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Pathologic effects of chronic administration of hydrochlorothiazide, with and without sodium nitrite, to F344 rats.

Lijinsky W, Reuber MD.

LBI-Basic Research Program, NCI-Frederick Cancer Research Facility, MD 21701.

The diuretic drug hydrochlorothiazide was administered to 24 male and 24 female F344 rats as a mixture of 0.1% in powdered food. A parallel group of the same size was given 0.1% hydrochlorothiazide plus 0.2% sodium nitrite in the food. A third group received 0.2% sodium nitrite in the food and there was a similar group of untreated controls. The treatments were well tolerated and there was no significant life shortening. A majority of the rats given hydrochlorothiazide, with or without nitrite, developed chronic progressive nephropathy, which was more severe in males than in females. Associated with this were diffuse parathyroid hyperplasia in both groups receiving the drug, also more severe in males than in females, and parallel increases in lesions of the blood vessels (mural thrombosis of the heart and polyarteritis). The few adenomas of the parathyroid and tubular cell adenomas of the kidney in rats ingesting hydrochlorothiazide were not statistically significant.

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The effect of chronic hydrochlorothiazide administration on renal function in the rat.

Walter SJ, Shirley DG.

Hydrochlorothiazide was administered at two doses to Long-Evans rats for 7-10 days. Both doses resulted in an initial natriuresis and diuresis. After 1 day of treatment the natriuresis abated, but the diuresis persisted. The mechanisms responsible for these chronic effects were investigated by performing clearance and micropuncture studies on all animals; collections were made from late proximal tubules and from early and late regions of distal tubules. Values for total glomerular filtration rate and single-nephron filtration rate in thiazide-treated rats were not significantly different from those in control animals. The delivery of sodium to the end of the proximal convoluted tubule was considerably reduced in each group of thiazide-treated rats. Although sodium delivery to the early distal tubule was also significantly lower than in control animals, the difference had disappeared by the late distal tubule. It is concluded that the return of sodium excretion to control levels during chronic hydrochlorothiazide administration is a consequence of increased fractional reabsorption by the proximal tubules, secondary to a thiazide-induced sodium depletion. This results in less sodium being delivered to the nephron site at which thiazides exert their major inhibitory effect. Fluid delivery to the end of the proximal convoluted tubule and to the early distal tubule was significantly reduced in thiazide-treated rats; in animals given the higher dose of diuretic it was also significantly reduced at the end of the distal tubule. Nevertheless, in both thiazide-treated groups urine flow rate was elevated, suggesting that reabsorption of water from the collecting ducts is reduced during chronic thiazide administration.

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Thiazide treatment of hypertension. Effects of thiazide diuretics on serum potassium, magnesium, and ventricular ectopy.

Hollifield JW.

