Enalapril protect human lymphocytes from genotoxicity of Hydrochlorothiazide.

Hydrochlorothiazide (HCTZ) belongs to the thiazide diuretics family that is used for the treatment of hypertension. Enalapril is another drug that is used for the treatment of hypertension. Recently, both drugs were combined in a single medication called vaseretic that showed a strong synergistic effect against hypertension. The aim of this investigation is to examine genotoxicity of HCTZ/enalapril on chromosomal damage by measuring the frequency of sister-chromatid exchanges (SCEs) in cultured human lymphocytes. Findings showed that HCTZ (5µg/mL) significantly increased SCEs frequency (P<0.01) in cultured cells relative to the untreated cells. The levels of SCEs induced by Enalapril (10µg/mL) was similar to the level detected in the untreated cultures (P>0.05). Interestingly, SCEs induced by combined treatment were significantly lower than HCTZ alone (P<0.05). Thus, enalapril seems to protect lymphocytes from genotoxicity induced by HCTZ. Neither HCTZ nor enalapril treatment (alone or in combination) induced changes in the mitotic index and the proliferative index (P>0.05). In conclusion, HCTZ increased SCEs in cultured lymphocytes, and this increase is reduced by enalapril.

[The phenomenon of resistance to a thiazide diuretic in acute kidney failure]. / Izuchenie fenomena rezistentnosti k tiazidovomu diuretiku pri ostroi pochechnoi nedostatochnosti.

The resistance to hypothiazid (hydrochlorothiazide) during the development of acute renal insufficiency (ARI) induced by glycerin injection was studied in rat experiments. Natriuretic, kaliuretic, and hydrouretic activity of the diuretic decreased two days after injection of a glycerin solution. In this period hypothiazid excretion with the urine was least. Ten days later, despite the restoration of the water- and electrolyte-excretion function of the kidneys and normalization of hypothiazid excretion with the urine, the natriuretic effect of the drug was still very poor. This is indirect evidence of the long-term affection of the receptors for the thiazid diuretics during the development of ARI. The affection remains even after the excretory function of the kidneys is restored. The high correlation between the cumulative excretion of hypothiazid with the urine and natriuresis encountered in intact animals was weaker in rats with acute renal insufficiency.

The impact of ibuprofen on the efficacy of antihypertensive treatment with hydrochlorothiazide in elderly persons.

BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) may alter blood pressure through their inhibitory effects on prostaglandin biosynthesis. Such potential hypertensive effects of NSAIDs have not been adequately examined in the elderly, who are the largest group of NSAID users. METHODS: We performed a randomized, double-blind, two-period crossover trial of ibuprofen (1800 mg per day) vs placebo treatment in patients older than 60 years of age with hypertension controlled with hydrochlorothiazide. While continuing their usual thiazide dosage, subjects were randomized to a 4-week treatment period (ibuprofen or placebo) followed by a 2-week placebo wash-out period and a second 4-week treatment period with the alternative therapy. Supine and standing systolic and diastolic blood pressures were measured weekly. RESULTS: Of 25 randomized subjects, 22 completed the study protocol (mean age = 73 +/- 6.7 years). Supine systolic blood pressure and standing systolic blood pressure were increased significantly with ibuprofen treatment, compared with placebo. Mean supine systolic blood pressures were 143.8 +/- 21.0 and 139.6 +/- 15.9 mmHg on ibuprofen and placebo, respectively (p = .004). Mean standing systolic blood pressures were 148.1 +/- 19.9 and 143.4 +/- 17.9 mmHg on ibuprofen and placebo, respectively (p = .002). CONCLUSION: We conclude that 1800 mg per day of ibuprofen does induce a significant increase in systolic blood pressure in older hypertensive patients treated with hydrochlorothiazide. NSAID therapy may negatively impact the control of hypertension in elderly patients.

