Adrenocortical steroids increase renal thiazide diuretic receptor density and response.
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The density of the rat renal pharmacologic receptor for thiazide-type diuretics, as quantitated by the maximal specific binding of (3H)metolazone, decreased to one-third normal after adrenalectomy. Selective glucocorticoid (dexamethasone or RU-28362) replacement increased thiazide receptor density to or above the normal level over the dose range of steroid that decreased thymus weight, which served as a bioassay for glucocorticoid activity. Mineralocorticoid (fludrocortisone or aldosterone), in doses that did not decrease thymus weight, also increased thiazide diuretic receptor density to or above normal. The addition of glucocorticoid (RU-28362) to maximal aldosterone increased thiazide receptor above that produced by aldosterone alone and to threefold normal. Similarly, the addition of aldosterone to high-dose RU-28362 also increased thiazide receptor density above that produced by the glucocorticoid alone and to threefold normal. Hence, the effects of glucocorticoids and mineralocorticoids appeared to be additive. The increase in renal thiazide receptor density produced by fludrocortisone, at a dose that elicited both mineralocorticoid and glucocorticoid effects, was unrelated to the basal (prethiazide) renal excretion of sodium, potassium, chloride, or calcium. However, fludrocortisone-pretreated animals responded to bendroflumethiazide with a greater natriuresis than did controls. In addition, the magnitudes of the thiazide-elicited natriuresis and chloriuresis correlated significantly with thiazide receptor. It was concluded that both the density of the renal thiazide receptor and the quantity of sodium and chloride reabsorbed by the thiazide-sensitive Na-Cl cotransporter in the kidney are under adrenocortical regulation. (+info)
Mild hypertension: a clinical trial conducted in hospital general practice.
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To compare findings in a hospital trial of hypotensive drugs with those in a general practice trial several patients with mild hypertension were studied at the same time in hospital and in general practice. They received bendrofluazide and potassium chloride or bendrofluazide, potassium chloride, and reserpine according to a double-blind crossover protocol, and blood biochemical values were studied over eight weeks and six months. When reserpine was withdrawn from nine women they followed a modified protocol comparing bendrofluazide and potassium chloride with potassium chloride alone. The blood pressure values measured by the general practitioners were similar to those measured in hospital. Both the diuretic alone and the diuretic with reserpine produced significant falls in blood pressures. Although plasma renin activity increased on diuretic treatment, continued treatment did not produce a further increase, and levels gradually declined towards normal. (+info)
Combination diuretic treatment in severe heart failure: a randomised controlled trial.
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OBJECTIVES: (a) To test the hypothesis that a fixed 3 day course of the combination of a thiazide and loop diuretic is as effective as more prolonged treatment in the management of severe resistant cardiac failure. (b) To compare two thiazide diuretics (bendrofluazide and metolazone) in combination with loop diuretics in the treatment of severe resistant cardiac failure. DESIGN: Randomised study with a 2 x 2 factorial design. SETTING: Provincial teaching hospital. PATIENTS: 33 consecutive patients (40 episodes) admitted with severe congestive cardiac failure (New York Heart Association class III or IV) unresponsive to intravenous loop diuretics for 48 hours. MAIN OUTCOME MEASURES: Change in daily weight and serum electrolytes and clinical improvement in heart failure. RESULTS: Diuresis was established during 37 of 40 episodes; of the rest two patients died in hospital. On 36 occasions improvement was sufficient to allow discharge from hospital. Median (range) maximal weight loss was -5.05 (-11.3 to 1.6) kg after the addition of bendrofluazide and -5.6 (-12.2 to 4.8) kg after the addition of metolazone (NS). Area under the body weight loss against time curves showed no significant difference between the two thiazide diuretics. Median (range) maximal weight loss after three days of treatment was -5.4 (-12.2 to 4.8) kg and -5.5 (-10.3 to 1) kg after a more prolonged course of median (range) 5.6 (1 to 13) days (NS). Area under the body weight loss time curves showed no significant difference between the two durations of treatment. Bendrofluazide was associated with fewer electrolyte disturbances. CONCLUSIONS: Bendrofluazide and metolazone were equally effective in establishing a diuresis in patients with severe congestive cardiac failure resistant to loop diuretics. A fixed three day course of the combination was as effective as a longer course. (+info)
Blockade of distal nephron sodium transport attenuates pressure natriuresis in dogs.
