利尿薬と生体膜

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Physiological studies on diuretics have revealed that the main action site of diuretics is the tubular membrane. However, more detailed mechanism on molecular basis still remains obscure. We have first tried to obtain the electronic state of loop diuretics (ethacrynic acid and furosemide) and thiazide diuretics. The result was further examined from the aspect of the tubular membrane and mitochondrial membrane of the kidney. The electronic state of these diuretics was calculated by simple Mickel Molecular Orbital Method. The result showed that these diuretics have an electron accepting nature. This specific nature of ethacrynic acid and furosernide could be related to our biochemical experimental result which these diuretics inhibited the electron transport system in mitochondria of rat kidney. This reduction of energy production might explain the inhibition of tubular sodium reabsorption by loop diuretics. Other possibility might be some electrostatic or charge transfer interaction between these diuretics and the action site of the tubular membrane.<BR>On the other hand, thiazide diuretics has not any effect on mitochondrial respiration. A more advanced molecular orbital calculation (CNDO/2) and structure activity relation analysis by Hansch and Fujita on thiazide diuretics and their analogues showed that formal charges of the 3rd, 4th, 5th and 6th carbons of thiazide ring and hydrophobic index of the atom or group introduced to the 4th carbon atom were mainly related to diuretic activity. We assumed a receptor model for thiazide diuretics probably located in the urinary surface of tubular membrane consisted of a hydrophobic center and the four electrostatically reactive carbon atoms.
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利尿薬と生体膜

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