Furosemide-induced Changes Research Articles

The Acute Effects of Furosemide on Na-K-Cl Cotransporter-1, Fetuin-A and Pigment Epithelium-Derived Factor in the Guinea Pig Cochlea.

BackgroundFurosemide is a loop diuretic used to treat edema; however, it also targets the Na-K-Cl cotransporter-1 (NKCC1) in the inner ear. In very high doses, furosemide abolishes the endocochlear potential (EP). The aim of the study was to gain a deeper understanding of the temporal course of the acute effects of furosemide in the inner ear, including the protein localization of Fetuin-A and PEDF in guinea pig cochleae.Material and MethodAdult guinea pigs were given an intravenous injection of furosemide in a dose of 100 mg per kg of body weight. The cochleae were studied using immunohistochemistry in controls and at four intervals: 3 min, 30 min, 60 min and 120 min. Also, cochleae of untreated guinea pigs were tested for Fetuin-A and PEDF mRNA using RNAscope® technology.ResultsAt 3 min, NKCC1 staining was abolished in the type II fibrocytes in the spiral ligament, followed by a recovery period of up to 120 min. In the stria vascularis, the lowest staining intensity of NKCC1 presented after 30 min. The spiral ganglion showed a stable staining intensity for the full 120 min. Fetuin-A protein and mRNA were detected in the spiral ganglion type I neurons, inner and outer hair cells, pillar cells, Deiters cells and the stria vascularis. Furosemide induced an increased staining intensity of Fetuin-A at 120 min. PEDF protein and mRNA were found in the spiral ganglia type I neurons, the stria vascularis, and in type I and type II fibrocytes of the spiral ligament. PEDF protein staining intensity was high in the pillar cells in the organ of Corti. Furosemide induced an increased staining intensity of PEDF in type I neurons and pillar cells after 120 min.ConclusionThe results indicate rapid furosemide-induced changes of NKCC1 in the type II fibrocytes. This could be part of the mechanism that causes reduction of the EP within minutes after high dose furosemide injection. Fetuin-A and PEDF are present in many cells of the cochlea and probably increase after furosemide exposure, possibly as an otoprotective response.

Upregulation of hypothalamic arginine vasopressin by peripherally administered furosemide in transgenic rats expressing arginine vasopressin-enhanced green fluorescent protein.

Furosemide, which is used worldwide as a diuretic agent, inhibits sodium reabsorption in the Henle's loop, resulting in diuresis and natriuresis. Arginine vasopressin (AVP) is synthesized in the supraoptic nucleus (SON), paraventricular nucleus (PVN), and suprachiasmatic nucleus (SCN) of the hypothalamus. The synthesis AVP in the magnocellular neurons of SON and PVN physiologically regulated by plasma osmolality and blood volume and contributed water homeostasis by increasing water reabsorption in the collecting duct. Central AVP dynamics after peripheral administration of furosemide remain unclear. Here, we studied the effects of intraperitoneal (i.p.) administration of furosemide (20 mg/kg) on hypothalamic AVP by using transgenic rats expressing AVP-enhanced green fluorescent protein (eGFP) under the AVP promoter. The i.p. administration of furosemide did not affect plasma osmolality in the present study; however, eGFP in the SON and magnocellular divisions of the PVN (mPVN) were significantly increased after furosemide administration compared to the control. Immunohistochemical analysis revealed Fos-like immunoreactivity (IR) in eGFP-positive neurons in the SON and mPVN 90 min after i.p. administration of furosemide, and AVP heteronuclear (hn) RNA and eGFP mRNA levels were significantly increased. These furosemide-induced changes were not observed in the suprachiasmatic AVP neurons. Furthermore, furosemide induced a remarkable increase in Fos-IR in the organum vasculosum laminae terminals (OVLT), median preoptic nucleus (MnPO), subfornical organ (SFO), locus coeruleus (LC), nucleus of the solitary tract (NTS), and rostral ventrolateral medulla (RVLM) after i.p. administration of furosemide. In conclusion, we were able to visualize and quantitatively evaluate AVP-eGFP synthesis and neuronal activations after peripheral administration of furosemide, using the AVP-eGFP transgenic rats. The results of this study may provide new insights into the elucidation of physiological mechanisms underlying body fluid homeostasis induced by furosemide. This article is protected by copyright. All rights reserved.

