The physiological basis of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare dyspnoea-fatigue syndrome caused by a progressive increase in pulmonary vascular resistance and eventual right ventricular (RV) failure. In spite of extensive pulmonary vascular remodelling, lung function in PAH is generally well preserved, with hyperventilation and increased physiological dead space, but minimal changes in lung mechanics and only mild to moderate hypoxaemia and hypocapnia. Hypoxaemia is mainly caused by a low mixed venous oxygen tension from a decreased cardiac output. Hypocapnia is mainly caused by an increased chemosensitivity. Exercise limitation in PAH is cardiovascular rather than ventilatory or muscular. The extent of pulmonary vascular disease in PAH is defined by multipoint pulmonary vascular pressure-flow relationships with a correction for haematocrit. Pulsatile pulmonary vascular pressure-flow relationships in PAH allow for the assessment of RV hydraulic load. This analysis is possible either in the frequency domain or in the time domain. The RV in PAH adapts to increased afterload by an increased contractility to preserve its coupling to the pulmonary circulation. When this homeometric mechanism is exhausted, the RV dilates to preserve flow output by an additional heterometric mechanism. Right heart failure is then diagnosed by imaging of increased right heart dimensions and clinical systemic congestion signs and symptoms. The coupling of the RV to the pulmonary circulation is assessed by the ratio of end-systolic to arterial elastances, but these measurements are difficult. Simplified estimates of RV-pulmonary artery coupling can be obtained by magnetic resonance or echocardiographic imaging of ejection fraction.

IDH3 mediates apoptosis of alveolar epithelial cells type 2 due to mitochondrial Ca2+ uptake during hypocapnia.

In adult respiratory distress syndrome (ARDS) pulmonary perfusion failure increases physiologic dead-space (VD/VT) correlating with mortality. High VD/VT results in alveolar hypocapnia, which has been demonstrated to cause edema formation, atelectasis, and surfactant depletion, evoked, at least in part, by apoptosis of alveolar epithelial cells (AEC). However, the mechanism underlying the hypocapnia-induced AEC apoptosis is unknown. Here, using fluorescent live-cell imaging of cultured AEC type 2 we could show that in terms of CO2 sensing the tricarboxylic acid cycle enzyme isocitrate dehydrogenase (IDH) 3 seems to be an important player because hypocapnia resulted independently from pH in an elevation of IDH3 activity and subsequently in an increase of NADH, the substrate of the respiratory chain. As a consequence, the mitochondrial transmembrane potential (ΔΨ) rose causing a Ca2+ shift from cytosol into mitochondria, whereas the IDH3 knockdown inhibited these responses. Furthermore, the hypocapnia-induced mitochondrial Ca2+ uptake resulted in reactive oxygen species (ROS) production, and both the mitochondrial Ca2+ uptake and ROS production induced apoptosis. Accordingly, we provide evidence that in AEC type 2 hypocapnia induces elevation of IDH3 activity leading to apoptosis. This finding might give new insight into the pathogenesis of ARDS and may help to develop novel strategies to reduce tissue injury in ARDS.

Changes in cerebral compartmental compliances during mild hypocapnia in patients with traumatic brain injury.

The benefit of induced hyperventilation for intracranial pressure (ICP) control after severe traumatic brain injury (TBI) is controversial. In this study, we investigated the impact of early and sustained hyperventilation on compliances of the cerebral arteries and of the cerebrospinal (CSF) compartment during mild hyperventilation in severe TBI patients. We included 27 severe TBI patients (mean 39.5 ± 3.4 years, 6 women) in whom an increase in ventilation (20% increase in respiratory minute volume) was performed during 50 min as part of a standard clinical CO(2) reactivity test. Using a new mathematical model, cerebral arterial compliance (Ca) and CSF compartment compliance (Ci) were calculated based on the analysis of ICP, arterial blood pressure, and cerebral blood flow velocity waveforms. Hyperventilation initially induced a reduction in ICP (17.5 ± 6.6 vs. 13.9 ± 6.2 mmHg; p < 0.001), which correlated with an increase in Ci (r(2) = 0.213; p = 0.015). Concomitantly, the reduction in cerebral blood flow velocities (CBFV, 74.6 ± 27.0 vs. 62.9 ± 22.9 cm/sec; p < 0.001) marginally correlated with the reduction in Ca (r(2) = 0.209; p = 0.017). During sustained hyperventilation, ICP increased (13.9 ± 6.2 vs. 15.3 ± 6.4 mmHg; p < 0.001), which correlated with a reduction in Ci (r(2) = 0.297; p = 0.003), but no significant changes in Ca were found during that period. The early reduction in Ca persisted irrespective of the duration of hyperventilation, which may contribute to the lack of clinical benefit of hyperventilation after TBI. Further studies are needed to determine whether monitoring of arterial and CSF compartment compliances may detect and prevent an adverse ischemic event during hyperventilation.

