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Angiotensin converting enzyme inhibition worsens the excretory phase of diuretic renography for obstructive hydronephrosis.

PURPOSE: A growing body of evidence identifies the renin-angiotensin system as a key factor in the onset and progression of renal damage in chronic partial obstruction, which often represents a complex diagnostic challenge. A prospective study was undertaken to evaluate the role of captopril mercaptoacetyltriglycine-3 (MAG-3) renography as an early diagnostic test of obstruction. We report the results in a subgroup of children who underwent surgical correction for pyeloureteral obstruction. MATERIALS AND METHODS: Pyeloplasty was performed in 12 patients, including 10 males, 2 to 72 months old (median age 7) with unilateral hydronephrosis, including normal renal function and blood pressure. Basal and captopril enhanced diuretic renography with 99mtechnetium MAG-3 was performed within 24 hours using the same hydration and diuretic stimulus (0.75 mg./kg. furosemide), and 0.75 mg./kg. captopril was administered orally 60 to 90 minutes before scintigraphy. RESULTS: No adverse effects or modifications of the blood pressure were observed after captopril administration. The diuretic response was deeply worsened by angiotensin converting enzyme inhibition in each hydronephrotic kidney even when the basal study was only slightly abnormal (15-minute washout basal -27 +/- 16%, after captopril -9 +/- 13, p <0.005). After surgical correction the diuretic washout during angiotensin inhibition appeared normal in all patients (15-minute washout -56 +/- 14%). Separate renal function and parenchymal transit of MAG-3 were not modified by angiotensin converting enzyme inhibition, preoperatively or postoperatively. CONCLUSIONS: Our data confirm the influence of angiotensin on the kidney excretory system in human hydronephrosis and suggest a role for captopril enhanced diuretic renography in the early diagnosis of pyeloureteral obstruction. Further work is needed to evaluate angiotensin converting enzyme inhibition as a protective agent in obstructive nephropathy.

Angiotensin-Converting Enzyme Inhibitors↗

Contribution of the urea appearance rate to diuretic-induced azotemia in the rat.

Studies were performed to evaluate the contribution of the urea appearance rate to the elevated plasma urea concentration found during diuretic-induced sodium depletion. Negative sodium balance of -1162 + 29 microEq/100 g body wt was induced over a four day period by the administration of furosemide, 20 to 30 mg/kg/d i.p., to rats ingesting a sodium free diet. When compared with sodium replete controls, sodium depletion significantly increased the plasma urea concentration (65.0 +/- 3.1 vs. 26.4 +/- 1.1 mg/dl) through both an increase in the urea appearance rate (160 +/- 5.2 vs. 125 +/- 3.5 mg/day/100 g body wt), and a decrease in the urea clearance rate (1.99 +/- 0.14 vs. 3.16 +/- 0.12 ml/min/kg). The urea appearance rate increased on the first day of diuretic administration, remained elevated three days after stopping diuretics, rapidly returned to control levels after sodium repletion, and was significantly correlated with the magnitude of sodium deficit. Similar results were obtained when diuretic-induced sodium depletion was produced in adrenalectomized animals. After four days of sodium depletion the plasma concentration was increased for some amino acids but not for the plasma total amino acid, nitrogen concentration. The results indicate that sodium depletion increases the urea appearance rate through a mechanism that is independent of adrenal function. Thirty to sixty percent of the elevation in plasma urea concentration that occurs in the rat during diuretic-induced sodium depletion can be accounted for by an enhanced urea appearance rate.

Adrenalectomy↗

The effect of diuretics on components of the urinary kallikrein-kininogen-kinin system in man.

The effects of acute infusions of diuretics on components of the human urinary kallikrein-kininogen-kinin system were determined. Normal human subjects were given infusions of chlorothiazide and furosemide in doses calculated to produce a comparable natriuresis and diuresis. Alterations in urine electrolyte excretion, kinins, total and intact kininogen, and total active kallikrein were determined before and after the diuretic administration. Chlorothiazide caused a significant increase in total, but not active, kallikrein and had no effect on kinins and total or intact kininogen. Furosemide did not alter total or active kallikrein, or intact kininogen, but did decrease kinin and total kininogen excretion significantly. These differences in effects were not related to urinary sodium excretion or urinary flow because both diuretics produced comparable effects on these parameters. We conclude that acute infusions of diuretics do not activate the kallikrein-kininogen-kinin system and that some of the previously described effects of diuretics on this system may be related to their site of action.