Pathophysiology of Renal Calcium Handling in Acromegaly: What Lies behind Hypercalciuria?

Hypercalciuria is frequent in patients with acromegaly, but it is unclear how GH/IGF-I regulate renal calcium handling. Elevated fasting plasma calcium levels despite increased glomerular filtration suggest enhanced renal calcium reabsorption. The aim of this study was to investigate the impact of acromegaly on phosphocalcium metabolism. We conducted a prospective sequential study at a tertiary referral medical center and clinical investigation center (www.ClinicalTrials.gov Identifier: NCT00531908). Sixteen consecutive patients (five females/11 males) with acromegaly received a single iv infusion of 25 mg of furosemide to induce an acute increase in calcium and magnesium delivery to distal tubular segments during a high-sodium diet with stable dietary calcium, magnesium, and phosphate intake. Baseline plasma and urine electrolytes, plasma calciotropic hormones, and furosemide-induced changes in the fractional excretion and tubular reabsorption of Na, Ca, and Mg were measured before and 6 months (range, 1-12) after effective treatment of acromegaly. Serum IGF-I concentrations normalized in all the patients after acromegaly treatment. Compared with controlled acromegaly, active acromegaly was associated with higher fasting plasma (P = 0.0002) and urinary calcium (P = 0.0003) levels, lower PTH levels (P = 0.0075), higher calcitriol levels (P = 0.0137), higher phosphatemia (P<0.0001) and tubular phosphate reabsorption (P = 0.0002), and a lower calciuric (P = 0.0327) but not magnesiuric response to furosemide related to higher baseline and postfurosemide tubular calcium (P = 0.0034 and P = 0.0081, respectively), but not magnesium reabsorption. The IGF-I-mediated and PTH-independent increase in calcitriol synthesis in acromegaly is responsible for both absorptive hypercalciuria and increased fasting plasma calcium linked to enhanced distal tubular calcium reabsorption, as shown by the selectively diminished calciuric response to furosemide.

Endolymphatic Perfusion with EGTA-Acetoxymethyl Ester Inhibits Asphyxia- and Furosemide-Induced Decrease in Endocochlear Potential in Guinea Pigs

We examined the effect of the Ca(2+) concentration in the endolymph ([Ca](e)) or in the endolymphatic surface cells ([Ca](i)) on the endocochlear potential (EP) by using an endolymphatic or perilymphatic perfusion technique, respectively. (i) A large increase in [Ca](e) up to approximately 10(-3) M with a fall in the EP was induced by transient asphyxia ( approximately 2 min) or by the intravenous administration of furosemide (60 mg/kg), and a significant correlation was obtained between the EP and p[Ca](e) (= -log [Ca](e), r = 0.998). (ii) Perfusion of the endolymph with 10 mM EGTA for 5 min neither produced any significant change in the EP nor altered the asphyxia-induced change in EP (DeltaEP(asp)), suggesting that neither [Ca](e) nor the Ca(2+) concentration gradient across the stria vascularis contributed directly to the generation of the EP in the condition of low [Ca](e). In contrast, endolymphatic perfusion with high Ca(2+) (more than 10 mM) produced a decrease in EP and a significant correlation was obtained between the EP and the Ca(2+) concentration of perfusion solution (r = 0.982), suggesting that Ca(2+) permeability may exist across the stria vascularis. (iii) The administration of a Ca(2+) chelator, EGTA-acetoxymethyl ester (AM, 0.3 mM), to the endolymph, which produced a gradual increase in EP, suppressed significantly, by 60-80%, DeltaEP(asp) or furosemide-induced changes in EP. In contrast, perilymphatic administration of 0.5 mM EGTA-AM caused no significant suppression of the DeltaEP(asp). These findings suggest that [Ca](i) plays an important role in generating/maintaining a large positive EP.

