Manuel M A, Weiner M W
Biochim Biophys Acta. 1977 Jun 9;460(3):445-54. doi: 10.1016/0005-2728(77)90083-4.
Previous reports that ethacrynic acid and furosemide diminish mitochondrial P : O ratios and reduce (Na+ + K+)-ATPase activity suggested that these diuretics may inhibit mitochondrial phosphorylation reactions. This possibility was initially studied by determining the effects of ethacrynic acid and furosemide on [32P]ATP exchange activity of rat kidney mitochondria. Concentrations of both drugs at 10(-4) M or greater, significantly inhibited [32P]ATP exchange. To investigate the mechanism of this inhibition, the effects of ethacrynic acid and furosemide on the ATPase activity of intract mitochondria and sonicated submitochondrial particles were determined. Both diuretics inhibited ATPase activity of intact mitochondria at 10(-4) M. In contrast, ATPase of submitochondrial particles was significantly less susceptible to inhibition by the diuretics. These results suggested that ethacrynic acid anf furosemide inhibit adenine nucleotide transport across the mitochondrial membrane. This was directly tested by determining the effects of the diretics on the mitochondrial adenine nucleotide translocase. At 5-10(-4) M, both ethacrynic acid and furosemide significantly inhibited adenine nucleotide transport. These findings suggest that ethacrynic acid and furosemide may diminish renal tubular solute reabsorption by direct inhibition of adenine nucleotide transport across the mitochondrial inner membrane.
先前的报告指出，依他尼酸和呋塞米会降低线粒体的磷氧比并降低（钠+钾）-ATP酶活性，这表明这些利尿剂可能会抑制线粒体的磷酸化反应。最初通过测定依他尼酸和呋塞米对大鼠肾线粒体[32P]ATP交换活性的影响来研究这种可能性。两种药物浓度在10（-4）M或更高时，均显著抑制[32P]ATP交换。为了研究这种抑制作用的机制，测定了依他尼酸和呋塞米对完整线粒体和超声破碎的亚线粒体颗粒ATP酶活性的影响。两种利尿剂在10（-4）M时均抑制完整线粒体的ATP酶活性。相比之下，亚线粒体颗粒的ATP酶对利尿剂抑制的敏感性明显较低。这些结果表明，依他尼酸和呋塞米抑制腺嘌呤核苷酸在线粒体内膜上的转运。通过测定利尿剂对线粒体腺嘌呤核苷酸转位酶的影响直接对此进行了测试。在5-10（-4）M时，依他尼酸和呋塞米均显著抑制腺嘌呤核苷酸转运。这些发现表明，依他尼酸和呋塞米可能通过直接抑制腺嘌呤核苷酸在线粒体内膜上的转运来减少肾小管溶质重吸收。