Adult↗

Effectiveness of diuretic injection on the measurement of differential renal function using Tc-99m DMSA in patients with a dilated renal pelvis.

AIM: The aim of this study was to evaluate the effectiveness of diuretic injection for the measurement of differential renal function (DRF) with technetium-99m dimercaptosuccinic acid (Tc-99m DMSA) scintigraphy in patients with a dilated pelvis. MATERIALS AND METHODS: A total of 46 patients who were referred for both technetium-99m-L,L-ethylenedicysteine (Tc-99m L,L-EC) and Tc-99m DMSA imaging and found to have a dilated collecting system on Tc-99m EC scintigraphy were studied. Four to 5 hours after intravenous injection of Tc-99m DMSA, imaging was performed in the supine position, and posterior, anterior, left and right lateral, and left and right posterior oblique views were taken. After this study, furosemide was administered intravenously and 30 minutes later, additional images in the anterior and posterior views were obtained. RESULTS: The kidneys were evaluated into 2 groups. Group 1 comprised 12 kidneys that had an obstructive curve pattern on Tc-99m EC scans. Group 2 comprised 34 kidneys that had a nonobstructive dilated renogram curve pattern. DRF of the kidneys in each patient were calculated, and the values obtained from the standard and diuretic DMSA scans were compared with each other for all patients and each group. Considering all the patients, the values of mean DRF on both standard and diuretic DMSA images were 55.4%+/-21.2% and 55.4%+/-21.5%, respectively. There were no significant differences between DRF values of each kidney obtained by the 2 methods. When we compared the DRF values in groups 1 and 2, there were again no significant differences. In group 1, the values of mean DRF on standard and diuretic images were 51.7%+/-13.7% and 51.6%+/-13.9%, respectively, and in group 2, the values of mean DRF were 56.7%+/-23.4% and 56.7%+/-23.6%, respectively. CONCLUSION: In view of our study, diuretic administration seems to be an unnecessary intervention because it has no effect on the accuracy of DRF measurements using DMSA scintigraphy in patients with a dilated collecting system whether it is obstructed or not.

Adolescent↗

Plasma renin activity and blood pressure during long term treatment with propranolol and diuretic.

19 primary hypertensive patients were treated in random succession with diuretic, propranolol and the combination of both. It was found that the diuretic gave a sustained increase in plasma renin activity (PRA). There was a negative correlation between PRA level attained and blood pressure reduction. Propranolol treatment gave a sustained reduction of PRA. There was no correlation between PRA reduction and blood pressure reduction. When diuretic was combined with propranolol, PRA was in average at control level, and there was no correlation between the PRA reduction from diuretic value to combination value and the corresponding additional blood pressure fall. It is concluded that propranolol treatment does not transform patients to "low renin hypertensives" specifically sensitive to diuretic treatment.

Adult↗

99mTc DTPA scanning with diuretic washout. Is it useful in the investigation of obstruction in the presence of gross renal tract dilatation?

Diuretic-enhanced 99mTc DTPA renal scanning aims to determine whether or not a kidney is obstructed. In the presence of gross renal tract dilatation the validity of this technique is questioned. Twenty-eight patients (51 kidneys) with the prune belly syndrome, characterised by gross dilatation and tortuosity of the ureters, were studied. These patients underwent diuretic 99mTc DTPA scanning at the time of diagnosis and at yearly intervals thereafter. Long-term clinical follow-up (3 years) with serial serum creatinine was available in all children. In all cases renal function remained stable and on this basis urinary tract obstruction was excluded. Analysis of the first 99mTc DTPA scan included differential function, whole kidney mean transit time (WKMTT) and the time taken for tracer activity to fall to 75% of peak activity after diuretic stimulus (T75). Using the 99mTc DTPA scan, obstruction can be excluded if the WKMTT is less than 5 min or, in the presence of a prolonged WKMTT, if the diuretic stimulus results in a T75 of less than 5 min. A T75 of between 5 and 10 min is considered equivocal and a T75 exceeding 10 min means that obstruction cannot be excluded. 99mTc DTPA scanning, using these criteria for diagnosis, provided false positive information in 22 kidneys (43%). There were no false negatives. 99mTc DTPA scanning with diuretic washout, using WKMTT and T75 criteria, is not appropriate for the detection of renal tract obstruction in the presence of marked upper renal tract dilatation, since the false positive rate of 43% is unacceptably high.