MRI measurement of the BOLD-specific flow-volume relationship during hypercapnia and hypocapnia in humans.

It is widely assumed in fMRI that the relationship between cerebral blood flow (CBF) and volume (CBV) changes observed during end-tidal CO(2) (PETCO(2)) perturbations is equivalent to that elicited by neuronal activation. This assumption has been validated in PET studies insofar as relating total flow to total CBV changes, but remains unconfirmed for venous CBV changes, which pertains to the primary vascular compartment modulating the BOLD signal. In this study, we measured CBF and venous CBV changes in healthy subjects in response to graded hypercapnia and hypocapnia, induced using computerized end-tidal CO(2) targeting, with a DeltaPETCO(2) range of between -6 and +9 mm Hg. Hypercapnia was found to elicit robust increases in CBF and venous CBV, while hypocapnia produced decreases in both. We used steady-state flow and volume changes to estimate the power-law relationship for cortical and subcortical brain regions, and did not observe significant difference between the two. The combined fit resulted in a power coefficient of 0.18+/-0.02, substantially lower than Grubb's coefficient of 0.38, but comparable to previous observations during neuronal activation. These results confirm that the BOLD-specific flow-volume relationship during CO(2) challenges is similar to that characterizing neuronal activation.

Intraoperative carbon dioxide management and outcomes.

BACKGROUND AND OBJECTIVE: Intraoperative hyperventilation to induce hypocapnia has historically been common practice and has physiological effects that may be detrimental. In contrast, hypercapnia has effects that may be beneficial. As these effects may influence postoperative recovery, we investigated the association between variations in intraoperative carbon dioxide and length of hospital stay in patients who had elective colon resections and hysterectomies. METHODS: Data were extracted from electronic records for elective colon resections and hysterectomies done from 2002 to 2008. Patients were divided into four groups based on surgical procedure and use of laparoscopic technique. Parameters extracted for analysis included mean end-tidal carbon dioxide (EtCO2) during the surgical procedure as well as others previously purported to affect postoperative outcomes. In-hospital length of stay (LOS) was determined from administrative records and was used as the independent outcome variable. For each group, Poisson regression analysis was performed to find factors that were independently associated with the outcome. RESULTS: A total of 3421 case records in our database met inclusion criteria. Median EtCO2 was 31 mmHg. Median LOS was 7 and 5 days for open and laparoscopic colon resections, and 3 and 2 days for open and laparoscopic hysterectomies, respectively. Regression analysis revealed a statistically significant independent association between higher EtCO2 and reduced LOS for colon resection and open hysterectomy. CONCLUSION: There is a significant association between higher intraoperative EtCO2 and shorter LOS after colon resection and open hysterectomy. The common practice of inducing hypocapnia may be deleterious, and maintaining normocapnia or permitting hypercapnia may improve clinical outcomes.

Differential effects of chronic hypoxia and intermittent hypocapnic and eucapnic hypoxia on pulmonary vasoreactivity.

