypoxia stimulated lung DNA synthesis even when administered for only 6h, and the effects persisted for a few days after discontinuation of hypoxia. Hypercapnia did not stimulate DNA synthesis in lung. In 2 day hypoxic 5 day air rats the lung weight and lung DNA content increased, in 2 day air 5 day hypercapnic rats only the lung volume increased, and in 2 day hypoxic 5 day hypercapnic rats all parameters of lung growth,i.e., ling weight, DNA content and air volume increased as in 7 day hypoxic rats. The results suggest that adaptive or compensatory lung growth in hypoxia is brought about on one hand by the direct effect of low PO2 on lung cells, resulting in lung hyperplasia, and on the other hand by the mechanical stimulation of lung tissue by hyperventilation, causing lung distension.

Regional neurohypophysial and hypothalamic blood flow in rats during hypercapnia.

Regional cerebral blood flow (rCBF) was measured in the neurohypophysis and hypothalamus in normocapnic and hypercapnic rats using [14C]isopropyliodoamphetamine. Rats were surgically prepared using nitrous oxide and halothane and placed in plaster restraining casts. Hypercapnia was produced by increasing the fractional concentration of inspired CO2 (FICO2). rCBF in normocapnic rats was higher in the paraventricular nucleus, supraoptic nucleus, median eminence, and neural lobe than rates previously measured by use of diffusible tracers. During hypercapnia blood flow increased linearly with arterial PCO2 (PACO2) in all regions except the median eminence and neural lobe, which were not affected by hypercapnia. When rats were pretreated with phentolamine (1 mg/kg) to block the alpha-adrenergic receptors, blood flow in the median eminence and neural lobe increased significantly during hypercapnia. We conclude that blood flow in the cell bodies of the paraventricular nucleus and supraoptic nucleus is regulated differently during hypercapnia than blood flow in the nerve terminals in the median eminence and neural lobe. Furthermore, vasodilation produced by increased CO2 is offset by alpha-receptor stimulation in the median eminence and neural lobe.

Effects of vasodilatation and acidosis on the blood-brain barrier

Hypercapnia protects the blood-brain barrier against disruption during acute hypertension. Our goal was to determine whether protection of the blood-brain barrier by hypercapnia may be related to an affect of acidosis on the barrier, vasodilatation produced during hypercapnia, or attenuation of increases in cerebral venous pressure by hypercapnia. Pial vessels were examined in rats by means of fluorescent microscopy. We examined disruption of the blood-brain barrier in response to acute hypertension during hypercapnia (vasodilatation with acidosis), during topical adenosine (vasodilatation without acidosis), and during passive increases in cerebral venous pressure produced by venous occlusion during hypercapnia. Acute hypertension in normocapnic rats increased venular pressure and disrupted the blood-brain barrier in venules. During topical adenosine, acute hypertension increased venular pressure, disrupted the blood-brain barrier, and often produced bleeding from cerebral venules. Hypercapnia alone increased venular pressure, and acute hypertension produced only a modest further increase in venular pressure, with minimal disruption of the blood-brain barrier. Venous occlusion in hypercapnic rats increased venular pressure and disrupted the blood-brain barrier. We conclude that vasodilatation and acidosis produced by hypercapnia do not protect the blood-brain barrier from disruption during acute hypertension. Protection by hypercapnia during acute hypertension appears to be related to attenuation of increases in cerebral venous pressure.

The effect of prolonged hypoxia on striated muscle pH regulation.

The extracellular acid-base status of mammals exposed to low inspired PO2 for prolonged periods of time has been studied extensively (Bouverot, 1985). However, less is known regarding the intracellular acid-base status during prolonged hypoxia. In a previous study we observed that the intracellular pH of striated muscles of rats subjected to 3 weeks of hypobaric hypoxia was not significantly different from that of normoxic rats (Gonzalez and Clancy, 1986b). However, when the cells were acid-loaded by rendering the animals hypercapnic, the decreases in intracellular pH of tibialis anterior, quadriceps and diaphragm were significantly less than in hypercapnic normoxic rats. The magnitude of cell pH regulation, as measured by the apparent non-bicarbonate buffer value, ranged from 3 (tibialis anterior) to 12 (diaphragm) times greater in the hypobaric hypoxic than the normoxic animals. This augmentation of striated muscle pH regulation during hypercapnia in hypobaric hypoxic rats could result from increased physicochemical buffering and/or increased efflux of proton equivalents. The question arises as to whether augmentation of these cellular pH- regulating mechanisms resulted from intrinsic changes in the cell interior and/or the sarcolemma engendered by the prolonged hypoxia or whether extracellular factors which enhance these cellular pH-regulating mechanisms were increased to a greater extent in the hypercapnic hypoxic rats than in the hypercapnic normoxic rats. To resolve this question cell pH regulation of diaphragms from prolonged hypoxic and normoxic rats was studied under in vitro conditions. Under these conditions the contribution of extracellular factors to cell pH regulation was the same in diaphragms from hypoxic and normoxic rats. Therefore, any difference in cell pH regulation should be attributable to intrinsic changes in one or more of the cell pH-regulating mechanisms.