Identification of the nonlinearity governing even-order distortion products in cochlear potentials

In order to characterize the cochlear transducer nonlinearities which are involved in the generation of the summating potential (SP), we investigated the effect of a change in the electrical operating point of the cochlear transducer on the SP. The electrical operating point of the cochlear transducer was affected by suppressing reversibly the endocochlear potential (EP). This was realized by intravenous injection of furosemide in guinea pig. A differential recording technique was used in the basal turn of the cochlea to measure locally generated even-order distortion products: the SP and the second harmonic component (2F 0) of the cochlear microphonics (CM). These potentials were evoked by 2 and 8 kHz stimuli presented at 60 dB SPL. Following furosemide injection, the SP changed polarity twice over time. The zero crossings of the SP coincided with a minimum in the amplitude of 2F 0. Concomitantly, the phase of 2F 0 shifted about 120°. The changes in the electrical even-order products were comparable to the changes that occurred in a mechanical even-order intermodulation distortion product (the difference tone F 2−F 1 otoacoustic emission) after furosemide application (Mills et al., J. Acoust. Soc. Am. 94 (1993) 2108–2122). The combined results suggest that only one sigmoidal transfer function may account for the SP, 2F 0, and the emission of the difference tone F 2−F 1, and that shifts in the operating point of the transfer function would be the major cause behind the furosemide-induced changes in the even-order distortion products. The sigmoidal transfer function is likely associated with the mechano-electrical transducer channel at the apical pole of the outer hair cell.

Intracellular pH and calcium in frog early distal tubule: effects of transport inhibitors.

1. The K+ channels of the apical membrane of the diluting segment (early distal tubule, EDT) of the frog are involved in the regulation of transepithelial NaCl transport. These channels are sensitive to pHi and intracellular Ca2+ (Ca2+i). Inhibition of transport by furosemide (frusemide) results in a compensatory increase in K+ channel activity. The aims of the present study were to determine whether pHi or Ca2+i were altered by furosemide, and to identify the means by which such changes were brought about. 2. Experiments were performed using single, microperfused EDT segments. Measurements of pHi and Ca2+i were made using the intracellular fluorescent probes, 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF) and fura-2, respectively. 3. Furosemide increased pHi and Ca2+i. The intracellular alkalinization was the result of an alkaline shift in the set-point of the basolateral Na(+)-H+ exchanger. This response was dependent upon the increase in Ca2+i. 4. The increase in Ca2+i produced by furosemide was due to the release of Ca2+ from intracellular stores. Depletion of these stores, by 2,5-di-t-butylhydroquinone (TBQ) and caffeine, prevented the furosemide-induced changes in Ca2+ and pH. 5. Furosemide-induced activation of Na(+)-H+ exchange was prevented by the calmodulin antagonist, W-7. 6. Thus furosemide elicits a rise in Ca2+i which, via calmodulin, results in activation of Na(+)-H+ exchange. The resulting intracellular alkalinization would be expected to increase channel activity.

Effects of furosemide on distortion product otoacoustic emissions and on neuronal responses in the anteroventral cochlear nucleus.

