Calcitonin Induced Oxidative Shift of Oxidation-Reduction State of Pyridine Nucleotide in Tubular Cells in Rat Kidney in situ

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Calcitonin, a calcium hormone which is considered to lower serum calcium and phosphate due to its inhibitory action on bone resorption, has also been shown by our hands to develop an action on the kidney that leads to alterations in efficiency of uriary excretion of calcium. Therefore, this hormone is considered to affect calcium fluxes at the plasma membrane of tubular cells either by changing its permeability or by changing the function of the Ca++ pump. In either case, alteration in the Ca++ concentration should take place in these cells. And, if Ca++ in the cell exerts a strong influence upon the regulation of metabolic processes, calcitonin is expected to develop considerable metabolic effects. In an attempt to make these points clear, we examined, in the rat kidney in situ, the effects of salmon calcitonin on the oxidation-reduction state of pyridine nucleotide and on the energy charge of adenine nucleotide. The effects were then compared with those of reagents that alter the Ca++ levels in these cells. Male rats of Sprague-Dawley strain were used after an overnight fast and ad lib intake of water. The oxidation-reduction state of pyridine nucleotide was directly and continuously recorded with an organ-microfluorometer. By this means, metabolic responses of superficial cells (proximal and distal convoluted tubulus) in the kidney in situ were detected. Energy charge was calculated from the concentration of adenine nucleotides (AMP, ADP and ATP) as determined by an enzymatic method. Calcitonin, extracted from salmon ultimobranchial body by the method of Copp, was used. All reagents were administered intravenously. Calcitonin injection resulted in an oxidative shift of pyridine nucleotide which commenced immediately and lasted for a considerable period of time. The response showed a dose-response relationship in the dose range of 0.01 to 2 MRC units. This oxidative response was accompanied by a significant increase in the energy charge. These effects were reproduced by intravenous EGTA which lowers Ca++ both in the extracellular fluid (ECF) and in the intracellular fluid (ICF), but not by parathyroidhormone which, in its early phase of action, lowers Ca++ in the ECF and elevates Ca++ in the ICF, nor by intravenous CaCl2 that elevates Ca++ in both compartments. It is suggested therefore that the calcitonin effects reflects a metabolic consequence of the f a11 of Ca++ in the ICF. The rats pretreated with the maximum doses of calcitonin (more than 2 MRC units) did not exhibit the oxidative response to pentachlorophenol, an uncoupler which selectively oxidizes mitochondrial pyridine nucleotide. They developed an oxidative response, however, to pyruvate which oxidizes NADH in the cytosol compartment. In parathyroidectmized rats, though calcitonin failed to produce the oxid-ative shift, the response became demonstrable by a prior administration of succinate which is supposed to reduce mitochondrial NAD. These results led us to conclude that the fraction of pyridine nucleotide which responds to calcitonin consists mainly of NADH of mitochondrial compartment. In mitochondria, because of "monopoly of the succinate route", succinoxidase activity must be suppressed when NADH is actively oxidized. Therefore, we propose such sequence of events as that the calcitonin-induced fall of Ca++ in cytosol of tubular cells causes suppression of succinate dehydrogenase (and therefore succinoxidase), which leads to an increase in NADH oxidation with the resultant augmentation of ATP synthesis.
Japan Society of Clinical Chemistryの論文

Calcitonin Induced Oxidative Shift of Oxidation-Reduction State of Pyridine Nucleotide in Tubular Cells in Rat Kidney in situ

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