Thiazide diuretics are considered to be the cornerstone of contemporary antihypertensive therapy and are generally recommended as the initial treatment for patients with mild to moderate, uncomplicated hypertension. Hypokalemia and hypomagnesemia are two metabolic alterations that are associated with long-term thiazide therapy. Thirty-five patients (20 with low renin status and 15 with normal renin status) with mild to moderate essential hypertension were treated with hydrochlorothiazide in a dose-titration experiment after a four-week lead-in period. The initial daily dose was 12.5 mg; this was increased at four-week intervals to 25 mg, 37.5 mg, and 50 mg daily. The endpoint dose of this titration was that dose at which the patient's blood pressure normalized, or the dose of 50 mg, if that dose was reached. Patients were maintained on their endpoint dose of hydrochlorothiazide for 24 weeks of continuous thiazide monotherapy beyond the dose titration. The serum potassium and serum magnesium levels during the control period were 4.4 +/- 0.2 mmol/liter and 2.30 +/- 0.08 mg/dl, respectively. During dose titration, each incremental increase of hydrochlorothiazide produced a decrease in blood pressure and a stepwise decrease in serum potassium and magnesium levels. A previously reported study involving 38 patients with mild to moderate hypertension (22 with low renin status and 16 with normal renin status) used similar methods to study higher-dose thiazide therapy. An initial dose of 50 mg daily of hydrochlorothiazide was administered; this was increased at four-week intervals to 100 mg, 150 mg, and 200 mg. The serum potassium and serum magnesium levels during the control period were 4.5 +/- 0.2 mmol/liter and 2.1 +/- 0.18 mg/dl, respectively. In the hypertensive patients with normal renin status, doses of hydrochlorothiazide greater than 50 mg did not result in further blood pressure lowering effects; however, the undesirable effects of hypokalemia and hypomagnesemia continued to be manifested and increased at higher doses of hydrochlorothiazide. Thirty-eight patients who had previously experienced hypokalemia, palpitations, or cardiac arrhythmia were placed on hydroclorothiazide therapy for one to three months and were monitored for arrhythmias after treadmill exercise. The occurrence of premature ventricular contractions correlated significantly with the decrease in serum potassium (r = 0.73, p less than 0.001) and serum magnesium (r = 0.68, p less than 0.001) levels during hydrochlorothiazide therapy and with the product of the change of the two cations (r = 0.81, p less than 0.001).

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Outpatient conversion of treatment to potassium-sparing diuretics.

Ridgeway NA, Ginn DR, Alley K.

Thiazide diuretics frequently cause a decrease in serum potassium levels. In this study, 34 percent of patients taking hydrochlorothiazide had serum potassium levels below 3.5 meq/liter. The response of the serum potassium level was studied after treatment in 56 patients was switched from 50 mg of hydrochlorothiazide daily to either two capsules of hydrochlorothiazide/triampterene (Dyazide), or one tablet of hydrochlorothiazide/amiloride (Moduretic) daily, over nine to 15 months. The 24 patients whose treatment was changed to Dyazide had a rise in serum potassium levels from a mean of 3.56 meq/liter to 4.17 meq/liter in two to three weeks. The 32 patients whose treatment was changed to Moduretic had a rise in serum potassium levels from a mean of 3.76 meq/liter to 4.14 meq/liter in two to three weeks. The resultant rise in potassium levels was stable throughout the follow-up period in both groups. Patient acceptance of this change was excellent.

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[Combined effect of (2R, 4R)-2-(o-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarbo xyl ic acid (SA446) with hydrochlorothiazide or propranolol on development of hypertension in spontaneously hypertensive rats (SHR) by long-term administration]

[Article in Japanese]

Takada T, Nakata K, Yamauchi H, Iso T.

Effect of long-term oral administration of the converting enzyme inhibitor (2R, 4R)-2-(o-hydroxyphenyl)-3-(mercaptopropionyl)-4-thiazolidinecarboxylic acid (SA446) in combination with hydrochlorothiazide or propranolol on the development of hypertension was examined in spontaneously hypertensive rats (SHR). The development of hypertension in SHR was markedly suppressed by the treatment with SA446 (45 mg/kg, p.o.) for 17 weeks from 8 weeks of age, the pre-stage of hypertension. Long-term administration of hydrochlorothiazide (20 mg/kg, p.o.) also showed an obvious antihypertensive effect, but the effect was less potent than that of SA446. On the other hand, propranolol (20 mg/kg, p.o.) showed a slight or little antihypertensive effect. The combined administration of hydrochlorothiazide and SA446 produced a more potent antihypertensive effect than the administration of SA446 alone. On the other hand, the combined use of propranolol had no influence on the antihypertensive effect of SA446 by long-term administration in SHR. Plasma renin activities measured after 17 weeks treatment of the drugs indicated that the renin-angiotensin system was activated by hydrochlorothiazide. These results suggest that the antihypertensive effect of long-term administration of SA446 in SHR is enhanced by the combined administration of diuretics such as hydrochlorothiazide, which activates the renin-angiotensin system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3710315&dopt=Abstract hydrochlorothiazide Microzide