1. The objective of this study was to precisely evaluate the relationship between the threshold of neurons in the anteroventral cochlear nucleus (AVCN) and the properties of distortion product otoacoustic emissions (DPOAEs). Response areas of multiunit clusters in the AVCN and DPOAEs in the ear canal were measured alternately in the adult gerbil during furosemide-induced changes of the endocochlear potential. Stimulus frequencies of the probe tones for DPOAE measurement were in the range of f1 = 1.7-7.6 kHz and f2 = 2.0-9.0 kHz; the ratio f2:f1 was always 1.18. Stimulus amplitudes were varied in 5-dB steps from 30 to 80 dB SPL, with either equal amplitudes (L1 = L2) or unequal, with L1 set 10 dB above L2. Multiunit response areas were determined from cluster responses to a series of 100-ms tone bursts presented with a pseudo-random sequence in frequency and intensity. 2. Changes in the multiunit discharge properties after 50-75 mg/kg furosemide injection were as follows: the best frequency (BF) threshold increased from initial values in the range of 20-30 dB SPL to 50-80 dB SPL at 10-20 min postinjection and then recovered fully by 60-90 min. The spontaneous discharge activity decreased to zero before any changes in the frequency threshold curve were observed and did not return to initial values for several hours. Likewise, total discharge rates of stimulus elicited responses were reduced and tended to stay reduced even after BF threshold had fully recovered. 3. From the DPOAE measurements, the changes observed in the cubic distortion tone (CDT, 2f1-f2) emission after furosemide injection were as follows: at high levels of the probe tones, changes in the emission intensities generally stayed within a 10-dB range. The CDT amplitudes for low stimulus levels, however, were typically reduced by up to 40 dB, but recovered (depending on the furosemide dosage) by approximately 60-90 min. 4. At low to moderate stimulus levels of 40-60 dB SPL, there was a near perfect, minute-by-minute covariation of the ear canal CDT amplitude and the BF threshold measured in the AVCN. A 10-dB increase in threshold was associated with a 5- to 7-dB decrease in the CDT emission. 5. The optimum stimulus parameter set for the noninvasive estimation of cochlear performance from the CDT response was for stimulus amplitudes L1 = 50, L2 = 40 dB SPL. 6. This experiment demonstrates that CDT emissions at low stimulus levels are very good predictors of the thresholds of cochlear afferents, but this validity is lost for BF thresholds greater than approximately 60-70 dB SPL. 7. The ear canal CDT amplitude is better correlated with the BF threshold sensitivity of neuronal response areas in the AVCN than with the spontaneous discharge rate or absolute above-threshold discharge rates.

Furosemide treatment, angiotensin II, and renal growth and development in the rat.

Diuretics are commonly used to treat a variety of conditions, including progressive nephropathies, cardiovascular, and pulmonary diseases. Such treatment stimulates the production of angiotensin II, an important mediator of renal growth which may accelerate progressive glomerulosclerosis. To further study the effects of diuretic treatment on normal renal growth and development, weanling male Munich-Wistar rats received no drug, enalapril, furosemide, or both drugs for 6 wk; morphometric studies were then performed using standard light and electron microscopic techniques. Plasma renin activity was elevated by furosemide treatment. Cortical tubular growth was stimulated in rats receiving furosemide or both drugs; enalapril did not affect cortical tubular growth when compared with untreated animals. Glomerular volume was increased in furosemide-treated animals, primarily due to an increase in the proportion of mesangial cells, whereas enalapril decreased glomerular volume. Furosemide also increased the filtration surface area per glomerulus whereas enalapril decreased it. Concurrent enalapril treatment blocked the furosemide-induced changes in filtration surface area as well as attenuating overall glomerular and mesangial growth. Glomerular changes correlated with plasma renin activity. Furosemide stimulated glomerular growth, especially of mesangial cells, probably via stimulation of AngII production. Given the relationship of mesangial cell growth and progressive renal disease, diuretic therapy could thus accelerate glomerulosclerosis. Cortical tubular growth also increased with furosemide; however, enalapril had no effect, so factors besides angiotensin II appeared to modulate tubulointerstitial growth in these animals.

Gender differences in dehydration-induced mitral valve prolapse

Mitral valve prolapse (MVP) is a common cardiac valve abnormality that affects women more frequently than men. We have previously shown that mild dehydration induces echocardiographic signs of MVP in approximately 50% of healthy asthenic women with previously normal cardiac findings. The present study was designed to investigate whether dehydration can induce MVP in normal men. Ten healthy male volunteers with a mean body mass index of 24.2 kg/m 2, unremarkable history, and normal cardiac findings and echocardiogram were examined after mild diuresis with 20 mg furosemide. Significant decrease in weight, left ventricular end-diastolic dimension, and cardiac output were detected in all subjects after furosemide administration. In 1 (10%) of the 10 subjects echocardiographic MVP developed after furosemide administration. All furosemide-induced changes resolved with hydration. These results demonstrate that dehydration-induced MVP in men without characteristic body habitus of MVP occurs with substantially lower frequency than previously documented in women with the characteristic body habitus of MVP. This study suggests the importance of gender and body habitus in dehydration-induced MVP.

