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Abstract Post cardiac arrest syndrome is associated with high morbidity and mortality, which is related not only to a poor neurological outcome but also to respiratory and cardiovascular dysfunctions. The control of gas exchange, and in particular oxygenation and carbon dioxide levels, is fundamental in mechanically ventilated patients after resuscitation, as arterial blood gases derangement might have important effects on the cerebral blood flow and systemic physiology. In particular, the pathophysiological role of carbon dioxide (CO2) levels is strongly underestimated, as its alterations quickly affect also the changes of intracellular pH, and consequently influence metabolic energy and oxygen demand. Hypo/hypercapnia, as well as mechanical ventilation during and after resuscitation, can affect CO2 levels and trigger a dangerous pathophysiological vicious circle related to the relationship between pH, cellular demand, and catecholamine levels. The developing hypocapnia can nullify the beneficial effects of the hypothermia. The aim of this review was to describe the pathophysiology and clinical consequences of arterial blood gases and pH after cardiac arrest. According to our findings, the optimal ventilator strategies in post cardiac arrest patients are not fully understood, and oxygen and carbon dioxide targets should take in consideration a complex pattern of pathophysiological factors. Further studies are warranted to define the optimal settings of mechanical ventilation in patients after cardiac arrest.

Post cardiac arrest syndrome is associated with high morbidity and mortality, which is related not only to a poor neurological outcome but also to respiratory and cardiovascular dysfunctions. The control of gas exchange, and in particular oxygenation and carbon dioxide levels, is fundamental in mechanically ventilated patients after resuscitation, as arterial blood gases derangement might have important effects on the cerebral blood flow and systemic physiology. In particular, the pathophysiological role of carbon dioxide (CO2) levels is strongly underestimated, as its alterations quickly affect also the changes of intracellular pH, and consequently influence metabolic energy and oxygen demand. Hypo/hypercapnia, as well as mechanical ventilation during and after resuscitation, can affect CO2 levels and trigger a dangerous pathophysiological vicious circle related to the relationship between pH, cellular demand, and catecholamine levels. The developing hypocapnia can nullify the beneficial effects of the hypothermia. The aim of this review was to describe the pathophysiology and clinical consequences of arterial blood gases and pH after cardiac arrest. According to our findings, the optimal ventilator strategies in post cardiac arrest patients are not fully understood, and oxygen and carbon dioxide targets should take in consideration a complex pattern of pathophysiological factors. Further studies are warranted to define the optimal settings of mechanical ventilation in patients after cardiac arrest. [ABSTRACT FROM AUTHOR]

The intracellular pH (pHi) in the cytosol of mammalian central neurons is tightly regulated and small pHi-fluctuations are deemed to modulate inter-/intracellular signaling, excitability, and synaptic plasticity. The resting pHi of young rodent hippocampal pyramidal neurons is known to decrease alongside aging for about 0.1 pH-units. There is no information about the relationship between age and pHi of human central neurons. We addressed this knowledge gap using 26 neocortical slices from 12 patients (1-56-years-old) who had undergone epilepsy surgery. For fluorometric recordings, the slice-neurons were loaded with the pHi-sensitive dye BCECF-AM. We found that the pyramidal cells’ resting pHi (n = 26) descended linearly alongside aging (r = − 0.71, p < 0.001). This negative relationship persisted, when the sample was confined to specific brain regions (i.e., middle temporal gyrus, 23 neurons, r = − 0.68, p < 0.001) or pathologies (i.e., hippocampus sclerosis, 8 neurons, r = − 0.78, p = 0.02). Specifically, neurons (n = 9, pHi 7.25 ± 0.12) from young children (1.5 ± 0.46-years-old) were significantly more alkaline than neurons from adults (n = 17, 38.53 ± 12.38 years old, pHi 7.08 ± 0.07, p < 0.001). Although the samples were from patients with different pathologies the results were in line with those from the rodent hippocampal pyramidal neurons. Like a hormetin, the age-related mild pHi-decrease might contribute to neuroprotection, e.g., via limiting excitotoxicity. On the other hand, aging cortical neurons could become more vulnerable to metabolic overstress by a successive pHi-decrease. Certainly, its impact for the dynamics in short and long-term synaptic plasticity and, ultimately, learning and memory provides a challenge for further research. [ABSTRACT FROM AUTHOR]