Adolescent↗

Diuretic and cardiovascular effects of furosemide in rats.

Dose-response relationships of furosemide to its diuretic and cardiovascular actions and its effects on plasma renin activity (PRA) were evaluated in unanesthetized rats. A dose of 1 mg'kh-1 i.v. induced a small diuretic effect with no change in PRA. Furosemide at 5 mg'kg-1 provoked a clear diuretic effect (about 75) of the maximal effect) accompanied by a 20-25% plasma volume deficit but by only a twofold rise in PRA. Higher doses (10 and 40 mg.kg-1) induced a somewhat larger diuresis without further increases in plasma volume deficit or in PRA. Compared with the marked diuretic effect and plasma volume deficit, water intake increased only slightly (2 mL compared with the diuresis of 10 mL). Furosemide did not induce significant changes in blood pressure and heart rate, but it did alter the renin dependency of the blood pressure as assessed by Saralasin. These results indicate that furosemide has a steep dose-response curve for its effect on plasma volume and PRA; the relation is somewhat less steep for the diuretic action. Considering the large diuresis and plasma volume deficit, the changes in PRA and water intake induced by furosemide appear inappropriately small and suggest an inhibitory effect of furosemide on these parameters.

Animals↗

Interactions between volume expansion or diuretics and compensatory adaptation.

Glomerular filtration rate, urine flow, and Na excretion were measured 3--4 h after unilateral nephrectomy (1/2Nex) or sham operation in unanesthetized rats infused with isotonic saline (0.05--0.75 ml/min) and additionally injected with acetazolamind (20 mg/kg i.p.) or furosemide (5 mg/kg i.p., or 0.2 mg/kg i.v., or 2.0 mg/kg i.v.) or with both agents. Glomerular filtration rate of unilaterally nephrectomized rats averaged 50% of controls. Under all experimental conditions investigated, absolute water and Na excretions were similar in 1/2Nex and sham-operated rats. The fractional excretion (FE) of water and Na was increased 1.5- to 2.2-fold in 1/2Nex animals. The diuretic effects of volume expansion, of the two diuretic agents, and of contralateral nephrectomy consistently were additive. The "compensatory" increase of FESa following contralateral nephrectomy entailed a proportional increase of the diuretic effects of agents given subsequently. Urinary furosemide excretion 15 min after intravenous injection in unilaterally nephrectomized rats was smaller than in controls. The additivity of the diuretic effects of contralateral nephrectomy ("compensatory adaptation") and volume expansion and/or diuretic agents appears to be partly explained by different sites of action.

Adaptation, Physiological↗

High-NaCl diets increase natriuretic and diuretic responses in salt-resistant but not salt-sensitive SHR.

This study tested the hypothesis that NaCl-sensitive spontaneously hypertensive rats (SHR-S) display a defect in natriuretic and diuretic responses to acute volume loading that contributes to the rise in arterial pressure observed when the rats are fed a high-NaCl diet. Seven-week-old SHR-S and NaCl-resistant SHR rats (SHR-R) and normotensive (Wistar-Kyoto and Sprague-Dawley rats) were fed high- or basal NaCl diets. After 2.5 wk on the diets, preinstrumented conscious rats received an intravenous infusion (5% body wt; 0.5 ml/min) of isotonic saline, and urine was collected through a bladder catheter for 90 min. Control rats on the high-NaCl diet (compared with basal) excreted a significantly greater percentage of Na+ and volume load. In contrast, SHR-S on high-NaCl diet (compared with basal) had a very small increase in natriuretic response and no increase in diuretic response to volume expansion. The effect of renal denervation on natriuretic and diuretic responses to volume load was tested. In SHR-R on 1 and 8% NaCl diets, renal denervation had little or no effect on these responses, suggesting that renal nerves do not play a prominent role in the dietary NaCl-induced increases in the natriuretic and diuretic responses to volume load. These results demonstrate that NaCl-resistant rats rapidly adapt to diets high in NaCl content with increased natriuretic and diuretic responses to acute volume loading. The failure of SHR-S to adapt to the dietary challenge may result in volume loading and a secondary increase in arterial pressure after feeding.

Animals↗

Treatment of hyponatremic cirrhosis with ascites resistant to diuretics by urea.