Urinary Acidification Response to Furosemide Administration in Patients on Low-Dose Cyclosporine Therapy

The response of urinary acidification parameters and electrolytes to furosemide administration was prospectively studied in 9 psoriatic patients treated with a low-dose cyclosporine A schedule (initial dose: 5 mg/kg body weight) before beginning cyclosporine A, after 3 months on cyclosporine A and 1 month after cyclosporine A withdrawal. The test was also performed in 29 psoriatic patients after 3 months on 5 mg/kg body weight cyclosporine A treatment. There were no significant differences between before and after cyclosporine A treatment regarding furosemide-induced changes in urinary volume, sodium or potassium excretion. Contrarily, the post-furosemide urinary pH decrease and ammonium and titrable acid increase were significantly lower in cyclosporine-A-treated patients. Five of the 29 studied patients showed abnormal furosemide tests (17%). These patients had lower total serum CO2, urea and creatinine but similar serum potassium and fractional potassium excretion. We conclude that some patients treated with low-dose cyclosporine A therapy develop an abnormal tubular distal response to furosemide administration, suggesting an alteration in the H(+)-ATPase pump or a voltage-dependent mechanism.

Renal prostacyclin influences renal function in non-azotemic cirrhotic patients treated with furosemide

The influence of prostaglandins on renal function changes induced by furosemide was analyzed in 21 non-azotemic cirrhotic patients with ascites. Patients were studied in two periods of 120 min immediately before and after furosemide infusion (20 mg, ev). Furosemide caused an increase in creatinine clearance in 15 patients (group A: 99 ± 7 vs. 129 ± 5 ml/min; mean ± S.E.) and a reduction in the remaining six (group B: 102 ± 13 vs. 71 ± 9 ml/min). Parallel changes were observed in the urinary excretion of 6-Keto-prostaglandin-F 1α (metabolite of renal prostacyclin) which augmented after furosemide in 14 of the 15 patients from group A (478 ± 107 vs. 1034 ± 159 pg/min, p < 0.001) and decreased in all patients from group B (1032 ± 240 vs. 548 ± 136 pg/min, p < 0.05). In contrast, the urinary excretion of prostaglandin E 2 was stimulated by furosemide in all patients (group A, 92 ± 19 vs. 448 ± 60 pg/min, p < 0.001; and group B, 209 ± 63 vs. 361 ± 25 pg/min, p < 0.05). In all of the patients furosemide-induced changes (post- minus pre-furosemide values) in creatinine clearance were closely correlated in a direct and linear fashion with those in 6-Keto-prostaglandin-F α ( r = 0.74; p < 0.001). These changes were associated with a higher furosemide-induced natriuresis in group A than in group B (641 ± 68 vs. 302 ± 46 μmol/min, p < 0.001). In the basal period urinary 6-Keto-prostaglandin-F α was significantly higher ( p < 0.05) in group B than in group A, no differences being found in the remaining parameters, including plasma renin activity (group A, 9.7 ± 2.6 vs. group B, 12.0 ± 3.9 ng/ml per h) and urinary sodium output (group A, 30.1 ± 10.6 vs. group B, 11.8 ± 3.5 μmol/ min). In summary, our results suggest that renal prostacyclin metabolism influences renal response to furosemide in cirrhotic patients.

Atrial natriuretic factor, cyclic 3‘,5’‐guanosine monophosphate and prostaglandin E2 in liver cirrhosis: relation to blood volume and changes in blood volume after furosemide

