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The effect of tenidap on the anti-hypertensive efficacy of thiazide diuretics in patients treated for mild to moderate hypertension.

1. This randomised, placebo-controlled, double-blind, parallel-group study was conducted to assess the effect of tenidap sodium 120 mg, a novel anti-arthritic cytokine modulating drug, on the hypotensive efficacy of the thiazide diuretics hydrochlorothiazide or bendrofluazide. 2. Twenty-three male and female patients, aged 41-78 years, with mild to moderate, uncomplicated, essential hypertension controlled with thiazide diuretic therapy, received either a single daily dose of tenidap sodium 120 mg or matched placebo for 22 days in addition to their diuretic therapy. Changes between baseline and endpoint in supine and standing systolic and diastolic pressures and pulse rate were compared between treatment groups. 3. Daily treatment with tenidap reduced the anti-hypertensive efficacy of the thiazide diuretics. Blood pressure tended to increase marginally and the increase in mean standing diastolic pressure observed with tenidap was significantly greater than the change in the placebo group. All pressures tended to decrease in the placebo group and all endpoint measurements were within 7 mm Hg of baseline in both groups. 4. Treatment-related side effects of mild to moderate severity were reported in two subjects receiving tenidap, but in neither case was treatment discontinued. Two subjects receiving placebo also experienced side effects considered to be treatment-related and both were withdrawn from the study. 5. The results of this study suggest that tenidap may be given to patients treated for mild to moderate essential hypertension controlled with thiazide therapy; however, the patient's blood pressure should be regularly monitored.

Adult↗

Prescribing patterns of diuretics in multi-drug antihypertensive regimens.

Recent literature suggests that most hypertensives will require two or more drugs to achieve target blood pressure. Our objective was to estimate the proportion of patients receiving diuretics, including thiazides, for blood pressure control among those receiving two or more drugs. We studied 25,052 hypertensives in a tertiary care Veterans Affairs facility and identified individuals taking any thiazide or loop diuretic among patients receiving two, three, four, or more drugs. Rates of any diuretic use were 50%, 73%, and 89%, and decreased to 39.0%, 59.0%, and 72.5% for thiazide use, respectively. Rates of thiazide use were statistically significantly higher among African Americans compared with the general study population, but did not differ significantly in the elderly. Though overall diuretic use seems to be increasing as compared with previous studies, there is room for improvement in the use of thiazides in multi-drug hypertension regimens.

Aged↗

The use of isolated fish opercular epithelium as a model tissue for studying intrinsic activities of loop diuretics.

Isolated opercular epithelia of killifish (Fundulus heteroclitus) were mounted in an Ussing chamber. The epithelia displayed a transepithelial electrical potential difference (PD) of 10.6 +/- 0.3 mV (sea-water side negative) and a short-circuit current (SCC) of 72.1 +/- 2.1 microA cm-2. The electrical resistance was 160 +/- 3 omega cm2 (mean +/- SE, n = 269). The unidirectional flux of 36Cl from blood side to sea-water side compared well with the SCC. No net flux of 22Na or 24Na across the epithelium was observed. Raising of cyclic AMP levels by theophylline, 3-isobutyl-I-methyl-xanthine, isoprenaline and forskolin, increased SCC and PD. Prostaglandins PGE2 and to some extent PGF2 alpha inhibited SCC and PD. Inhibition of Na+-K+-ATPase by ouabain and orthovanadate reduced SCC and PD. Pretreatment of the epithelium with the stilbene disulphonic acid (DIDS) did not prevent the action of orthovanadate. Different types of diuretics were tested, but only the loop diuretics bumetanide, piretanide, and furosemide, rapidly and strongly inhibited PD and SCC and unidirectional 36Cl serosal to mucosal flux. Dose-response curves for these agents were parallel and EC50 values for effects on SCC were 40, 52, and 295 microM, respectively. The same relative activities of these diuretics have been seen in the renal thick ascending limb of Henle's loop (TALH). It is concluded that the killifish opercular skin responds to hormonal stimuli and various pharmacological agents in a manner similar to that of mammalian renal TALH. It should therefore be a useful model for studies of the modes of action and the structure-activity relationships of diuretics which act by inhibition of chloride transport or Na+-K+-ATPase activity.