We have studied the efficacy of urea in the treatment of hyponatremia and hydrosaline retention in cirrhotic patients with ascites resistant to diuretics. In 5 patients with hyponatremia and ascites resistant to a major diuretic treatment (200-400 mg spironolactone combined with 40-160 mg furosemide/day for 4 of them), urea intake (30-90 g/day) induced the following changes: the daily weight changed from a gain of 0.01 +/- 0.06 kg/day to a loss of 1.03 +/- 0.12 kg/day (p less than 0.001) (mean +/- SEM), serum sodium concentration rose from 128 +/- 1.3 to 133 +/- 1.4 mmol/l (p less than 0.01), sodium output increased from 24 +/- 4 to 82.5 +/- 11 mmol/day, diuresis increased from 1.05 +/- 0.10 to 2.24 +/- 0.24 liters/day (p less than 0.01). Despite an important weight loss, the creatinine clearance did not change significantly (53.6 +/- 4.5 ml/min before and 70.0 +/- 8.2 ml/min during urea). In patients responding to classical diuretics, urea as a monotherapy was less effective. From the 6 patients with resistant ascites, only 1 developed prerenal uremia after urea treatment. In order to enhance urea efficacy, it is important to take it together with a long-loop diuretic. Intermittent urea intake seemed to be useful in cirrhotic patients with hyponatremia associated with ascites resistant to diuretics and with low or normal blood urea concentrations.

Adult↗

ACE inhibitors versus diuretics: ALLHAT versus ANBP2.

The ALLHAT (The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial) trial enrolled hypertensive patients with at least one additional risk factor for coronary heart disease (CHD) to a comparison of the diuretic chlorthalidone, the calcium channel blocker, amlodipine, and the angiotensin-converting enzyme (ACE) inhibitor, lisinopril. Throughout the study, chlorthalidone decreased the systolic blood pressure to a slightly, but significantly greater extent (0.8-3.1 mmHg) than amlodipine or lisinopril. No significance differences were reported for amlodipine versus chlorthalidone or lisinopril versus chlorthalidone on the primary outcome of combined incidence of fatal CHD and nonfatal myocardial infarction. The findings of ALLHAT support the use of thiazide-type diuretics as first choice pharmacological therapy in at risk patients with hypertension. ANBP2 (The Second Australian National Blood Pressure Study) was also a comparison between diuretics (hydrochlorothiazide) and ACE inhibitors (enalapril) but was performed in older hypertensives that had few previous cardiovascular events. Diastolic blood pressure reduction was similar in both groups at all times. The risk of the primary outcome of all cardiovascular events or death from any cause was 11% lower in the ACE group than the diuretic group and the benefit was predominantly in men. Thus, ANBP2 suggests that in relatively healthy elderly hypertensive patients, ACE inhibitors should be preferred to diuretics.

Comment↗

The effects of antihypertensive drugs on serum lipids and lipoproteins. II. Non-diuretic drugs.

This review examines the effects of various antihypertensive drugs on blood lipids, lipoproteins, and apolipoproteins. A large number of studies have documented the elevation of total cholesterol, triglycerides, low density lipoprotein (LDL) cholesterol, and very-low density lipoprotein (VLDL) cholesterol with many thiazide-type diuretic drugs, albeit mainly in short term studies. When added to thiazide diuretics, both beta 1-selective and non-selective beta-blocking drugs elevate total triglycerides and VLDL triglycerides, lower high density lipoprotein (HDL) cholesterol and raise the ratio of total cholesterol to HDL cholesterol ratio. Most non-selective beta-blockers have similar effects when used as monotherapy, but the beta 1-selective agents appear not to affect HDL cholesterol in monotherapy. Prazosin appears free of adverse lipid effects and has improved lipid-lipoprotein concentrations in many studies. Preliminary data on several other drugs also suggest a favourable lipid profile and additional study is warranted - among these are guanabenz, clonidine, pindolol, labetalol, indapamide, and guanfacine. Elevations in serum triglycerides are often ignored on various counts, but triglycerides have been found to be a strong risk factor in European studies and in women over the age of 50 years in the Framingham study. Despite the unfavourable short term effects of diuretics, the theoretical risk of the lipid-lipoprotein changes remains unclear because HDL cholesterol and the total cholesterol to HDL cholesterol ratio are often unchanged. For this and other reasons, a long term trial comparing thiazide-type diuretics with drugs with the most favourable lipid-lipoprotein profile is needed. Until this is accomplished, in most settings diuretic-based regimens are still preferred initially since they are of proven, if limited, efficacy against the cardiovascular complications of hypertension.

Adrenergic alpha-Antagonists↗

Diabetes and diuretic-induced alterations in function of rat urinary bladder.