The carbonic anhydrase inhibitor dorzolamide can induce relaxation of retinal arterioles with a consequent increase in blood flow and oxygenation of the retina. It has been shown that the mechanisms underlying this relaxation are independent of extracellular acidosis and CO 2 . The purpose of the present study was to investigate the possible involvement of nitric oxide (NO) and intracellular acidosis in dorzolamide-induced relaxation of retinal arterioles. Porcine retinal arterioles were mounted in a wire myograph and dorzolamide induced relaxation was studied after 1) the addition of the NO synthase inhibitor l -NAME (3 × 10 −4 M) or the guanylyl cyclase inhibitor ODQ (3 × 10 −6 M), and 2) after loading the smooth muscle cells with the pH sensitive fluorophore SNARF-1-AM and studying changes in vascular tone and intracellular fluorescence after the induction of hypoxia, addition of lactate (10 −2 M), and extracellular acidification (pH = 7.0) alone and in the presence of dorzolamide (10 −3 M). Dorzolamide significantly relaxed retinal arterioles ( p < 0.03), and the effect was significantly higher in the presence of perivascular tissue than in isolated vessels at the highest concentration ( p < 0.01). In the presence of perivascular tissue dorzolamide-induced relaxation could be reduced by NO inhibition ( p < 0.02). Dorzolamide increased intracellular acidification ( p < 0.02) during extracellular acidosis, but there was no relation between relaxation and intracellular acidosis. In conclusion, dorzolamide-induced vasorelaxation depends on NO and the perivascular retinal tissue, but is independent of acidification in the extracellular and the intracellular space of retinal vascular smooth muscle cells. Other factors than NO and acidification are involved in dorzolamide-induced relaxation of retinal arterioles. [ABSTRACT FROM AUTHOR]

The beneficial effect of phosphodiesterase 5A inhibition in ischemia/reperfusion injury and cardiac hypertrophy is well established. Inhibition of the cardiac Na(+)/H(+) exchanger (NHE-1) exerts beneficial effects on these same conditions, and a possible link between these therapeutic strategies was suggested. Experiments were performed in isolated cat cardiomyocytes to gain insight into the intracellular pathway involved in the reduction of NHE-1 activity by phosphodiesterase 5A inhibition. NHE-1 activity was assessed by the rate of intracellular pH recovery from a sustained acidic load in the absence of bicarbonate. Phosphodiesterase 5A inhibition with sildenafil (1 μmol/L) did not affect basal intracellular pH; yet, it did decrease proton efflux (J(H); in millimoles per liter per minute) after the acidic load (proton efflux: 6.97±0.43 in control versus 3.31±0.58 with sildenafil; P<0.05). The blockade of both protein phosphatase 1 and 2A with 100 nmol/L of okadaic acid reverted the sildenafil effect (proton efflux: 6.77±0.82). In contrast, selective inhibition of protein phosphatase 2A (1 nmol/L of okadaic acid or 100 μmol/L of endothall) did not (3.86±1.0 and 2.61±1.2), suggesting that only protein phosphatase 1 was involved in sildenafil-induced NHE-1 inhibition. Moreover, sildenafil prevented the acidosis-induced increase in NHE-1 phosphorylation without affecting activation of the extracellular signal-regulated kinase 1/2-p90(RSK) pathway. Our results suggest that phosphodiesterase 5A inhibition decreases NHE-1 activity, during intracellular pH recovery after an acidic load, by a protein phosphatase 1-dependent reduction in NHE-1 phosphorylation. [ABSTRACT FROM AUTHOR]