Intermittent hypoxia (IH) resulting from sleep apnea can lead to pulmonary hypertension (PH) and right heart failure, similar to chronic sustained hypoxia (CH). Supplemental CO(2), however, attenuates hypoxic PH. We therefore hypothesized that, similar to CH, IH elicits PH and associated increases in arterial endothelial nitric oxide synthase (eNOS) expression, ionomycin-dependent vasodilation, and receptor-mediated pulmonary vasoconstriction. We further hypothesized that supplemental CO(2) inhibits these responses to IH. To test these hypotheses, we measured eNOS expression by Western blot in intrapulmonary arteries from CH (2 wk, 0.5 atm), hypocapnic IH (H-IH) (3 min cycles of 5% O(2)/air flush, 7 h/day, 2 wk), and eucapnic IH (E-IH) (3 min cycles of 5% O(2), 5% CO(2)/air flush, 7 h/day, 2 wk) rats and their respective controls. Furthermore, vasodilatory responses to the calcium ionophore ionomycin and vasoconstrictor responses to the thromboxane mimetic U-46619 were measured in isolated saline-perfused lungs from each group. Hematocrit, arterial wall thickness, and right ventricle-to-total ventricle weight ratios were additionally assessed as indexes of polycythemia, arterial remodeling, and PH, respectively. Consistent with our hypotheses, E-IH resulted in attenuated polycythemia, arterial remodeling, RV hypertrophy, and eNOS upregulation compared with H-IH. However, in contrast to CH, neither H-IH nor E-IH increased ionomycin-dependent vasodilation. Furthermore, H-IH and E-IH similarly augmented U-46619-induced pulmonary vasoconstriction but to a lesser degree than CH. We conclude that maintenance of eucapnia decreases IH-induced PH and upregulation of arterial eNOS. In contrast, increases in pulmonary vasoconstrictor reactivity following H-IH are unaltered by exposure to supplemental CO(2).

Effects of severe hypocapnia on expression of bax and bcl-2 proteins, DNA fragmentation, and membrane peroxidation products in cerebral cortical mitochondria of newborn piglets.

BACKGROUND: Hypocapnia occurs in the newborn infant inadvertently or as a therapeutic modality and may result in neuronal and mitochondrial alterations in the newborn brain. Since mitochondria regulate apoptosis, these alterations may initiate a cascade of reactions that lead to apoptotic cell death. OBJECTIVES: This study tests the hypothesis that hypocapnia results in increased expression of the pro-apoptotic protein Bax, fragmentation of DNA and membrane lipid peroxidation in cerebral cortical mitochondria (mt) of newborn piglets. METHODS: Studies were performed in three groups of anesthetized normoxic newborn piglets: hypocapnic (H, n = 5), ventilated at a PaCO(2) of 11-15 mm Hg; normocapnic (N, n = 5), ventilated at a PaCO(2) of 40 mm Hg; and corrected normocapnic (CN, n = 4), ventilated as H with CO(2) added to maintain normocapnia. Tissue ATP and phosphocreatine levels were determined. Mitochondrial membrane proteins were separated, transblotted and probed with antibodies to Bax and Bcl-2. Bands were detected by enhanced chemiluminescence and analyzed by imaging densitometry. mtDNA was isolated. Cell and mitochondrial membrane lipid peroxidation products were measured spectrofluorometrically. RESULTS: ATP and PCr concentrations were similar in the 3 groups. The ratio of Bax/Bcl-2 increased significantly in H compared to N and CN. mtDNA fragmentation was also significantly greater in H compared to N or CN. Membrane lipid peroxidation was higher in H than in N or CN; and in CN compared to N. CONCLUSIONS: The data demonstrate that severe hypocapnia results in increased Bax expression, DNA fragmentation, and membrane lipid peroxidation in mitochondria of cerebral cortical neurons of newborn piglets, and may result in apoptotic cell death.

Hypocapnia related changes in pain-induced brain activation as measured by functional MRI.

Stress, acute pain and chronic pain may often result in hyperventilation (HV) which produces hypocapnia. The aim of this fMRI-study was to investigate the influence of hypocapnia on cortical activation during noxious stimulation in 14 healthy volunteers. The intensity of voluntary HV was controlled by capnometry Three tasks were performed in the fMRI sessions: (I) three 3-min HV periods with 7-min periods of recovery in between; (II) mechanically induced phasic pain stimulation--pain task (PT); (III) tapping--motor task (MT). The last two of these protocols were performed under normocapnic and hypocapnic conditions. HV decreased the fMRI signal by 3-7% in all regions of the cortex and subcortical nuclei. This decrease was most prominent in the opercular, frontal and temporal areas. When the PT was performed during hypocapnia a strong reduction in cluster sizes and lower t-values in S1 and insular cortex were found. In contrast MT was accompanied by an increase in cluster sizes and higher t-values. From this we conclude that hypocapnia significantly influences the BOLD signal in nociceptive and motor systems, indicating that either the coupling between the BOLD effect and neuronal processing changed or that the activity in the cortical network which represents the pain processing is decreased. These effects should be considered for functional brain imaging studies on the nociceptive system.