Studies were done to characterize the bladder dysfunction associated with diabetes mellitus and to distinguish between changes occurring from increased diuresis and autonomic neuropathy. Four experimental conditions were compared: control, 4-wk-streptozocin-induced diabetes, sucrose feeding (diuretic), and galactose feeding (diuretic and sugar alcohol). A 10-fold increase in urine output and 25-50% increases in bladder weight, protein content, and DNA content were observed in all noncontrol treatment groups. Compliance properties were studied by measuring the intravesicular pressure as the bladder was infused with buffer in vitro. All treated bladders exhibited a reduction in plateau pressure and an increase in fluid capacity. Thus, diuresis results in an increased bladder size, which correlates with an alteration of compliance properties. Nervous system control in anesthetized rats was examined by monitoring contractions as the bladder was infused with buffer. Three distinct patterns of response were observed: normal, diabetic, and diuretic (galactose and sucrose treatments). The difference between responses in diuretic and diabetic animals suggests the presence of a diabetes-induced alteration in nerve regulation of the bladder. Reserpine pretreatment of control or diuretic models produced marked changes in the pattern of contractions, whereas pretreatment of diabetic rats had only modest effects. This suggests that diabetic bladders were lacking sympathetic control before the drug treatment. When rats treated for 4 wk with galactose were removed from this diet for 4 wk before testing, the bladders responded similarly to controls. This observation, coupled with the fact that galactose did not produce the same response as diabetes in the in vivo experiment, suggests that the galactose model does not produce irreversible functional neuropathies.

Animals↗

Time course of the changes in active and cryoactivatable renin in response to acute stimuli before and after diuretic therapy in man.

In order to elucidate whether inactive renin may represent a precursor of the active enzyme we examined the short-term effects of ambulation and of Captopril administration on active and cryoactivatable renin in patients with essential hypertension before and after 5 days of diuretic therapy. We have found that in the large majority of patients before diuretic the increments in active renin in response to these stimuli were moderate and associated with unchanged levels of cryoactivatable renin; significant decrements in cryoactivatable renin were observed only in a small group of patients in whom the increments in active renin induced by ambulation were unusually rapid and marked. Diuretic therapy caused parallel increments in baseline values of active and of cryoactivatable renin and potentiated the response of the active enzyme to ambulation and to Captopril; however, cryoactivatable renin was still unmodified during both the acute stimuli. Thus, it appears that, normally, the rise in active renin induced by ambulation and Captopril administration is associated, both before and after diuretic therapy, with unchanged levels of the inactive enzyme; however, before diuretic, abrupt increments in the demand for active renin can determine changes in opposite direction of inactive renin as if the latter were a precursor of the former.

Adolescent↗

Diuretic response to adenosine A(1) receptor blockade in normotensive and spontaneously hypertensive rats: role of pertussis toxin-sensitive G-proteins.

Adenosine A(1) receptor antagonists are being developed for use as diuretics in the treatment of hypertension, however, there is relatively little data in hypertensive animal models regarding the efficacy of these compounds. In addition, some controversy exists surrounding the role of pertussis toxin (PT)-sensitive G-proteins in the signaling pathway for receptors acted on by A(1) antagonists. Our objectives for this study were 1) to compare the diuretic, natriuretic, and cardiovascular effects of acute A(1) receptor blockade in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto rats (WKY); and 2) to determine whether the diuretic effects are mediated through a PT-sensitive mechanism. Acute administration of the selective A(1) antagonist 1, 3-dipropyl-8-cyclopentylxanthine (DPCPX; 10 microgram/kg/min) increased urine output (410 +/- 116 and 317 +/- 86 microliter/30 min/g kidney) and sodium excretion (90.3 +/- 25.6 and 76.8 +/- 18.2 micromol/30 min/g kidney) similarly in WKY and SHR, respectively. DPCPX significantly decreased mean arterial blood pressure in SHR (-11.4 +/- 2.7 mm Hg), but not WKY. Prior treatment with PT (30 microgram/kg i.v.) abolished the diuretic response to DPCPX in both SHR and WKY. In a subsequent experiment in PT-treated Sprague-Dawley rats, DPCPX failed to evoke a diuretic response, whereas coinfusion of furosemide with DPCPX induced marked diuresis. Our results indicate that acute DPCPX administration produces similar natriuretic/diuretic effects in SHR and WKY, with beneficial effects on blood pressure in SHR. PT abolishes the response to DPCPX, indicating that the natriuretic/diuretic response to DPCPX is mediated via blockade of A(1) receptors linked to tubular sodium transport through PT-sensitive G-proteins.