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The sodium excretory responses (UNaV) to acute changes in renal arterial pressure (RAP) during blockade of distal nephron sodium transport were evaluated in seven sodium-replete anesthetized dogs. The major distal sodium entry pathways were blocked by intrarenal infusion of amiloride (AM, 10(-5) mol/L) and bendroflumethiazide (BZ, 10(-6) mol/L). Infusion of AM plus BZ caused slight increases in renal blood flow (RBF, 4.1 +/- 0.5 to 4.6 +/- 0.4 mL.min-1.g-1; P < .001) but no changes in glomerular filtration rate (GFR, 0.96 +/- 0.05 to 1.01 +/- 0.07 mL.min-1.g-1; P = NS) or autoregulatory efficiency of RBF and GFR. There were significant increases in UNaV (2.7 +/- 0.7 to 5.2 +/- 0.6 mumol.min-1.g-1) and fractional excretion of sodium (FENa, 1.8 +/- 0.4% to 3.5 +/- 0.3%) and decreases in potassium excretion (0.59 +/- 0.10 to 0.35 +/- 0.06 mumol.min-1.g-1) during AM plus BZ infusion. During the control period and during repeat measurements in time control studies, decreases in RAP (150 to 100 mm Hg) elicited the usual decreases in UNaV (slope, 0.022 +/- 0.007 mumol.min-1.g-1.mm Hg-1; P < .01). After administration of AM plus BZ, there was a marked attenuation of the pressure-natriuretic responses, and the slopes of the RAP versus UNaV and RAP versus FENa relations at RAP levels above 100 mm Hg were not significantly different from zero. However, the pressure-natriuresis response was maintained at arterial pressure between 75 and 100 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS) (+info)
A diuretic is more effective than a beta-blocker in hypertensive patients not controlled on amlodipine and lisinopril.
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The combination of an angiotensin-converting enzyme inhibitor and a calcium antagonist has a synergistic effect in patients with more severe hypertension. However, when this combination fails to control blood pressure, it is not clear which drug is then additive. The aim of this work was to study in a double-blind, randomized, crossover design the effect on blood pressure of the addition of either a thiazide diuretic (bendrofluazide, 5 mg once daily) or a beta-blocker (atenolol, 100 mg once daily) or placebo each for a month in hypertensive patients who are not adequately controlled on the combined treatment of amlodipine 5 mg once daily and lisinopril 5 mg twice daily. Eighteen patients with a supine diastolic pressure of more than 90 mm Hg after at least 1 month on the combined treatment of amlodipine and lisinopril were enrolled in the study. The results show that in patients whose blood pressures are not controlled by the combination of amlodipine and lisinopril, the addition of bendrofluazide 5 mg once daily causes a significant fall in blood pressure compared with placebo and a significantly greater fall than 100 mg atenolol once daily. (+info)
Local clinical guidelines: description and evaluation of a participative method for their development and implementation.
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BACKGROUND: National guidelines are rarely followed by immediate change in clinical behaviour. We present our experience of an active educational method for local development and implementation of a guideline. OBJECTIVE: To evaluate the effectiveness of a participative method for developing local clinical guidelines. METHODS: A trial in a district of the effect of guideline development incorporating active participation of intended recipients on subsequent relevant prescribing. It was carried out in Wirral Family Health Services Authority district (the Wirral peninsula) comprising 69 general practices covering a population of 345,763. An exemplar guideline on 'hypertension in the elderly' was developed by the method described. The principal recommended drug was bendrofluazide 2.5 mg once daily. The differences in prescribed daily doses (PDD) of bendrofluazide 2.5 mg tablets per quarter per 1000 prescribing units (age-weighted population) between the intervention district and England as a whole was measured. RESULTS: Comparison of the intervention district with England data demonstrates a median difference of 122.49 PDD before and 206.34 PDD after guideline production, this change is statistically highly significant (Mann-Whitney two-tailed P < 0.0001; 95% CI = 36.51-104.77). Grouped regression analysis shows no significant difference (0.89) in slope gradients before guideline production (P = 0.35, 95% CI = -3.97-5.76), but the difference in slope gradients after (12.95) is statistically highly significant (P < 0.0001; 95% CI = 8.17-17.73). The data suggests that the change in clinical behaviour persisted for at least two years. CONCLUSION: Participation of intended recipient general practitioners and local specialists in the development of a guideline by an active educational method as described was followed by a favourable change in clinical behaviour which persisted for at least two years. (+info)
Influence of renal nerves and sodium balance on the acute antidiuretic effect of bendroflumethiazide in rats with diabetes insipidus.