Action Potentials↗

Inhibitory effects of chemically-different 'loop' diuretics on chloride transport across the bullfrog cornea.

Frog (Rana catesbeiana) corneas were mounted in an Ussing chamber, modified to facilitate dissection and to avoid edge damage to the epithelial tissue during mounting and measurements. When bathed in Conway solution of pH 7.4 the corneas displayed highly stable electrical properties, with a transepithelial potential difference (PD) of 16.6 +/- 1.O mV and a short-circuit current (SCC) of 10.3 +/- 0.8 microA cm-2. The DC resistance was 2.0 +/- 0.15 k omega X cm2 (mean +/- SE, n = 45). An increase in the intracellular cyclic AMP level induced by prostaglandin E2 and by 3-isobutyl-1-methylxanthine (IBMX) resulted in an increase in SCC. Ortho-vanadate, an inhibitor of Na+-K+-ATPase, reduced SCC. The acidic loop diuretics furosemide, bumetanide and the levorotatory form of indacrinone (MK-196) reduced SCC by about 50% at concentrations of 500, 100 and 46 microM, respectively. The (-)form of MK-196 was four times more active than the (+)form. Dimethylation of the SO2NH2 group reduced the activity of bumetanide. The basic diuretics muzolimine (Bay G 2821) and MK-447, were found, similarly, to reduce SCC by about 50% at concentrations of 500 microM. In view of their 'high ceiling' type of saluretic effects in whole animals, these basic agents should therefore be classified as 'loop' diuretics. The effects of these structurally highly different 'loop' diuretics are similar in epithelia which secrete (cornea) and in those which absorb (the renal thick ascending limb of Henle's loop; TALH) chloride ions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Acute blood pressure and urinary responses to single dose combinations of captopril and diuretics in conscious spontaneously hypertensive rats.

The present studies involved oral administration of captopril alone or in combination with individual diuretics in conscious, freely-moving spontaneously hypertensive rats (SHR). Both blood pressure (BP) and urinary fluid and electrolyte excretion were concomitantly measured. Captopril, 10 mg kg-1, caused a decrease in BP (-18 +/- 3 mm Hg) which was not significantly different from control (-10 +/- 2 mm Hg). Diuretics alone also failed to alter BP. However the BP-lowering effect of captopril was readily potentiated by concomitant administration of a single oral dose of frusemide (10 and 30 mg kg-1) in proportion to the magnitude of urinary loss. Hydrochlorothiazide at 1 and 3 mg kg-1 oral and metolazone at 0.3 and 1 mg kg-1 oral induced fluid loss similar to frusemide at 10 mg kg-1 and all produced comparable BP reduction in combination with captopril (25-32 mm Hg). Triamterene did not increase fluid excretion and was ineffective. In SHR with bilateral ureteral ligation, the synergistic effect of frusemide was abolished while that of hydrochlorothiazide still occurred with a delayed onset. It is concluded that concomitant measurement of BP and urinary excretion in conscious, freely-moving SHR is a useful technique for studying new antihypertensive drugs. Using this preparation it was found that enhancement of the acute hypotensive response to captopril with concomitant diuretic therapy occurs within 10 min and is primarily related to the fluid and Na loss, regardless of the diuretic agent used.

Animals↗

Influence of loop diuretics and anions on passive potassium influx into human red cells.

Passive K influx into human red cells was measured with and without Cl ions, Na ions and loop diuretics. Ouabain and loop diuretics appear to inhibit specifically and respectively the Na pump and (Na+K) 'co-transport'. Inhibitors of other pathways, e.g. 4,4'-diisothiocyantostilbene-2,2'-disulphonic acid or amiloride did not inhibit passive K influx. Loop diuretics inhibited with high apparent affinity in Na-containing media and with low apparent affinity in Na-free media where there was a substantial Cl-dependent component. The Cl concentration dependence was measured using six anion substitutions for Cl. With NO3, acetate and gluconate, the curves were sigmoidal and not fully saturable at 150 mM-Cl; with iodide and thiocyanate, the curves were convex; with sulphate, there was saturation at 120 mM-Cl. The half-maximal K influx as a function of [Na]0 was 40 mM for the Cl-dependent flux component and 12 mM for the diuretic-sensitive flux.