Plasma concentrations of atrial natriuretic factor (ANF) and cyclic 3',5'-guanosine monophosphate (cGMP) were measured in 11 cirrhotic patients with ascites, 11 cirrhotic patients without ascites and 15 control subjects. The following were determined in 15 of the cirrhotic patients and in all the control subjects: blood volume (BV) and furosemide-induced changes in BV, plasma values of ANF, cGMP, angiotensin II (AII), aldosterone (Aldo), arginine vasopressin (AVP) and urinary excretion rates of cGMP, prostaglandin E2 (PGE2), water and sodium. Basal plasma levels of ANF and cGMP were higher in patients with cirrhosis than in controls, but were the same in both groups of cirrhotics (ANF: cirrhosis with ascites 12.7, without ascites 13.4, and in controls 5.8 pmol l-1 (medians); cGMP: 7.7, 7.4 and 4.3 nmol l-1, respectively). BV was less reduced after furosemide in the cirrhotic patients (6.0%) than in the healthy subjects (10.1%), but basal BV did not differ. Urinary sodium excretion rates after furosemide were significantly lower in the cirrhotic patients than in the controls. PGE2 excretion rate increased after furosemide in the cirrhotic patients (0.29 to 0.66 pmol min-1; P less than 0.01) but not in the controls (0.31 to 0.38 pmol min-1). After furosemide ANF and cGMP decreased slightly in both groups whereas AII and Aldo increased; AVP increased in the controls, but not in the cirrhotic patients. In conclusion, plasma values of ANF and cGMP are increased in liver cirrhosis both with and without ascites. This and the elevated PGE2 excretion after furosemide may be compensatory phenomena in order to facilitate renal sodium excretion.

Prognostic value of the ischemic test in ocular myasthenia gravis

Furosemide-induced changes of cochlear potentials were used as a model to study the influence of arachidonic acid metabolites on ion movements within the cochlea. No influence was exerted by the drugs Esculetin — blocking the synthesis of lipoxygenase products — and Dazoxiben — suppressing thromboxane A2 levels within the cochlea. A weakening of the furosemide-induced changes of the endocochlear potential was found when infusing the thromboxane (TX) receptor antagonists BM 13 505 and BM 13 177 before furosemide was given. This effect was also observed when pre-treating the guinea pig with a specific platelet-activating factor receptor antagonist, BN 52 021, before the diuretics was given. Summating potential and cochlear microphonics remained insignificantly changed against controls. The results suggest that a TX receptor contributes to the control of ion movements within the cochlea. A possible involvement of loop diuretics' receptors is discussed.

The time-course of furosemide-induced strial changes in guinea pigs after pretreatment with daltroban

It was shown previously (Ernst et al., 1989) that pretreatment of guinea pigs with a thromboxane (TX) receptor antagonist attenuates the decline of the endocochlear potential (EP) induced by furosemide. The present paper is aimed at investigating a possible correlation between the electrophysiological data and ultrastructural changes of the stria vascularis by electron microscopy. The dosages of 40, 60, and 80 mg/kg furosemide were injected after the pretreatment with the TX receptor antagonist daltroban and compared to controls which were injected with furosemide only. It was found at all furosemide concentrations that the strial changes 10 min after injection were nearly unchanged against controls. 30 min after furosemide injection, the most pronounced changes were seen when pretreating the animals: a clear reduction of the marginal cell swelling and edema in general were observed at 40 and 60 mg/kg furosemide. The guinea pigs injected with 80 mg/kg furosemide after pretreatment displayed nearly the same changes as controls.

Arachidonate metabolites change furosemide-induced cochlear potentials

Furosemide-induced changes of cochlear potentials were used as a model to study the influence of arachidonic acid metabolites on ion movements within the cochlea. No influence was exerted by the drugs Esculetin — blocking the synthesis of lipoxygenase products — and Dazoxiben — suppressing thromboxane A 2 levels within the cochlea. A weakening of the furosemide-induced changes of the endocochlear potential was found when infusing the thromboxane (TX) receptor antagonists BM 13 505 and BM 13 177 before furosemide was given. This effect was also observed when pre-treating the guinea pig with a specific platelet-activating factor receptor antagonist, BN 52 021, before the diuretics was given. Summating potential and cochlear microphonics remained insignificantly changed against controls. The results suggest that a TX receptor contributes to the control of ion movements within the cochlea. A possible involvement of loop diuretics' receptors is discussed.

