PubMed · 5013855
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A P Haines, P J Shoenberg. 1972-03-04. Hyperpyrexia and overdose.. https://doi.org/10.1136/bmj.1.5800.632-c
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1. L-type Ca2+ channel currents (I(Ca)) were measured in guinea-pig ventricular myocytes (22 degrees C, 300 ms steps from -45 to +10 mV). Pulsing at 0.5 Hz reduced I(Ca) within 5 min to 92 +/- 3% (mean +/- S.E.M., n = 14) and within 10 min to 83 +/- 4 % ('run-down' with reference to I(Ca) after a 5 min equilibration period). 2. Bath-applied cytochalasin D (cytD, 10 microM) reduced I(Ca) to 75 +/- 4% within 5 min and to 61 +/- 4% within 10 min ('cytD reduction of I(Ca)') by reduction of maximal Ca2+ conductance (suggested by fits of time course and of current-potential (I-V) curves). 3. Preincubation with phalloidin (bath applied, 100 microM, 5 h) prevented the cytD reduction of I(Ca). Since phalloidin specifically blocks F-actin depolymerization, cytD reduction of I(Ca) is linked to depolymerization of F-actin. 4. CytD did not attenuate the beta-adrenergic stimulation of I(Ca) (30 nM isoproterenol), suggesting that A kinase anchoring proteins are unlikely to mediate the cytD reduction of I(Ca). The cytD reduction of I(Ca) was abolished by extra-/intracellular acidosis (pH(o) 6.9), by cell dialysis of 5 mM BAPTA, or by serine/threonine protein phosphatase inhibitors. 5. Actin-depolymerizing factor (ADF)/cofilin are proteins that bind to actin, mediate a pH-sensitive depolymerization of F-actin, and are activated by dephosphorylation. Western blots from hearts perfused with solutions containing zero or 10 microM cytD indicated that cytD reduces the ratio of phosphorylated to total ADF/cofilin content by 50%. 6. The data support the concept that cytD mediates dephosphorylation and activation of ADF/cofilin, leading to depolymerization of F-actin with a subsequent reduction of I(Ca).
1. Arachidonic acid (AA) exerts multiple physiological and pathophysiological effects in the brain. By continuously measuring the intracellular pH (pH(i)) and Ca2+ levels ([Ca2+]i) in primary cultured rat cerebellar granule cells, we have found, for the first time, that 20 min treatment with 10 microM AA resulted in marked increases in Ca2+ and H+ levels in both the cytosol and nucleus. 2. A much higher concentration (40 mM) of another weak acid, propionic acid, was needed to induce a similar change in pH(i). The [Ca2+]i increase was probably caused by AA-induced activation of Ni2+-sensitive cationic channels, but did not involve NMDA channels or the Na+-Ca2+ exchanger. 3. AA-induced acidosis occurs by a different mechanism involving predominantly the passive diffusion of the un-ionized form of AA, rather than a protein carrier, as proposed by Kamp & Hamilton for fatty acids (FAs) in artificial phospholipid bilayers (the 'flip-flop' model). The following results, which are similar to those observed in lipid bilayers, support this conclusion: (1) FAs containing a -COOH group (AA, linoleic acid, alpha-linolenic acid, and docosahexaenoic acid) induced intracellular acidosis, whereas a FA with a -COOCH3 group (AA methyl ester) had little effect on pH(i), (2) a FA amine, tetradecylamine, induced intracellular alkalosis, and (3) the AA-/FA-induced pH(i) changes were reversed by bovine serum albumin. 4. Further evidence in support of a passive diffusion model, rather than a membrane protein carrier, is that: (1) there was a linear relationship between the initial rate of acid flux and the concentration of AA (2-100 microM), (2) acidosis was not inhibited by 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid, a potent inhibitor of the plasma membrane FA carrier protein, and (3) the involvement of most known H+-related membrane carriers and H+ conductance has been ruled out. 5. Since AA can be released under both physiological and pathophysiological conditions, the possible significance of the AA-evoked increases in H+ and Ca2+ in both the cytoplasm and nucleoplasm is discussed.
1. In McArdle's disease, muscle glycogenolysis is blocked, which results in absent lactate and enhanced ammonia production in working muscle. Using McArdle patients as an experimental model, we studied whether lactate and ammonia could be mediators of the exercise pressor reflex. 2. Changes in muscle interstitial ammonia and lactate were compared with changes in blood pressure and muscle sympathetic nerve activity (MSNA) during static arm flexor exercise at 30% of maximal contraction force. Muscle interstitial changes in lactate and ammonia were assessed by microdialysis of the biceps muscle, and MSNA by peroneal nerve microneurography, in six McArdle patients and 11 healthy, matched controls. One McArdle patient also had myoadenylate deaminase deficiency, a condition associated with abolished ammonia production in exercise. 3. Exercise-induced increases were higher in McArdle patients vs. controls for MSNA (change of 164 +/- 71 vs. 59 +/- 19%) and blood pressure (change of 47 +/- 7 vs. 38 +/- 4 mmHg). Interstitial lactate increased in controls (peak change 1.3 +/- 0.2 mmol x l(-1)) and decreased in McArdle patients (peak change -0.5 +/- 0.1 mmol x l(-1)) during and after exercise. Interstitial ammonia did not change during exercise in either group, but was higher post-exercise in McArdle patients, except in the patient with myoadenylate deaminase deficiency who had a flat ammonia response. This patient had an increase in MSNA and blood pressure comparable to other patients. MSNA and blood pressure responses were maintained during post-exercise ischaemia in both groups, indicating that sympathetic activation was caused, at least partly, by a metaboreflex. 4. In conclusion, changes in muscle interstitial lactate and ammonia concentrations during and after exercise are temporally dissociated from changes in MSNA and blood pressure in both patients with McArdle's disease and healthy control subjects. This suggests that muscle acidification and changes in interstitial ammonia concentration are not mediators of sympathetic activation during exercise.