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Abstract: This study was aimed to examine whether the changes of protein expression of sodium transporters in the ischemic penumbra are associated with the pathogenesis of ischemia-induced brain edema and/or brain cell injury. An experimental model of cerebral ischemia was made by permanent middle cerebral artery occlusion (pMCAO) in rats and the changes of protein expression of sodium transporters in the ischemic penumbra were examined by immunoblotting. Extensive infarction was observed in the frontal and parietal cortical and subcortical areas at 3 and 6h after pMCAO. Immunoblotting analyses revealed significantly increased expressions of electrogenic NBC (241±11% at 3h and 154±9% at 6h, P <0.05) and NHE1 (144±3% at 3h and 170±9% at 6h, P <0.05), compared with sham-operated controls. In contrast, Na–K-ATPase expression (78±6% at 3h and 85±3% at 6h, P <0.05) was significantly decreased. The expression of NCX1 was unchanged at 3h, but was significantly increased at 6h (141±3%, P <0.05). In addition, the expressions of neuronal (NeuN) and astroglial cell (GFAP) proteins were decreased, whereas the expression of oligodendrocyte protein (CNPase) was unchanged. Taken together, the selectively increased expressions of NHE1, electrogenic NBC, and NCX1 and decreased expression of Na–K-ATPase in the ischemic penumbra are likely to contribute to the secondary brain cell damages presumably through intracellular Na+ accumulation, cell swelling, and intracellular Ca2+ overload. [Copyright &y& Elsevier]

We studied the participation of adrenal medulla (AM) chromaffin cells in hypercapnic chemotransduction. Using amperometric recordings, we measured catecholamine (CAT) secretion from cells in AM slices of neonatal and adult rats perfused with solutions bubbled with different concentrations of CO2. The secretory activity augmented from 1.74 ± 0.19 pC/min at 5% CO2 to 6.36 ± 0.77 pC/min at 10% CO2. This response to CO2 was dose dependent and appeared without changes in extracellular pH, although it was paralleled by a drop in intracellular pH. Responsiveness to hypercapnia was higher in neonatal than in adult slices. The secretory response to hypercapnia required extracellular Ca2+ influx. Both the CO2-induced internal pH drop and increase in CAT secretion were markedly diminished by methazolamide (2 µM), a membrane-permeant carbonic anhydrase (CA) inhibitor. We detected the presence of two CA isoforms (CAI and CAII) in neonatal AM slices by in situ hybridization and real-time PCR. The expression of these enzymes decreased in adult AM together with the disappearance of responsiveness to CO2. In patch-clamped chromaffin cells, hypercapnia elicited a depolarizing receptor potential, which led to action potential firing, extracellular Ca2+ influx, and CAT secretion. This receptor potential (inhibited by methazolamide) was primarily attributable to activation of a resting cationic conductance. In addition, voltage-gated K+ current amplitude was also decreased by high CO2. The CO2-sensing properties of chromaffin cells may be of physiologic relevance, particularly for the adaptation of neonates to extrauterine life, before complete maturation of peripheral and central chemoreceptors. [ABSTRACT FROM AUTHOR]