[Comparative study of potassium-sparing effects of triamterene and amiloride in the treatment with hydrochlorothiazide]. / Sravnitel'noe izuchenie kaliisberegaiushchego éffekta triamterena i amilorida pri lechenii gidrokhlortiazidom.

Hydrochlorothiazide (HCT), 25 or 50 mg a day, alone and in combination with triamterene (T), 50 and 100 mg, respectively, or amiloride (A), 2.5 and 5 mg, respectively, was examined for effects on daily urinary potassium and sodium excretion. Daily sodium excretion was increased 1.5-2-fold with a double dose of the combined drugs as compared with their single dose. T and A produced additive effects on the natriuretic action of HCT. Lower doses of HCT and T failed to prevent urinary potassium loss, but their potassium-sparing effect was shown with their double dose. This effect was largely displayed by A given in a single or double dose. Lower serum potassium levels were seen with all the drugs, but this was less marked with HCT combined with T or A than with HCT monotherapy. Their double dose reduced serum potassium levels to an insignificantly greater extent. In some cases, the elderly patients developed hyperkalemia during the combined therapy. Thus, with the routine dose ratios, A showed a slightly higher potassium-sparing effect than did T. Some patients taking HCT in combination with T showed reddish-brown crystals and casts in the urinary sediment, which may indicate its tubular interstitial damaging action. Consequently, use of the combined drugs is more preferable than HCT monotherapy, and HCT in combination with A is likely to be more preferable than that with T.

The effect of high-dose short-term ibuprofen on antihypertensive control with hydrochlorothiazide.

The effect of high-dose ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), on the blood pressure of treated hypertensive patients was evaluated in a randomized, placebo-controlled, double-blind, crossover trial with 24-hour ambulatory blood pressure monitoring. Twelve middle-aged black women with essential hypertension, controlled with 50 mg hydrochlorothiazide per day, randomly received 3200 mg ibuprofen and a placebo for 8 days. Each treatment phase was separated by a 1-week washout period. Ambulatory blood pressure monitoring (ABPM), body weight, and 24-hour urinary excretion of sodium, creatinine, and prostaglandin E2 (PGE2) were determined at the end of each treatment phase. Mean (+/- SEM) 24-hour systolic and diastolic blood pressures were 122/85 (+/- 2.9/1.7) and 125/85 (+/- 3.0/1.1) during the placebo and ibuprofen phases, respectively. Mean ABPM during six consecutive 4-hour periods also revealed no significant differences between placebo and ibuprofen. We conclude that 3200 mg ibuprofen per day for up to 1 week induced little change in blood pressure in hypertensive who are receiving hydrochlorothiazide.

Binding of hydrochlorothiazide to erythrocytes.

Hydrochlorothiazide (HCT) was administered orally to healthy volunteers and intravenously to rabbits. HCT concentrations in plasma (Cp) and erythrocytes (Ce) were determined by a high-performance liquid chromatographic method. Ce was about 9-fold that of Cp 24 h after the administration to volunteers, and 8-fold 6 h after the administration to rabbits. From the results of the in vitro binding study which was done with rabbit erythrocytes, at least the presence of three kinds of binding site for HCT was expected. The first binding site was characterized by extremely high affinity and very low capacity, and was unaffected by acetazolamide, known as a carbonic anhydrase inhibitor. The second one was characterized by medium affinity and medium capacity, and disappeared under the presence of acetazolamide and may be due to the carbonic anhydrase of erythrocytes. The third one was characterized by low affinity, but its binding capacity was extremely high and apparently unsaturable in the HCT concentration range studied (0.5-100 micrograms/ml = 1.68-336 microM). The binding of HCT to erythrocytes seems to be dominated by the second binding site in the therapeutic range (under 1 microgram/ml of plasma).

Effect of calcium-entry blockers on the diuretic response to hydrochlorothiazide in the rat.