Alteraciones gasométricas en pacientes cirróticos hospitalizados / Gasometric alterations in hospitalized cirrhotic patients

Introducción y objetivos: Aunque se ha descrito la existencia de diversas alteraciones del intercambio gaseoso en la cirrosis, existen pocos estudios que las hayan estudiado de forma prospectiva. El objetivo de este trabajo fue conocer la frecuencia y gravedad de dichas alteraciones en los pacientes cirróticos hospitalizados, correlacionándolas con el grado de disfunción hepática. Pacientes y métodos: Se estudiaron 50 pacientes cirróticos consecutivos (41 varones) que requirieron ingreso hospitalario por descompensación de su hepatopatia (ascitis, encefalopatía hepática, hepatitis alcohólica y hemorragia digestiva alta), y que no presentaban procesos pulmonares ni cardiacos agudos o crónicos que pudiesen producir hipoxemia. Los pacientes fueron agrupados según su estadio de Child-Pugh (A, n = 13; B, n = 21; C, n = 16). En siete pacientes se constató la presencia de una hepatitis alcohólica sobre añadida grave (HAAG). En todos ellos se realizó una gasometría arterial basal antes de ser dados de alta, y se efectuó un ecocardiograma transtorácico con contraste en caso de sospecha de síndrome hepatopulmonar (SHP). Resultados: Se observó una discreta hipoxemia global (80,9 mmHg) sin diferencias según el grado de Child-Pugh. La hipocapnia fue significativamente más marcada en los pacientes con estadio Child C que en aquellos con estadios A y B (31,2 ± 3,1 frente a 38,1 ± 4,3 y 36,3 ± 5mmHg; p < 0,05), respectivamente. En cambio, los pacientes cirróticoscon HAAG presentaron un hipocapnia significativamente menor que aquellos otros sin HAAG (31,2 ± 3,1 frente a 36,3 ± 5 mmHg; p < 0,05). En el análisis multivariante, las variables con valor pronóstico independiente para la presencia de hipocapnia fueron la protrombina, la albúmina y el sodio plasmáticos. Se constató la presencia de SHP en 8 pacientes (16%). Conclusiones: La alteración gasométrica más frecuentes de la cirrosis es la alteración del gradiente alvéolo-arterial de oxígeno, que se acentúa conforme empeora la función hepática. La hipocapnia, aunque supatogenia no es bien conocida, podría constituir una mecanismo compensador de la hipoxemia o bien ser el resultado de la activación de los centros respiratorios centrales por sustancias no aclaradas en el hígado

Background and objectives: Gas exchange alterations have been described in cirrhotic patients; but by the moment, a few prospective studies have focused in them. The aim of this study was to describe the frequency and severity of gasometric alterations in hospitalized cirrhotic patients, a their correlation with hepatocellular disfunction. Patients and methods: 50 consecutive cirrhotic patients (41 males) admited for liver decompensation (ascites, liver encephalopathy, alcoholichepatitis and upper gastrointestinal bleeding) without acute or chronic cardiopulmonary disfunction were included in the study. Patients were classificated according with Child-Pugh score (A, n = 13; B, n =21; C, n = 16). Severe alcoholic hepatitis (SAH) was confirmed in 7 patients. Arterial gasometry was performed in all patients before discharge. Contrast echocardiography was performed in any case of suspicion of hepatopulmonary syndrome (HPS). Results: Light hypoxemia was observed (80.9 mmHg), without differences with Child-Pugh. Hypocapnia was significantly more evident in Child C than in A and B (31.2 ± 3.1 vs. 38.1 ± 4.3 y 36.3 ± 5 mmHg; p <0,05), respectively. Cirrhotic patients with SAH showed a significantly higher hypocapnia by comparison with others (31.2 ± 3.1 vs. a 36.3 ± 5mmHg; p < 0.05). In multivariate analysis, independent prognostic variables for hypocapnica were plasmatic levels of protrombin time, albumin and sodium. HPS was confirmed in 8 patients (16%). Conclusions: The most prevalent gas exchange abnormality in cirrhosis was the alteration of alveolar-arterial oxygen tension gradient, directly correlated with hepatocellur disfunction. Hypocapnia could be a compensatory mechanism or the result of the activation of central respiratory centres by non-depurated substances by the liver

Morphological changes in the rat carotid body 1, 2, 4, and 8 weeks after the termination of chronically hypocapnic hypoxia.