Anions↗

The effect of loop diuretics on Cl- transport in smooth muscle of the guinea-pig vas deferens and taenia from the caecum.

1. The role of Na+, K+, Cl- co-transport, identified in the previous paper (Aickin & Brading, 1990), has been characterized further by investigation of the effects of loop diuretics on Cl- movements in the smooth muscle cells of guinea-pig vas deferens measured by 36Cl fluxes and Cl(-)-sensitive microelectrodes. Some flux experiments were also repeated in the taenia from the guinea-pig caecum. 2. Frusemide (2 mM) reduced the steady-state Cl- content, slowed 36Cl loss into Cl(-)-free solution and both slowed and reduced Cl- accumulation by Cl(-)-depleted cells of the vas deferens. When anion exchange was inhibited by the presence of DIDS, (4,4'-diisothiocyanostilbene-2,2'-disulphonic acid), frusemide further slowed the loss of Cl- into Cl(-)-free solution, further reduced Cl- accumulation such that Cl- uptake amounted to a level consistent with a passive distribution and halted the rise in the intracellular Cl- activity (aiCl) at levels above about 10 mM. 3. Application of the higher-affinity loop diuretics bumetanide and piretanide in vas deferns had no significant effect on 36Cl efflux into Cl(-)-free solution or on the initial rate of rise of aiCl but reduced the final level attained. In the presence of DIDS, however, both agents further slowed efflux into Cl(-)-free solution, and halted the rise in aiCl at levels above about 10 mM. Measurement of greatly slowed intracellular pH transients on removal and readdition of external Cl- (Clo-) in the presence of frusemide suggests that the larger effects of this drug are mediated by inhibition of anion exchange as well as of co-transport. 4. The relative potency of the loop diuretics, investigated in the presence of DIDS was: bumetanide greater than piretanide greater than frusemide. This sequence was found in both vas deferens, using direct measurement of aiCl, and taenia, using 36Cl uptake. 5. Comparison of data from the vas and taenia showed that 36Cl efflux into Cl(-)-free, HCO3(-)-free solution was about twice as fast in the taenia, and that bumetanide or piretanide reduced this efflux to about the same rate as that observed in the vas with or without the loop diuretic. DIDS caused a similar absolute reduction of efflux in both preparations. 6. Stimulation of 36Cl efflux on readdition, and inhibition on removal of Nao+ in the presence of DIDS, was much greater in the taenia than in vas and in both preparations was blocked by bumetanide or piretanide.(ABSTRACT TRUNCATED AT 400 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

Effects of loop diuretics on the suppression tuning of distortion-product otoacoustic emissions in rabbits.

The suppression tuning of distortion-product otoacoustic emissions (DPOAEs) is commonly assumed to measure frequency selectivity, because the dominant features of suppression-tuning curves (STCs) are similar to the principal properties of the neural-tuning curves (NTCs) of single auditory-nerve fibers. In the present study, several common loop diuretics were used to affect the DPOAE-generation process to determine if reversible ototoxicity could adversely modify the characteristics of STCs, in a manner similar to that shown previously for NTCs. Contour plots of DPOAE level in the presence of a series of variable-level suppressor tones were obtained before and after administering diuretic drugs that reversibly reduced or eliminated DPOAEs. Primary-tone pairs were centered at 2.8 or 4 kHz, with L1 = L2, or L2 < L1. From the resulting plots, STC parameters including tip frequency, threshold at the tip frequency, and Q10 dB measures of tuning were extracted for four suppression criteria of 3, 6, 9, and 12 dB. In the pre-drug nonototoxic state, suppression tuning depended on both primary-tone level (L1, L2), and the relative levels of the primaries (L1-L2), with tuning being sharper for lower- than for higher-level equilevel primaries, and sharpest for offset-level primary tones. Following drug injection, the expected decrease in sharpness of tuning evidenced by changes in Q10 dB as well as the dramatically elevated tip thresholds normally seen for NTCs under similar conditions, were not observed. Overall, Q10 dB increased or decreased more or less randomly, with a slight tendency for STCs to become sharper than prior to drug dosing, for the two highest suppression criteria. The STC-tip frequencies demonstrated significant decreases following diuretic administration that were weakly correlated with the associated decreases in DPOAE amplitude. The most consistent changes in response to the drug-induced reduction in DPOAE level were increases in the STC-tip thresholds. However, these changes were relatively small and rarely exceeded 10 dB. In the absence of notable changes in overall STC shape, a major finding was a change in the effectiveness of suppression following ototoxic insult. However, when the amount of suppression was expressed as a percentage of the DPOAE remaining, the effects of diuretic dosing were often almost completely obscured. Overall, the results demonstrated that when the generation of DPOAEs was interfered with by the introduction of a suppressor tone to produce STCs that resemble NTCs, STCs behaved quite differently following reversible cochlear insult than their previously documented neural counterparts. These findings imply that STCs do not assess the frequency-selective aspects of the cochlear amplification process in a manner similar to NTCs.