The influence of the calcium-entry blockers, verapamil, nifedipine and diltiazem on hydrochlorothiazide-induced diuresis was determined in hydrated conscious rats. Nifedipine significantly inhibited hydrochlorothiazide-induced 5-h excreted urine volume and urinary sodium with little effect on potassium excretion. Both verapamil and diltiazem significantly enhanced urinary sodium excretion with no effect on either urine volume or potassium excretion. These results are of interest in view of the current use of nifedipine as an anti-hypertensive agent, alone or in combination with a thiazide diuretic.

Effect of calcium-entry blockers on the diurectic response to hydrochlorothiazide in the rat

The influence of the calcium-entry blockers, verapamil, nifedipine and diltiazem on hydrochlorothiazide-induced diuresis was determined in hydrated conscious rats. Nifedipine significantly inhibited hydrochlorothiazide-induced 5-h excreted urine volume and urinary sodium with little effect on potassium excretion. Both verapamil and diltiazem significantly enhanced sodium excretion with no effects on either urine colume or potassium excretion. These results are of interest in view of the current use of nifedipine as an anti-hypertensive agent, alone or in combination with a thiazide diuretic

Potassium-sparing effect of trilostane in hydrochlorothiazide-treated rats and dogs.

Trilostane, which inhibits three beta-hydroxysteroid dehydrogenase and aldosterone synthesis in rats and monkeys, significantly attenuated the oral potassium-wasting effect of hydrochlorothiazide (HCTZ) in rats and dogs when coadministered with the diuretic. The steroid reduced the kaliuretic and enhanced the natriuretic (and hyperreninemic) activity of HCTZ in rats, thereby promoting the urinary sodium/potassium ratio. Trilostane completely prevented HCTZ-induced hypokalemia in dogs and tended to reduce the degree of secondary aldosteronism. The combination also promoted hematocrit of dogs by 8% and decreased serum Na+ concentration by 7 meq/liter. When administered alone, trilostane increased canine serum potassium levels slightly and promoted rat urinary Na+/K+ ratio. Results confirm previous reports of antikaliuretic activity of trilostane in diuretic-treated rats. Further, the data indicate that frank hypokalemia induced in dogs by hydrochlorothiazide can be prevented by adjunctive trilostane therapy without eliciting hyperkalemia.

Potassium bicarbonate supplementation blocks the hypocalciuric response to hydrochlorothiazide in rats.

Bicarbonate salts and thiazide diuretics each lower urinary calcium excretion. This study was undertaken to compare the effects of administering oral sodium or potassium bicarbonate supplements (4.5 mmol./day of each salt) each with or without hydrochlorothiazide (10 mg./kg. body weight/day) on urinary calcium excretion in rats. Urinary calcium decreased (p less than 0.01) by about 50 per cent after sodium bicarbonate supplementation and potassium bicarbonate supplementation. The hypocalciuric response to each bicarbonate salt was similar. However, although hydrochlorothiazide depressed urinary calcium in rats consuming sodium bicarbonate, rats receiving equimolar supplements of potassium bicarbonate did not lower urinary calcium when given hydrochlorothiazide, despite evidence of the expected thiazide-mediated diuresis. It is concluded that in the rat potassium bicarbonate loading blocks the ability of hydrochlorothiazide to lower urinary calcium excretion.

Reversal of diuretic-induced secondary hyperaldosteronism and hypokalemia by enalapril (MK-421): a new angiotensin-converting enzyme inhibitor.