Animals↗

Thiol adducts of ethacrynic acid: a correlation of the rate of liberation of ethacrynic acid with the onset and magnitude of the diuretic response.

It is thought that a derivative of ethacrynic acid (EA) must possess an intact alpha, beta-unsaturated ketone group in order to be capable of eliciting a diuretic response. The 2,3-dimercapto-1-propanol and the cysteine adducts of ethacrynic acid lack such a functional group and still have diuretic activity, especially the cysteine adduct. An in vitro study showed that various thiol adducts of EA liberate EA and the accompanying thiol at a rate that is primarily dependent on the nature of the functional groups present in the thiol portion of the adduct. When the thiol adducts of EA were injected into dogs, the cysteine and mercaptoethylamine hydrochloride adducts which rapidly release EA under specific in vitro conditions were as effective as EA in producing a diuretic response. The onset of action was also similar to that of EA. The thiosalicylic acid adduct of EA releases the accompanying thiol at an intermediate rate in vitro and was less effective than EA in a small dose (3.3 mumol/kg) and the peak response to it was slower to develop. Other adducts that release EA and the accompanying thiol slowly in vitro either produce a very weak response which takes considerable time to develop or are completely devoid of diuretic activity. Thus, the onset and magnitude of the diuretic response produced by various thiol adducts of EA (with the possible exception of the cysteine adduct) are governed primarily by the rate of in vivo release of EA.

Analysis of Variance↗

[Captopril in mild and moderate arterial hypertension resistant to diuretic therapy. A multicenter study].

PURPOSE: To evaluate the antihypertensive effect of captopril in mild and moderate hypertensive patients uncontrolled with diuretics. METHODS: Low dose of captopril (25 to 50 mg) bid were associated during 9 weeks in 120 patients previously treated with 100 mg of hydrochlorothiazide. A subgroup of patients (74) were followed additionally for 3 weeks with the same dose of the drugs administered as a single dose. The patients were clinically evaluated after two weeks placebo, and each three weeks of active drugs. Blood pressure normalization were considered when diastolic arterial pressure was < or = 90 mmHg. Laboratory tests were measured before diuretic, before captopril and at the end of combined twelve weeks treatment. RESULTS: After 15 days washout, the baseline supine arterial pressure, 168 +/- 2/ 109 +/- 1 mmHg decrease significantly with diuretic to 151 +/- 1/ 101 +/- 1 mmHg and the drop was further increased with captopril b.i.d., with a mean dose of 44 +/- 1 mg, to 137 +/- 1/ 90 +/- 1 mmHg. Blood pressure normalization was obtained in 58% patients with captopril b.i.d. and in 63% as single dose. Blood pressure normalization was achieved in 63% of non-white patients and in 56% patients over 45 years old. Plasmatic potassium decreased significantly with diuretic and did not recovered when captopril was associated. CONCLUSION: Our results indicate that the addition of low dose of captopril twice or once a day may result in a marked additional blood pressure reduction in cases of insufficient control by the diuretic alone.

Adolescent↗

Comparative effects of loop diuretics on AVP-receptor binding and AVP-sensitive adenylate cyclase activity.

The effects of loop diuretics (azosemide, ethacrynic acid and furosemide) on arginine vasopressin (AVP) receptor-adenylate cyclase components were compared in rat renal basolateral membranes. AVP binding was inhibited by these loop diuretics at concentrations above 10(-4) M. At the IC50 of azosemide and ethacrynic acid, the Kd values were significantly increased, while the Bmax values remained unchanged. These findings indicate an inhibitory effect of loop diuretics at high concentrations on the AVP binding to its receptors. Both the basal (AVP-unstimulated) and AVP-stimulated cyclic AMP productions were also inhibited by addition of these drugs. The inhibitions of the AVP binding and AVP-sensitive adenylate cyclase activity were dose-dependent. The above findings suggest that loop diuretics, especially azosemide and ethacrynic acid, can inhibit the basal and AVP-sensitive adenylate cyclase activities directly and also indirectly via the AVP receptor, at least in part. Comparing the loop diuretics, azosemide exerts a similar effect to ethacrynic acid, and they have a more potent antagonistic effect than furosemide with respect to AVP adenylate cyclase activation.

Adenylyl Cyclases↗