The effect of increasing [K+]0 on 3H-glycogen levels was examined in mouse cerebral cortical slices. K+ stimulates in a time- and concentration-dependent manner the hydrolysis of 3H-glycogen. Over 70% of the maximal effect is reached within 30 sec and the EC50 for the glycogenolytic action of K+ is 11 mM. Significant 3H-glycogen hydrolysis occurs at 5-12 mM [K+]0, concentrations reached by the ion in the extracellular space during neuronal activity. The K+-evoked glycogenolysis is Ca2+-dependent, and is inhibited by Ca2+-channel blockers such as Ni2+ and Mn2+, but not by Cd2+, nifedipine, and omega-conotoxin. Furthermore, the effect of K+ is not enhanced by the Ca2+-channel agonist Bay K 8644. This type of pharmacological profile suggests that the activation of voltage-sensitive Ca2+ channels of the T subtype mediates the glycogenolytic action of K+. This set of observations suggests that K+ released in the extracellular space by active neurons may promote the mobilization of energy substrates and therefore play a role in the coupling between neuronal activity and energy metabolism.
Adenosine promotes a concentration-dependent hydrolysis of 3H-glycogen newly synthesized from 3H-glucose by mouse cerebral cortical slices. The EC50 for this effect is 7 microM. Theophylline antagonizes the glycogenolysis induced by adenosine with an EC50 of 80 microM. The rank-order of potencies of adenosine agonists is adenosine 5'-cyclopropyl-carboxamide greater than 2-chloroadenosine much greater than N6-cyclohexyladenosine = adenosine, suggesting that adenosine promotes glycogenolysis via receptors of the A2 type. This contention is substantiated by the weak stereospecificity observed for the glycogenolytic action of D- and L-(phenylisopropyl)-adenosine. The glycogenolysis elicited by adenosine at 10 and 100 microM is inhibited by ouabain at 10 microM, a concentration of the cardiac glycoside not significantly affecting 3H-glycogen levels per se. Interestingly, the previously demonstrated glycogenolytic action of vasoactive intestinal peptide (Magistretti et al., 1981, 1984) and of norepinephrine (Quach et al., 1978) is also antagonized by ouabain. These results demonstrate the existence of a metabolic action of adenosine, which is sensitive to ouabain and appears to be mediated by A2 receptors. The concentrations at which adenosine promotes glycogenolysis are of the same order of magnitude as those reached extracellularly by the nucleoside during neuronal depolarization (Pull and McIlwain, 1972). This set of observations therefore supports the notion that adenosine plays a modulatory role in the coupling between neuronal activity and energy metabolism in the CNS.
α1‐Antichymotrypsin (α1‐ACT) is a secreted serine proteinase inhibitor of the serpin family. It is strongly upregulated during the inflammatory phase of wound repair to control the undesirable destructive side effects of cathepsin G which is released from infiltrating neutrophils. We have shown that α1‐ACT and its mouse homologue spi2 exhibit a classic acute phase response after cutaneous injury in murine and human skin. The induction of spi2 gene expression following wounding is significantly less pronounced in diabetic mice. Transient overexpression of spi2 or α1‐ACT significantly increased wound tensile strength in two independent diabetic models: in genetically diabetic mice, gene gun mediated delivery of spi2 or α1‐ACT cDNA increased the average wound strength by 42%(P = 0.001) and 21%(P = 0.013) at d5 post‐wounding respectively. In a STZ induced diabetic rat model the breaking strength of adenovirally spi2‐ or α1‐ACT‐infected wounds increased by 20%(P = 0.049) and 23%(P = 0.004) at d7 after injection respectively. Moreover, the topical application of human α1‐ACT protein to wounds of diabetic mice had a significant and dose dependent effect on tensile strength at d5 post‐wounding (21% increase, P = 0.003). Histological analyses of these wounds indicated less infiltration of neutrophils in the treated wounds. α1‐ACT appears to be a key mediator between proteolysis and cytokine agonism and antagonism. Our data indicate that this balance is disturbed in diabetic wounds and that α1‐ACT might act as a switch to initiate wound healing in diabetic ulcers.
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