Acoustic Stimulation↗

Comparison of cannabidiol, antioxidants, and diuretics in reversing binge ethanol-induced neurotoxicity.

Binge alcohol consumption in the rat induces substantial neurodegeneration in the hippocampus and entorhinal cortex. Oxidative stress and cytotoxic edema have both been shown to be involved in such neurotoxicity, whereas N-methyl-d-aspartate (NMDA) receptor activity has been implicated in alcohol withdrawal and excitoxic injury. Because the nonpsychoactive cannabinoid cannabidiol (CBD) was previously shown in vitro to prevent glutamate toxicity through its ability to reduce oxidative stress, we evaluated CBD as a neuroprotectant in a rat binge ethanol model. When administered concurrently with binge ethanol exposure, CBD protected against hippocampal and entorhinal cortical neurodegeneration in a dose-dependent manner. Similarly, the common antioxidants butylated hydroxytoluene and alpha-tocopherol also afforded significant protection. In contrast, the NMDA receptor antagonists dizocilpine (MK-801) and memantine did not prevent cell death. Of the diuretics tested, furosemide was protective, whereas the other two anion exchanger inhibitors, L-644,711 [(R)-(+)-(5,6-dichloro2,3,9,9a-tetrahydro 3-oxo-9a-propyl-1H-fluoren-7-yl)oxy acetic acid] and bumetanide, were ineffective. In vitro comparison of these diuretics indicated that furosemide is also a potent antioxidant, whereas the nonprotective diuretics are not. The lack of efficacy of L-644,711 and bumetanide suggests that the antioxidant rather than the diuretic properties of furosemide contribute most critically to its efficacy in reversing ethanol-induced neurotoxicity in vitro, in our model. This study provides the first demonstration of CBD as an in vivo neuroprotectant and shows the efficacy of lipophilic antioxidants in preventing binge ethanol-induced brain injury.

Animals↗

Hypokalaemia and diuretics: an analysis of publications.

Published data have been used to define the characteristics of the fall in serum potassium concentration after taking diuretics and the efficacy of the various treatments given to prevent or correct it. The average fall is less after the usual doses of frusemide (about 0.3 mmol/l) than after the usual doses of thiazides (about 0.6 mmol/l) and is little influenced by the dose or duration of treatment. The fall with a given drug is the same in heart failure and hypertension, but the initial serum potassium concentration is higher in heart failure, so that the final value is lower in hypertension. In standard doses potassium supplements are less effective than potassium-retaining diuretics in correcting the hypokalaemia. The relation between the average serum potassium value and the frequency of low values (hypokalaemia) is such that very low values after taking diuretics are unusual in patients with hypertension or heart failure. Hypokalaemia would almost disappear as an important complication of diuretic treatment if it was defined as a value less than 3.0 mmol/l rather than as a value less than 3.5 mmol/l.

Chlorothiazide↗

Use of diuretics in cardiovascular disease: (2) hypertension.

Hypertension is a common condition associated with increased mortality and multiple morbidities. Evidence based management of hypertension is known to improve both the short term and the long term outcomes in patients with this condition. There are several general measures and pharmacological agents that are known to treat hypertension adequately. Diuretics, in particular low dose thiazide and thiazide-like diuretics, are widely used in the treatment of hypertension. They have excellent outcome data and high safety and low side effects profiles. In this article, the physiology, pharmacological actions, side effects, and outcome data of the use of diuretics in hypertension are reviewed. In addition, the effective use of diuretics in the management of hypertension is discussed.