Participation of the Prostaglandin System in Furosemide-Induced Changes of Renal Function in Anesthetized Rats

The possible mediation of the endogenous prostaglandin and kallikrein-kinin systems of changes in renal function induced by furosemide was studied in anesthetized rats. Increasing doses of furosemide infusion (0.03, 0.1, and 0.3 mg/kg/min) caused dose-related diuresis, natriuresis, kaliuresis, and decreased renal blood flow and urinary osmolality without any significant changes in mean arterial blood pressure. Pretreatment with the prostaglandin synthetase inhibitor indomethacin resulted in marked reduction of the water and sodium excretion induced by furosemide. It also blunted renal vasoconstriction and renin release by furosemide, but the glomerular filtration rate was not affected. Pretreatment with aprotinin, a kallikrein inhibitor, failed to affect the renal response to furosemide. The results indicate that the renal prostaglandin system, but not the kallikrein-kinin system, participates in the effect of furosemide on renal functions mainly through electrolyte transport inhibition in the renal tubule.

Interactions of diuretics with the renal kallikrein-kinin and prostaglandin systems

The renal kallikrein-kinin system may participate in the diuretic, natriuretic and antihypertensive effect of diuretics. This possibility was investigated by studying the influence of hydrochlorothiazide on blood pressure and urinary kallikrein excretion in patients with essential hypertension. Furthermore, the effect of kallikrein-blockade and prostaglandin-synthesis inhibition on the acute furosemide-induced changes of diuresis, natriuresis, GFR and renal plasma flow were studied in normotensive subjects. Thiazide treatment normalized the reduced kallikrein excretion of the hypertensive patients. The fall in mean arterial blood pressure was significantly correlated with the increase in urinary kallikrein excretion. In the normotensive subjects aprotinin-induced kallikrein inhibition failed to alter the acute response to furosemide, whereas indomethacin attenuated the diuretic and natriuretic effect of furosemide. The combination of indomethacin and aprotinin had a greater suppressive effect on plasma renin activity than indomethacin alone, suggesting a participation of kallikrein in renin release. An increase in the activity of the renal kallikrein-kinin system may contribute to the long-term antihypertensive effect of thiazide diuretics but it does not seem to be involved in the acute renal responses to furosemide.

Effects of indomethacin and tolmetin on furosemide-induced changes in renin release.

SummaryProstaglandin synthetase inhibitors, indomethacin and tolmetin, blocked furosemide-induced increase in renin secretion whether the furosemide was given intravenously or into the renal artery. Tolmetin and indomethacin did not affect the natriuretic, kaliuretic or calciuretic response to furosemide. Therefore, blockade of furosemide-in-duced renin release does not appear to require an alteration in sodium or calcium load at the macula densa. Thus, the site of action of prostaglandin synthetase inhibitors on renin release is probably subsequent to the signal perceived by the macula densa.

Influence of Inhibitors of the Renin-Angiotensin System and the Renal Prostaglandins on Furosemide-induced Changes in Renal Blood Flow

The effects of inhibitors of the renin-angiotensin system and prostaglandin synthesis were used to study furosemide-induced changes in renal hemodynamics. Extracellular fluid volume expansion augmented the increase in renal blood flow to furosemide when compared to hydropenic animals. Indomethacin, a prostaglandin synthetase inhibitor, blunted the effect of furosemide in volume-expanded animals. Neither SQ 20,881, an angiotensin I converting enzyme inhibitor, nor 1-Sar-8-A1a-angiotensin II, an angiotensin II antagonist, modified the response to the diuretic. The initial transient decrease in renal blood flow seen following furosemide was not modified by volume expansion, indomethacin, SQ 20,881 or 1-Sar-8-A1a-angiotensin II.

Propranolol antagonism to the effect of furosemide on the compostion of endolymph in guinea pigs.

Furosemide, administered intravenously (50 mg/kg) to guinea pigs, caused an increase in the sodium concentration and a decrease in the potassium concentration of endolymph, and a fall in the endolymphatic potential. The furosemide-induced electrolyte changes were prevented by pretreatment of five guinea pigs with propranolol given intravenously (2 mg/kg). The fall in the endolymphatic potential was not prevented by propranolol. Local administration of furosemide to the perilymphatic or endolymphatic space caused a fall in the endolymphatic potential, but had no effect upon the concentrations os sodium and potassium of endolymph. These studies provide additional information suggesting the mutual independence of the endolymphatic potential and sodium and potassium concentration gradients.