Carbon dioxide influence on nitric oxide production in endothelial cells and astrocytes: Cellular mechanisms

Viktig studie som nevner hvordan CO2 forholder seg til NO og vasodilasjon. Nevner mekanismene bak eNOS og nNOS og hva som faktisk skjer i cellene. Denne studien er på celler, men beskriver mye av det som skjer in vivo og refererer til andre viktige studier.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073030/

«Cerebral vessels may regulate cerebral blood flow by responding to changes in carbon dioxide (CO2) through nitric oxide (NO) production. »

«NO levels in endothelial cells increased during hypercapnia by 36% in 8 hours and remained 25% above baseline. NO increase in astrocytes was 30% after 1 hour but returned to baseline at 8 hours. NLA blocked NO increase in endothelial cells under hypercapnia.»

«This study suggests that cerebral endothelial cells and astrocytes release NO under normocapnic conditions and NO production is increased during hypercapnia and decreased during hypocapnia independent of pH. Further, this demonstrates that endothelial cells may play a pivotal role in chemoregulation by modulating NOS activity.»

«Modulation of cerebral vascular tone in response to changes in the arterial partial pressure of carbon dioxide (pCO2) is defined as chemoregulation. In humans hypocapnia produces vasoconstriction resulting in decreased cerebral blood flow (CBF), whereas hypercapnia produces vasodilation and increased CBF (Lavi et al., 2003). »

«Using nitric oxide synthase (NOS) inhibitors, several in vivo studies have suggested that vasodilation in response to increased pCO2may be mediated by NO (Lavi et al., 2006). »

«Under hypercapnic conditions (pCO2 56.3±8.7 mmHg), NO concentration increased from baseline levels to a mean of 10±0.6×10-10M during the first 4 hours (Figure 1A). NO concentration peaked at 36% (10.2±0.5×10-10M) above baseline at 8 hours and stabilized 25% (9.4±0.5×10-10M) above baseline until completion of the experiment.»

«By plotting NO changes as a function of pCO2, we could disregard time as a variable in NO production (Figure 3) to establish that changes in NO levels correlate with changes in pCO2 (R=0.99).»

CO2 og NO

«Under hypercapnic conditions (pCO2 56.3±8.7 mmHg), human fetal astrocytes increased NO production by 30% over baseline values to a mean level of 2.5±1.2×10-10M in the first hour of hypercapnia (Figure 2). NO production then gradually decreased to control levels after 8 hours and remained at control levels for the remainder of the experiments.»

CO2 og NO i astrocytt

«The pH values were kept stable within a neutral gap under normocapnic (7.39±0.01), hypercapnic (7.36±0.02) and hypocapnic (7.40±0.01) conditions.»

» Stimulation of NOS in the endothelial cells is consistent with the NO-dependent vasodilation and increased CBF that occur in vivo during hypercapnia, as has been shown in rats (Iadecola, 1992) and in primates (Thompson et al., 1996). Decreased NO production by endothelial cells also correlates with the in vivo vasoconstrictive response to hypocapnia shown previously (Lavi et al., 2003;Thompson et al., 1996).»

«Thus, it is unlikely that eNOS is responsible for the early or fast phase response during chemoregulation in vivo. There are several explanations for this phenomenon. First, nitrite (NO2), being a storage pool of NO, can be reduced to NO under acidic and hypoxic conditions in vivo (Cosby et al., 2003). Under these conditions nitrite releases NO in the presence of deoxygenated hemoglobin in blood (Cosby et al., 2003;Nagababu et al., 2003) or neuroglobin (Burmester et al., 2000) in neurons acting as a nitrite reductase (Petersen et al., 2008). »

«The chemoregulatory response to CO2 changes in vivo is rapid, occurring on the order of milliseconds; our results did not demonstrate this component of the chemoregulatory response.»

«Cerebrovascular reactivity in response to CO2 is impaired in diabetic or hypertensive patients with endothelial dysfunction (Lavi et al., 2006), suggesting an important role for endothelial cells in modulating CBF response to CO2. »

«It has been reported that the ATP-sensitive K+ channels play a pivotal role in microvessel vasodilation of the cerebral cortex in response to decreased pH corresponding to mild hypercapnia and that a NOS inhibitor could not alter this vasodilation (Nakahata et al., 2003).»

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