Antihypertensive Agents↗

Plasma arginine vasopressin in hyponatraemic patients receiving diuretics.

Random estimations of plasma arginine vasopressin concentration were undertaken in 6 non-oedematous patients receiving diuretic therapy for hypertension, who were admitted to hospital with severe hyponatraemia. Hyponatraemia resolved within 2 weeks of discontinuing the diuretic. Measurable amounts of plasma arginine vasopressin were detected in all 6 patients. Sequential biochemical measurements in one patient, performed when plasma sodium concentration and osmolality were returning to the normal range, disclosed that urine osmolality remained higher than plasma osmolality during the first 5 days, when urine volume and sodium excretion were low. Thus the rise in plasma sodium was not initially related to water diuresis. The ability to excrete a water load was severely limited on the fifth day, but improved progressively by the tenth and seventeenth days. Diuretic-induced hyponatraemia is associated with incomplete suppression of anti-diuretic hormone secretion arising from non-osmotic stimulation, in conjunction with transient impairment of renal diluting ability which could be due to net sodium deficit.

Aged↗

Plasma electrolytes in elderly patients taking fixed combination diuretics.

Plasma potassium and sodium concentrations were measured in a group of elderly patients taking maintenance thiazide diuretic therapy alone, with a potassium supplement or in combination with a potassium sparing diuretic. Fixed dose combinations of a thiazide and potassium sparing diuretic did not significantly reduce the prevalence of hypokalaemia and the combination of amiloride-hydrochlorothiazide was associated with a disproportionate number of cases of hyponatraemia. The desirability of the current widespread use of fixed dose combination diuretics over less expensive single agents is questioned.

Aged↗

Laboratory experience for understanding the physiological basis of diuretic therapy.

A combined lecture and laboratory experience was designed to enhance medical school students' understanding of the physiological basis of diuretic therapy. Studies are performed by students in anesthetized dogs to determine the effects of four clinically useful diuretics on renal function. The objective of the experience is to 1) learn the mechanisms of action, clinical indications, and adverse effects of diuretics; 2) review the renal physiology of glomerular filtration and sodium metabolism; and 3) complete analysis and interpretation of experimental data. These sessions provide an effective practical educational experience in applying the scientific method to begin to understand the physiology and pharmacology of diuretics.

Animals↗

Ion and diuretic specificity of chimeric proteins between apical Na(+)-K(+)-2Cl(-) and Na(+)-Cl(-) cotransporters.

The mammalian kidney bumetanide-sensitive Na(+)-K(+)-2Cl(-) and thiazide-sensitive Na(+)-Cl(-) cotransporters are the major pathways for salt reabsorption in the thick ascending limb of Henle's loop and distal convoluted tubule, respectively. These cotransporters serve as receptors for the loop- and thiazide-type diuretics, and inactivating mutations of corresponding genes are associated with development of Bartter's syndrome type I and Gitleman's disease, respectively. Structural requirements for ion translocation and diuretic binding specificity are unknown. As an initial approach for analyzing structural determinants conferring ion or diuretic preferences in these cotransporters, we exploited functional differences and structural similarities between Na(+)-K(+)-2Cl(-) and Na(+)-Cl(-) cotransporters to design and study chimeric proteins in which the NH(2)-terminal and/or COOH-terminal domains were switched between each other. Thus six chimeric proteins were produced. Using the heterologous expression system of Xenopus laevis oocytes, we observed that four chimeras exhibited functional activity. Our results revealed that, in the Na(+)-K(+)-2Cl(-) cotransporter, ion translocation and diuretic binding specificity are determined by the central hydrophobic domain. Thus NH(2)-terminal and COOH-terminal domains do not play a role in defining these properties. A similar conclusion can be suggested for the Na(+)-Cl(-) cotransporter.

Animals↗

Angiotensin II AT1 receptor antagonism prevents detrimental renal actions of acute diuretic therapy in human heart failure.

