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  • Petrat et al could show that

    2022-08-12

    Petrat et al. could show, that even a low dosage of 10-mg/kg glycine (133 μmol/kg) has a beneficial effect on the small intestine after I/R. In regard to glycine, β-alanine has a clearly higher EC50 to the GlyR and activates the receptor with an efficiency of only 34.6%.16, 17 Therefore, it can be calculated that an amount of 384-μmol/kg β-alanine are required to evoke an equipollent effect on the small intestine. The applied dosages of β-alanine (10, 30, and 100 mg/kg) corresponded to amounts of 112, 336, and 1124 μmol/kg, respectively. Thus, only the highest dosage of β-alanine would be able to diminish the accumulation of macrophages and to attenuate tissue damage of the small intestine.16, 17 In fact, this postulate was experimentally verified (Fig. 4). In line with this conclusion, Zhang et al. found that a dosage of 200-mg/kg taurine, which has a 10-fold lower affinity to the GlyR than glycine itself, was necessary to attenuate tissue injury and to diminish tumor necrosis factor alpha-release after intestinal I/R in rats.17, 27 Unfortunately, such a high dosage of taurine evoked ventricular fibrillation and breathing arrest during the ischemic period in the applied rat tribe of this study (unpublished data). Together with the fact that β-alanine effected neither systemic parameters (as Darunavir Ethanolate receptor and breathing rate, acid-base balance, and glucose) nor lactate concentration, a metabolic action can be safely excluded, and a receptor-dependent effect in intestinal I/R seems most likely. Besides the congruent protection of β-alanine and glycine, obviously, via GlyR, there were some differing effects elicited by these amino acids. In previous studies, glycine ameliorated hypotension during reperfusion and diminished ALAT-activity in plasma. In contrast, β-alanine had only a slight effect (Fig. 1, Fig. 2). And vice versa, all three dosages of β-alanine clearly affected a normalization of the plasma sodium level in I/R, whereas glycine did not show any influence on sodium concentration in vivo. However, the physiological impact of such small changes in sodium needs to be evaluated. These discrepancies between beneficial properties point to an additional receptor-independent effect in I/R of both amino acids. Most likely, the exclusive effect of β-alanine on sodium level was mediated by its metabolization to carnosine, a dipeptide with well-known osmoregulatory capabilities. Although carnosine can offer further cytoprotective abilities, a beneficial effect on the small intestine seems highly unlikely because it is only available in muscle due to rapid cleavage in plasma and intestine.28, 29, 30 Under the experimental conditions, the basal plasma glycine concentration in rats was about 280 μM, whereas fasting plasma of 24 preoperative bypass patients showed an average glycine concentration of around 220 μM. This discrepancy in basal glycine level should correlate with a different basal opening probability of the GlyR and thus should influence the efficacy of intravenously infused β-alanine on the GlyR. Therefore, we calculated the opening probability of GlyRs under different basal glycine levels, using the modeling software Kintecus with experimentally determined parameters for the homomeric GlyR.9, 32 This model combines the facts that the GlyR offers five bindings sites for agonists, whereas the receptor-dependent chloride channel does not open before three agonists have bind. Owing to the calculations, the opening probability of GlyR was around 0.27% under the chosen experimental conditions in rats. In contrast, the opening probability is predicted to be two-fold lower (0.12%) in fasting plasma of preoperative bypass patients. Thus, a lower plasma glycine concentration seems to correlate with a lower opening probability of GlyRs. Since β-alanine could improve the outcome even under the chosen experimental conditions in rats, a relative higher effect in fasting patients after application of β-alanine would be very strongly expected. To prove whether the beneficial effect of β-alanine correlates with the available plasma glycine concentration and thus with a number of activated GlyRs, appropriate animal studies with fasting rats are under the way.