PubMed · 368521
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P M Vanhoutte, W J Janssens. 1978. Local control of venous function.. https://doi.org/10.1016/0026-2862(78)90055-9
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1. We investigated the effect of acidosis on the sarcomere length (SL) dependence of tension generation, in comparison with the effect of inorganic phosphate (P(i)), in rat skinned ventricular trabeculae. The shift of the mid-point of the pCa-tension relationship associated with an increase in SL from 1.9 to 2.3 microm (DeltapCa(50)) was studied. 2. Decreasing pH from 7.0 to 6.2 lowered maximal and submaximal Ca(2+)-activated tension and increased DeltapCa(50) in a pH-dependent manner (from 0.21 +/- 0.01 to 0.30 +/- 0.01 pCa units). The addition of P(i) (20 mM) decreased maximal tension and enhanced the SL dependence, both to a similar degree as observed when decreasing pH to 6.2 (DeltapCa(50) increased from 0.20 +/- 0.01 to 0.29 +/- 0.01 pCa units). 3. Further experiments were performed using 6 % (w/v) Dextran T-500 (molecular weight approximately 500 000) to osmotically reduce interfilament lattice spacing (SL, 1.9 microm). Compared with that at pH 7.0, in the absence of P(i) the increase in the Ca(2+) sensitivity of tension induced by osmotic compression was enhanced at pH 6.2 (0.18 +/- 0.01 vs. 0.25 +/- 0.01 pCa units) or in the presence of 20 mM P(i) (0.17 +/- 0.01 vs. 0.24 +/- 0.01 pCa units). 4. H(+), as well as P(i), has been reported to decrease the number of strongly binding cross-bridges, which reduces the co-operative activation of the thin filament and increases the pool of detached cross-bridges available for interaction with actin. It is therefore considered that during acidosis, the degree of increase in the number of force-generating cross-bridges upon reduction of interfilament lattice spacing is enhanced, resulting in greater SL dependence of tension generation. 5. Our results suggest that the Frank-Starling mechanism may be enhanced when tension development is suppressed due to increased H(+) and/or P(i) under conditions of myocardial ischaemia or hypoxia.
The Na(+)/H(+) exchanger (NHE) is activated during ischemia-reperfusion in an effort to restore intracellular pH to normal levels. Inhibition of NHE with non-selective amiloride derivatives has been shown to be neuroprotective and to attenuate free fatty acid efflux during ischemia-reperfusion. We evaluated the effects of SM-20220 (20 microM), a highly selective and specific NHE inhibitor, applied topically onto rat cerebral cortex prior to and during a 20-min period of ischemia. SM-20220 application significantly reduced the ischemia-evoked efflux of myristic, palmitic, and arachidonic acids during both ischemia and reperfusion with significant decreases in linoleic and docosahexaenoic levels during reperfusion. This study confirms the importance of NHEs in eliciting free fatty acid efflux, inhibition of which may be an essential component of the neuroprotective benefits of NHE inhibitors in ischemia-reperfusion injury.
Using H9c2 cells derived from rat cardiomyocytes, we investigated the mechanism of cell death during hypoxia in the presence of serum and glucose. Hypoxic cell death is by necrosis and is accompanied by metabolic acidosis. Moreover, hypoxic cell death is inhibited by Hepes buffer as well as by 2-deoxyglucose, an inhibitor of glycolysis, indicating that metabolic acidosis should play an essential role in hypoxic injury. The involvement of phosphoinositide 3-kinase (PI 3-kinase), which is known to activate glucose metabolism, was examined using its inhibitor, LY290042, or adenovirus-mediated gene transfer. Hypoxic cell death was inhibited by LY294002 in a dose-dependent manner. Overexpression of dominant negative PI 3-kinase was found to reduce cell death, whereas wild-type PI 3-kinase enhanced it. Dominant negative PI 3-kinase also reduced glucose consumption and acidosis, but this was stimulated by wild-type PI 3-kinase. The data indicate that PI 3-kinase stimulates cell death by enhancing metabolic acidosis. LY294002 significantly reduced glucose uptake, showing that PI 3-kinase regulates glycolysis at the step of glucose transport. These findings indicate the pivotal role of glucose metabolism in hypoxic cell death, and reveal a novel death-promoting effect of PI 3-kinase during hypoxia, despite this enzyme being considered to be a survival-promoting factor.