Background: This study was prompted by concern that administration of bicarbonate for correction of lactate acidosis aggravates a low intracellular pH (pHi). In healthy subjects we evaluated skeletal muscle pHi using 31P-magnetic resonance spectroscopy during 5-minute rhythmic handgrip to provoke intracellular acidosis.Methods: Subjects were randomized to treatment with bicarbonate or saline infused intravenously in a cross-over study design with 1 h between trials.Results: In response to rhythmic handgrip, muscle venous O(2) hemoglobin saturation decreased from 51 +/- 4% to 36 +/- 2% and lactate increased from 1.0 +/- 0.1 to 4.9 +/- 0.5 mmol/l with a reduction in pH from 7.43 +/- 0.01-7.23 +/- 0.01 (P<0.05). pHi decreased from 7.06 +/- 0.02-6.36 +/- 0.08 (P<0.05). Infusion of bicarbonate increased the arterial blood concentration from 26 +/- 1 to 39 +/- 1 mmol/l (P<0.05). The arterial CO(2) partial pressure decreased from 5.6 +/- 0.2 to 5.2 +/- 0.3 kPa during rhythmic handgrip, whereas it increased to 5.9 +/- 0.2 kPa (P<0.05) during infusion of bicarbonate. Bicarbonate treatment also increased pH of arterial and venous blood (7.55 +/- 0.01 vs. 7.44 +/- 0.02 and 7.31 +/- 0.01 vs. 7.23 +/- 0.02, respectively; P<0.05). In the last min of rhythmic handgrip the decrease in pHi was attenuated by the administration of bicarbonate (6.60 +/- 0.11 vs. 6.40 +/- 0.12; P<0.05).Conclusion: During exercise-induced metabolic acidosis, intravenous administration of bicarbonate increased the buffering capacity of blood and attenuated the decrease in intracellular muscle pH, although there was a small increase in the arterial carbon dioxide pressure. [ABSTRACT FROM AUTHOR]

The cardiac subtype of Na+/H+ exchanger (NHE-1) plays an important role in the regulation of intracellular pH (pHi) and also can be a major route for Na+ influx. Although intracellular ATP is required for the optimal function of NHE-1, the regulation of the exchanger by ATP is less well characterized. This study was designed to investigate which intracellular ATP generated by oxidative phosphorylation or by glycolysis is dominant for the activation of NHE-1 in intact cardiac myocytes. Isolated guinea pig ventricular myocytes were loaded with the pHi-sensitive fluorescent indicator, 2′-7′-bis(carboxyl)-5′,6′-carboxy fluorescein (BCECF), and exposed to 20 mM 2-deoxyglucose (2-DG) or 2 mM sodium cyanide (CN) to inhibit glycolysis or oxidative phosphorylation, respectively. The activity of NHE-1 was estimated with pHi recovery following transient application of 15 mM NH4Cl (NH4Cl prepulse). After the NH4Cl prepulse, pHi decreased from 7.00 ± 0.03 (mean ± S.E.) to 6.60 ± 0.06 and recovered to 6.94 ± 0.13 at 10 min (n = 7). The pHi recovery was suppressed in the presence of 2-DG (6.67 ± 0.05, p < 0.01, n = 7), but was not changed in the presence of CN (6.88 ± 0.18, n = 6). Since there was no difference in the intrinsic H+ buffering power, the estimation of the net acid efflux demonstrated that the activity of NHE-1 was significantly depressed in 2-DG. The inhibitory effect of 2-DG was not due to more extensive depletion of global intracellular ATP or secondary to the change in either intracellular Na+ or Ca2+ concentration. We concluded that ATP generated by glycolysis rather than by oxidative phosphorylation is essential to activate NHE-1 in ventricular myocytes. [ABSTRACT FROM AUTHOR]

Here we propose that the Western world lifestyle disrupts phosphate metabolism and homeostasis due to caloric or acidic hyperphagia. Psychic factors such as social defeat due to stressed social coexistence characterized by reduced activity and chronic hypoventilation (hypercapnia) also play a role. At least two mechanisms mediate the harmful vascular effects of phosphates with intracellular acidosis being a feature in both of them. First, insufficient lifestyle and adjacent diet together with the psychosomatic mechanism of social defeat (mainly through chronic hypercapnic acidosis) lead to insulin resistance characterized by the classical Cardiometabolic Syndrome. Secondly, overload with fixed acids caused by renal insufficiency or acidic diet (due to intracellular metabolic acidosis) leads to our here proposed Exhausting Buffer Syndrome (EBS) which tends to elevate serum inorganic phosphate levels. These two mechanisms overlap and are regulated through genetically determined processes that drive the disruption of phosphate metabolism and lead to vascular calcification. To have a lower intake of calories and less acidic foods combined with low-grade hypocapnia, might be one of several solutions. (Neuropsychopharmacol Hung 2021; 23(1): 215-220)