New study sheds light on the responses to diuretics

February 12, 2003

Bethesda, MD - The recent news from the National Heart, Lung and Blood Institute that diuretics are superior to newer drugs in lowering high blood pressure and preventing fatal complications was more than welcome for a public weary and cash strapped from purchasing expensive drugs. Diuretics were once the primary treatment for hypertension, which affects about one in four adults. But their use declined in recent years as newer, costlier drugs were introduced.

There are three types of diuretic medicines. All work to lower the amount of salt and water in the body, which assists in lowering blood pressure. Thiazide diuretics are the only type of diuretic that dilate (widen) the blood vessels, which also helps to lower blood pressure; potassium-sparing diuretics reduce the amount of water in the body but, unlike the other diuretics, preserve the body's potassium; and loop-acting diuretics, which cause the kidneys to increase the flow of urine, thereby reducing the amount of water in the body and thus lowering blood pressure. All are available by prescription.

This is the good news.

Unfortunately, as patients return to diuretics, many will find the presence of "diuretic resistance," explained in part by increased sodium absorption in downstream renal (kidney) tubule segments related to increased sodium delivery. Furosemide and hydrochlorothiazide (HCTZ) are diuretics commonly used in clinical practice. Furosemide exerts its diuretic action by binding to the Na-K-2Cl cotransporter in the thick ascending limb and blocking ion transport. HCTZ exerts its diuretic action by binding to the Na-Cl cotransporter in the distal convoluted tubule. Increased sodium delivery to the distal nephron may result in enhanced sodium absorption downstream of the distal site of diuretic action.

Recent research on the cause of disorders of water and electrolyte balance suggests that long-term adaptive mechanisms may be important in these disorders and may involve altered expression of transporter proteins such as aquaporin water channels and sodium transporters. Therefore, it appears possible that diuretic resistance produced by long-term diuretic administration is in part due to adaptive increases in the abundance of sodium transporters in the distal nephron and collecting ducts.

A joint effort by Korean and American researchers sought to explain the molecular basis of the adaptive mechanisms in long-term use of diuretics. They believed that a secondary increase in distal delivery of sodium may induce compensatory changes in the abundance of sodium transporters downstream from the primary site of the diuretic action. To test their hypothesis, they administered either furosemide or HCTZ for seven days to rats, and investigated the effects on the expression of sodium transporter proteins by using semiquantitative immunoblotting and immunohistochemical testing on tissue from rat kidneys.

The Study
The authors of "Upregulation of Na+ Transporter Abundances in Response to Chronic Thiazide or Loop Diuretic Treatment in Rats," are Ki Young Na, Kwon Wook Joo, Jung Sang Lee, and Jin Suk Han, Department of Internal Medicine, Seoul National University, Clinical Research Institute of Seoul National University Hospital, Seoul, South Korea; Yoon Kyu Oh, Department of Internal Medicine, Eulji Medical College, Seoul, South Korea; Jae-Ho Earm, Department of Internal Medicine, Chungbuk National University, Cheongju, South Korea; Mark A. Knepper, Laboratory of Kidney and Electrolyte Metabolism, National Institutes of Health, Bethesda, MD; and Gheun-Ho Kim, Department of Internal Medicine, Hallym University Hangang Sacred Heart Hospital, Seoul, South Korea. Their findings appear in the January 2003 edition of the American Journal of Physiology--Renal Physiology. The publication is one of 14 journals published each month by the American Physiological Society (APS).

Methodology
Male Sprague-Dawley rats weighing 170-230 g were placed in metabolism cages three days prior to the beginning of the study. Control and treated rats were designated randomly, and all were provided with a daily, fixed amount of finely ground regular rat chow (18 g/ 200 g body weight/day) and two separate bottles of drinking water, one containing 0.8 percent NaCl and 0.1 percent KCl, and the other containing tap water. All the rats ate all of the offered rat chow and showed a steady increase in body weight throughout the study period.

Rats were anesthetized, implanted with osmotic minipumps, and provided 12 mg/day of furosemide. Furosemide was dissolved in a 1.7 percent ethanolamine solution. Control rats were implanted with minipumps containing vehicle (ethanolamine) alone. The laboratory animals also received either 3.75 mg/day of HCTZ or vehicle for seven days. During the course of the studies, daily urine was collected to evaluate responses to the diuretics. Semiquantitative immunoblotting and immunohistochemical testing of tissue from rat kidneys were then conducted.

Results
These data provide important new information relevant to clinical use of these diuretics and address an important physiological issue: What is the effect of increased distal fluid delivery on transporter abundances?

The main results showed that the sodium channel expressed in connecting tubule and collecting duct, ENaC, increased its abundance in response to chronic infusion of either diuretic, consistent with previous research studies showing increased sodium absorption in these segments. In addition, furosemide induced an increased abundance of NKCC2 (Na-K-2Cl cotransporter), while HCTZ induced an increased abundance of NCC (thiazide-sensitive Na-Cl cotransporter). The important clinical implication of this study is that the diuretic tolerance associated with long-term diuretic use may be caused by increases in the abundance of distal Na+ transporters.

Conclusions
Hypertension is a leading killer in the United States. This study examines the physiological processes that determine the body's tolerance to long-term use of diuretics. These findings may lead to an increased number of number of hypertensive patients who can use this more effective and less expensive drug - a positive step for public health.
-end-
Source: January 2003 edition of the American Journal of Physiology--Renal Physiology, one of 14 scientific journals published each month by the American Physiological Society (APS).

The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.

American Physiological Society

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