Morphological changes in the rat carotid bodies 1, 2, 4, and 8 weeks after the termination of chronically hypocapnic hypoxia (10% O2 for 8 weeks) were examined by means of morphometry and immunohistochemistry. The rat carotid bodies after 8 weeks of hypoxic exposure were enlarged several fold with vascular expansion. The carotid bodies 1 and 2 weeks after the termination of 8 weeks of hypoxic exposure were diminished in size, although their diameter remained larger than the normoxic controls. The expanded vasculature in chronically hypoxic carotid bodies returned to the normoxic control state. In the carotid bodies 1 week after the termination of chronic hypoxia, the density of NPY fibers was remarkably increased and that of VIP fibers was dramatically decreased in comparison with the density in chronically hypoxic carotid bodies. In the carotid bodies 2 and 4 weeks after the termination of hypoxia, the density of SP and CGRP fibers was gradually increased. In the carotid bodies 8 weeks after the termination of hypoxia, the appearance of the carotid body returned to a nearly normoxic state, and the density of SP, CGRP, VIP, and NPY fibers also recovered to that of normoxic controls. These results suggest that the morphological changes in the recovering carotid bodies start at a relatively early period after the termination of chronic hypoxia, and a part of these processes may be under the control of peptidergic innervation.

Ketamine attenuates hypocapnia-induced neuronal damage in the caudoputamen in a rat model of chronic cerebral hypoperfusion.

We previously demonstrated that the caudoputamen was exclusively further damaged by hypocapnia in a rat with chronic cerebral hypoperfusion which is characterized by white matter lesions (WML) and a well-established model for patients with cerebrovascular diseases and/or dementia, and suggest that this process may be the cause of long lasting postoperative delirium or brain dysfunction in such patients. In the present study, we investigated whether ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist, could attenuate the neuronal damage in the caudoputamen. Ketamine, at doses of 10 and 20 mg/kg, which was given intraperitoneally before hypocapnia induction, attenuated the aggravation of WML score, neuronal damage, and astroglial proliferation in the rat caudoputamen. These results suggest that ketamine may be beneficial for preventing postoperative brain dysfunction, especially in patients with cerebrovascular diseases and/or dementia induced by hypocapnia, which is likely to occur in the mechanical ventilation used during surgery.

Caudoputamen is damaged by hypocapnia during mechanical ventilation in a rat model of chronic cerebral hypoperfusion.

BACKGROUND AND PURPOSE: Postoperative brain dysfunction, such as delirium, is a common complication of anesthesia and is sometimes prolonged, especially in patients with cerebrovascular disease. In the present study we investigated the effect of hypocapnia during anesthesia on neuronal damage using a rat model of chronic cerebral hypoperfusion. METHODS: Chronic cerebral hypoperfusion was induced by clipping the bilateral common carotid arteries in male Wistar rats. Fourteen days after the operation, these animals were mechanically ventilated for 2 hours and then kept in suitable conditions for an additional 14 days. Twenty-four rats were assigned to 4 groups: those with chronic cerebral hypoperfusion with either hypocapnia or normocapnia during anesthesia, and those given sham operation with either hypocapnia or normocapnia. White matter lesions in the brain sections were evaluated with Klüver-Barrera staining. Proliferation of glial cells was estimated with the use of immunohistochemistry of glial fibrillary acidic protein, a marker for astroglia, and CD11b, a marker for microglia. Computer-assisted morphometry was applied to the immunohistochemical results of microtubule-associated protein 2 to evaluate the loss of neurons. RESULTS: The histological damage was localized almost exclusively in the white matter in the rats subjected to chronic cerebral hypoperfusion but without hypocapnia. Neuronal damage and astroglial proliferation occurred with aggravated white matter lesions in the caudoputamen in the rats with chronic cerebral hypoperfusion and hypocapnia. No lesions were observed in sham-operated rats with either hypocapnia or normocapnia. CONCLUSIONS: These results indicate that hypocapnia during anesthesia causes tissue damage in the caudoputamen, which may be responsible for long-lasting postoperative delirium in patients with stroke and/or dementia.

Hypocarbia during the first 24 postnatal hours and white matter echolucencies in newborns < or = 28 weeks gestation.