The study reported here prospectively evaluated the prevention of diuretic-induced secondary hyperaldosteronism and hypokalemia by a converting enzyme inhibitor, enalapril (MK 421). Eighteen normal subjects were randomized into three groups: (1) a HCTZ group (hydrochlorothiazide (HCTZ) 50 mg/day); (2) a MK-421 group (MK-421 10 mg/day); and (3) a HCTZ + MK-421 group [HCTZ 50 mg/day plus MK-421 10 mg/day]. Following a five-day control and a 28-day treatment period, the HCTZ group demonstrated an attenuated but persistent secondary hyperaldosteronism and hypokalemia, the MK-421 group manifested a gradual decline in aldosterone secretion, and the HCTZ + MK-421 group had a delayed but effective correction of secondary hyperaldosteronism and hypokalemia at 28 days but not before. In conclusion, MK-421 reversed diuretic-induced secondary hyperaldosteronism and hypokalemia after 28 days of hydrochlorothiazide therapy. Therefore, converting enzyme inhibitors, such as enalapril, provide useful adjunctive therapy in diuretic-treated patients, but potassium supplementation may be required before the start of four weeks of combined therapy.

Effects of nonsteroidal anti-inflammatory drugs (NSAID) on renal excretion of sodium and water, and on body fluid volume in rats.

Effects of nonsteroidal anti-inflammatory drugs (NSAID) on urine volume and urinary sodium excretion, and on plasma volume and extracellular fluid volume were examined in conscious rats. The basal urine volume and urinary sodium excretion were decreased and the increased urine volume and urinary sodium excretion elicited by saline load (25 ml/kg) and by hydrochlorothiazide (10 mg/kg) were inhibited after oral administration of NSAID in doses which inhibited the rat carrageenin-induced hind paw edema (indomethacin, 1--10 mg/kg; tolmetin, 3--30 mg/kg; phenylbutazone, 3--30 mg/kg; aspirin, 30--300 mg/kg), but aminopyrine (30--300 mg/kg) did not show such an effect. The inhibitory activity on renal function was diminished gradually with repeated administration of NSAID. NSAID (indomethacin, 3 mg/kg; tolmetin, 10 mg/kg; phenoxybenzamin, 10 mg/kg; aspirin, 100 mg/kg) increased plasma volume and extracellular fluid volume of rats after repeated medication for 3 or 5 days, but the body fluid volume expansion disappeared with further repeated administration of NSAID. These results suggest that NSAID may inhibit the intrarenal role of prostaglandins and decrease sodium and water excretion in urine with resulting increased body fluid volume. Tolerance to these actions of NSAID developed after repeated administration.

A new method for the production of experimental diabetes in rabbits.

Oral administration of 250 mg hydrochlorothiazide/kg, with previous i.v. injection of 4 i.u. soluble insulin or s.c. injection of protamine-zinc insulin, has been found to produce stable hyperglycaemia in rabbits irrespective of sex. It is thought that insulin helps the selective action of hydrochlorothiazide on the beta cells by removing the protective glucose barrier. Although stimulation of glucagon or some extra-pancreatic mechanism at the initial stage could not be altogether ruled out, the central action of the drug is supported by the finding that the hydrochlorothiazide-induced hyperglycaemia was lowered by the sulphonylurea derivative, chlorpropamide.

The effects of probenecid and thiazides and their combination on the urinary excretion of electrolytes and on acid-base equilibrium.

The effects of commonly used therapeutic doses of hydrochlorothiazide and probenecid, given singly and in combination, on the urinary excretion of monovalent and divalent ions and on acid-base equilibrium were studied in four patients with idiopathic hypercalciuria.Probenecid had no effect on the urinary excretion of monovalent ions but resulted in a sustained increase in the urinary excretion of calcium, magnesium and citrate and a temporary increase in the urinary excretion of ammonium, in addition to its well-known effects on uric acid metabolism. A temporary fall in serum phosphorus levels was also observed.Probenecid also modified the response to hydrochlorothiazide in that the urinary excretion of calcium, magnesium and citrate was greater during combined therapy than when hydrochlorothiazide was administered alone. Probenecid prevented or abolished the increase in serum uric acid levels associated with the use of thiazide but did not modify the effects of hydrochlorothiazide on the urinary excretion of sodium, chloride, potassiu, phosphorus, ammonium, titratable acid and bicarbonate.