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To examine the role of the renal nerves and sodium depletion for the acute antidiuretic response to bendroflumethiazide (BFTZ; 25 microg/hr) in rats with diabetes insipidus (DI), renal clearance experiments were performed in the following groups of conscious, chronically instrumented male Brattleboro rats with vasopressin-deficient DI: Control (n = 7), BFTZ (n = 9), BFTZ + sodium replacement (n = 7) and BFTZ + chronic bilateral renal denervation (n = 6). Urine flow rate and urinary sodium concentration were measured drop-by-drop with a sodium-sensitive electrode and by collection of urine in vials placed on an electronic balance. This allowed computer driven, servo-controlled, independent i.v. replacement of sodium and fluid losses, respectively. Mean arterial pressure, glomerular filtration rate (GFR) and proximal tubular water and sodium handling, assessed by lithium clearance (C(Li)), were stable in the control group. BFTZ produced a marked antidiuretic response (deltaV = -79%; deltaUrine osmolality = +218%) associated with decreases in GFR (-28%), C(Li) (-62%), free water clearance (-100%) and plasma Na (-5 mM). Fractional water reabsorption was increased by 19% in the proximal tubules and by 7% in segments beyond. Sodium replacement did not modify the fall in GFR or the antidiuresis, but partly prevented the increase in fractional proximal water reabsorption. Bilateral renal denervation did not affect the response to BFTZ. We conclude that the acute antidiuretic effect of BFTZ is independent of sodium balance and renal nerve activity and is elicited by a reduction in GFR accompanied by an increase in fractional water reabsorption in the proximal tubules and in the distal nephron. (+info)
Mechanism of antidiuresis caused by bendroflumethiazide in conscious rats with diabetes insipidus.
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1. The mechanism underlying the antidiuretic effect of thiazide diuretics in diabetes insipidus (DI) is unknown. This study addressed two specific questions: is the reduction in urine flow rate (V) related to a decrease in the delivery of fluid from the pars recta of the proximal tubules ('distal delivery'), and are there any changes in the expression and/or intracellular distribution of vasopressin stimulated water channels (AQP2) in the collecting ducts, during chronic thiazide-induced antidiuresis? 2. Nine Brattleboro rats with vasopressin-deficient DI were treated for 5 days with bendroflumethiazide (BFTZ), 9 mg kg(-1) day(-1) orally, and 9 Brattleboro rats were left untreated. BFTZ-treated DI rats showed a fall in V from approximately 200 to approximately 75 ml day(-1) and an increase in urine osmolality from approximately 130 to approximately 400 mosmol kg(-1). 3. BFTZ-induced antidiuresis was associated with a persistent loss of sodium, but not of potassium. After 5 days of treatment, clearance studies in conscious rats showed a tendency towards decreases in effective renal plasma flow (-7%), GFR (-12%) and lithium clearance (C(Li); used as marker for distal delivery) (-25%), compared with untreated controls, but none of these changes were statistically significant. There was no apparent relationship between C(Li) and V in BFTZ-treated or untreated DI rats. 4. BFTZ treatment did not change the expression of AQP2 in homogenates of cortex, outer or inner medulla from DI rats, or from normal Long Evans rats. Light and electron microscopic immunocytochemistry revealed no changes in intracellular distribution of AQP2 in principal cells from inner medullary collecting ducts of BFTZ-treated DI rats. 5. We concluded, (i) that although the antidiuretic effect of BFTZ in rats with DI is associated with a net loss of Na, the decrease in V shows no association with changes in distal delivery, as estimated by C(Li). (ii) Antidiuretic treatment with BFTZ does not alter the expression of subcellular distribution of AQP2 water channels in the collecting ducts. The mechanism underlying the chronic antidiuresis caused by thiazide diuretics in DI remains elusive. (+info)