The purpose of the present study was to test the hypothesis that newborns < or = 28 wk gestation who have a PCO(2) measurement in the lowest gestational age-specific quartile (hypocarbia) on the first day of life are not at increased risk for ultrasonographic white matter echolucency (EL) after adjustment for confounders. The sample consisted of 799 infants < or = 28 wk gestation born during 1991-1993. Forty-eight infants with EL were classified as cases and compared with 751 controls, i.e. those without EL. We performed univariable comparisons, stratified analyses, and multivariable logistic regression. In the univariable analyses, hypocarbia on the first day of life was associated with an increased EL risk. The odds ratios for the hypocarbia-EL relationship were prominently elevated in the strata of infants who did not have other major risk factors for EL (e.g. gestational age 26-28 wk, normothyroxinemia, no characteristics of antenatal infection). In the multivariable analyses, the association diminished after adjustment with a hypocarbia propensity score (odds ratio = 1.7; 95 % confidence interval, 0.8-3.2) or with potential confounders.

Repetitive hyperpnoea causes peripheral airway obstruction and eosinophilia.

Hyperpnoea of canine peripheral airways with dry air results in airway obstruction, mucosal damage, and inflammation. The purpose of this study was to evaluate the effect of repeated dry air challenge (DAC) on airway obstruction, reactivity and the development of airway inflammation in dogs. Canine peripheral airways received DAC (delivered under general anaesthesia through a bronchoscope) every 48 h for two weeks. Peripheral airway resistance and reactivity were measured prior to each DAC. After the final DAC, bronchoalveolar lavage fluid (BALF) cells and soluble mediators from challenged and control airways were measured. Repeated bronchoscopy had no effect on airway mechanics. Repeated DAC produced cumulative increases in peripheral airway resistance and peak obstructive response to DAC. The response to hypocapnia was also increased in airways receiving repeated DAC. However, when the response to agonists was expressed as a change from baseline, consistent significant increases were not observed. Repeated bronchoscopy produced insignificant changes in BALF cells and eicosanoid mediators. Repeated DAC produced marked eosinophilic inflammation and increased prostaglandins D2, E2, and F2alpha, as well as leukotrienes C4-E4. In conclusion, repeated dry air challenge in dogs in vivo causes persistent airway obstruction and inflammation not unlike that found in human asthma.

Alterations in respiratory neuronal activities in the medullary 'pre-Bötzinger' region in hypocapnia.

'Pre-inspiratory' neuronal activities in a rostral ventrolateral medullary 'pre-Bötzinger' complex have been hypothesized to generate eupnea. Respiratory-modulated neuronal activities were recorded in this region in decerebrate, vagotomized, paralyzed, and ventilated cats, having bilateral carotid sinus nerve sections. As end-tidal partial pressures of carbon dioxide were reduced to hypocapnic levels, all neuronal activities which were tonic or expiratory inspiratory ('pre-inspiratory') either ceased or lost respiratory-modulation. Similarly, most expiratory and inspiratory expiratory activities did not maintain a phasic discharge. Half of the inspiratory neuronal activities did continue a phasic discharge, which commenced after phrenic activity or became independent of the phrenic rhythm. Results do not support a fundamental role of the 'pre-Bötzinger' complex in the neurogenesis of eupnea. Some neuronal activities can establish a phasic discharge in hypocapnia which is independent of the central respiratory rhythm. At normocapnia, this independent discharge is superseded and incorporated into the ponto-medullary respiratory neuronal circuit which generates eupnea.

The effects of hyper- and hypocarbia on intraparenchymal arterioles in rat brain slices.

This investigation examined the direct effects of hyper- and hypocarbia on intracerebral resistance vessels within an intact neuronal synctium. Hippocampal rat brain slices were superfused with artificial cerebrospinal fluid (aCSF). Arterioles were located and diameter changes in response to alterations in aCSF carbon dioxide tension (pCO2) were monitored with videomicroscopy. Microvessels dose dependently dilated and constricted during hyper- and hypocarbia, respectively. A two-fold rise in pCO2 produced a 20% increase in diameter, while a 47% decrease in pCO2 vasoconstricted microvessels by 11%. This is the first model allowing the investigation of the direct actions of physiologic mediators on discrete intracerebral resistance vessels in situ. The results suggest that intracerebral microvessels significantly respond to changes in pCO2 and may be intimately involved in alterations in cerebral vascular resistance.