Although effective in relieving symptoms of edema in congestive heart failure (CHF), diuretic-induced natriuresis may be associated with reductions in glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), which subsequently may reduce the duration of natriuresis. Moreover, recent studies have reported that the preservation of GFR is an important predictor of survival in human CHF. We hypothesized that the acute detrimental renal hemodynamic and tubular responses to furosemide in symptomatic human CHF will be attenuated by AT(1) receptor blockade with losartan. We defined the renal hemodynamic and tubular actions and aldosterone responses to furosemide (40 mg, orally) in the presence of acute AT(1) receptor antagonism (losartan, MSD, 50 mg orally) vs. placebo in 10 subjects with CHF (New York Heart Association II-III) in a double-blind, placebo-controlled crossover study. Furosemide with placebo increased sodium excretion and reduced ERPF and GFR (P < 0.05 vs. baseline). After 4 h, sodium excretion compared with baseline was decreased (P < 0.05). In contrast, furosemide with losartan resulted in a greater increase in sodium excretion but without reductions in ERPF and GFR (P < 0.05 vs. placebo). After 4 h, sodium excretion was greater compared with the placebo group. Importantly, plasma aldosterone tended to increase in the placebo group, whereas it was decreased (P < 0.05 vs. baseline) only in the losartan group. These studies underscore the pathophysiological role of the AT(1) receptor in mediating detrimental renal and adrenal properties of diuretics in human CHF. AT(1) receptor antagonism preserves GFR and renal blood flow and enhances sodium excretion during acute diuretic therapy in addition to inhibiting aldosterone secretion. These findings support the use of AT(1) receptor blockade for human CHF requiring acute diuretics to improve renal hemodynamic and tubular function and to suppress aldosterone.

Aldosterone↗

Diuretic-induced hyponatremia.

Diuretics are one of the most common causes of severe hyponatremia. Yet, despite several relevant studies and years of clinical experience, the mechanism and optimal treatment of diuretic-induced hyponatremia remain unclear. What is clear is that most cases are caused by thiazide rather than loop diuretics and that severe hyponatremia can develop very rapidly in susceptible patients. In this review, I will discuss the pathogenesis, clinical features, prevention, and treatment of diuretic-induced hyponatremia in the hope that increased awareness and understanding will reduce the incidence and complications of this potentially life-threatening syndrome.

Benzothiadiazines↗

Effect of diuretics on sodium and chloride permeability in the rat papillary collecting duct.

While in vivo data suggests that diuretics such as furosemide and hydrochlorothiazide alter inner medulla collecting duct (IMCD) cell electrolyte transport, this has not been confirmed by in vivo studies nor have the mechanisms been evaluated. This study evaluated the direct effect of these diuretics as well as amiloride on sodium and chloride unidirectional permeability in the isolated perfused rat IMCD. In the absence of diuretics, the permeability of sodium was lower than that of chloride (0.63 +/- 0.05 compared with 0.83 +/- 0.08 micrometer/s), although both were relatively impermeable when compared to water. Furosemide (10(-4)) and hydrochlorothiazide (10(-3)) both increased the diffusional permeability of chloride by approximately 30% (0.80 +/- 0.06 to 1.04 +/- 0.09 micrometer/s, p < 0.01, and 0.74 +/- 0.09 to 0.98 +/- 0.10 micrometer/s, p < 0.02, respectively). However, sodium permeability was unaltered. Inhibition of Na+, K+-ATPase by ouabain or cooling (4 degrees C) inhibited basal sodium but not chloride permeability while a maximal antidiuretic AVP concentration did not alter sodium or chloride permeability. However, increasing the lumen and bath sodium chloride concentration from 150 to 300 and 600 mM significantly increased both sodium and particularly chloride conductance. In contrast, amiloride (10(-4)) significantly reduced both sodium and chloride permeability. These studies support a direct effect of furosemide and hydrochlorothiazide on the IMCD and suggest that their in vivo effect is primarily mediated by facilitating the passive movement of chloride into the lumen via a favourable electrochemical gradient. These results also demonstrate that amiloride inhibits both sodium and chloride unidirectional permeability by mechanisms separate to that of the sulphonamide-related diuretics.

Amiloride↗