The effect of propranolol on urinary prostaglandin E2 after frusemide administration in healthy subjects

Summary We have evaluated the effect of propranolol on urinary prostaglandin E₂ (PGE₂) excretion after frusemide administration in 8 healthy subjects. Urine was collected for 60 min after frusemide administration (20 mg intravenously) with or without propranolol pretreatment, and urinary excretion of PGE₂, frusemide, and sodium were determined. Plasma renin activity (PRA) was also measured before and 60 min after frusemide administration.Urinary PGE₂ excretion after frusemide administration and frusemide-stimulated PRA were reduced after propranolol pretreatment. However, urine volume and the urinary excretion of frusemide and sodium were not influenced by propranolol pretreatment.These results suggest that urinary PGE₂ excretion after frusemide administration may be reduced by propranolol and that the mechanism responsible for the effect of proranolol on the frusemide-induced renal PGE₂ production may be, at least in part, secondary to inhibition of the renin-angiotensin system.     

Comparison of the acute vascular effects of frusemide and bumetanide.

The acute peripheral vascular and diuretic effects of intravenous frusemide 10 mg and 20 mg were compared with those of bumetanide 250 micrograms and 500 micrograms in a group of 10 salt depleted volunteers. Significant reductions in forearm blood flow (FBF) were observed after frusemide 10 mg (-0.77 ml 100 ml-1 min-1 P less than 0.05) and 20 mg (-0.75 ml 100 ml-1 min-1 P less than 0.01 at 15 min). No changes were observed after bumetanide. The reductions in blood flow produced by frusemide were significantly different from those of bumetanide (P less than 0.05) at 15 min. Increases in venous capacitance (VC) and mean arterial blood pressure (MAP) were observed after frusemide but these differences were not statistically different from placebo or bumetanide. No increases were seen after bumetanide. Plasma aldosterone concentrations were unchanged after either drug but plasma renin activity (PRA) was increased after frusemide 10 mg (4.42 +/- 1.01----8.50 +/- 1.90 ng A I ml-1 h-1 P less than 0.01) and 20 mg (4.01 +/- 0.72----7.81 +/- 2.27 ng A I ml-1 h-1 P less than 0.05). No increases were observed after bumetanide and significant differences between bumetanide and frusemide were observed (P less than 0.01). This study demonstrates that the acute peripheral arterial effects of frusemide are not observed after comparable diuretic doses of bumetanide. The differences appear to be related to the ability of the drugs to stimulate acute renin release from the kidney.     

Comparison of enalapril and propranolol in essential hypertension

Summary In 40 patients with essential hypertension, enalapril was compared with propranolol as an antihypertensive agent in a double-blind study. The patients were randomly given either enalapril 5–10–20 mg bid or propranolol 40–80–120 mg bid in a treatment consisting of step-by-step increases in dosage. When the diastolic blood pressure remained >90 mm Hg on the highest dosage, hydrochlorothiazide was added. Both enalapril and propranolol reduced blood pressure, although the patients tended to achieve lower blood pressures while on enalapril. More patients on propranolol required additional diuretic therapy than patients on enalapril.Propranolol reduced heart rate; with enalapril there were no changes in heart rate. Both drugs increased serum potassium and urea. Plasma renin substrate was reduced by enalapril, but raised by propranolol. Enalapril increased plasma renin activity and angiotensin I, while propranolol reduced both. Converting enzyme activity was lowered with enalapril but was unchanged with propranolol. Both drugs reduced angiotensin II. Plasma aldosterone concentration was more suppressed with propranolol than with enalapril.     

The effects of propranolol and digoxin on the acute vascular responses to frusemide in normal man.

To examine the importance of acute frusemide-induced renin release in the production of the acute peripheral venous and arterial responses to frusemide in man, the effects of two drugs, previously described as inhibitors of acute frusemide-induced renin release, propranolol and digoxin, were examined. Propranolol abolished the acute increases in venous capacitance and blood pressure and attenuated the increases in forearm vascular resistance produced by frusemide. The acute increases in plasma renin activity and plasma aldosterone concentrations were also abolished. Pre-treatment with digoxin had no effect on the acute peripheral vascular responses to frusemide and failed to inhibit the acute increases in plasma renin activity and plasma aldosterone produced by frusemide. The study provides further evidence of a relationship between acute frusemide-induced renin release and the acute peripheral vascular effects of frusemide in man.     

Response of the renin-angiotensin-aldosterone system to upright tilting and to intravenous frusemide: effect of prior metoprolol and propranolol.

1 Upright tilting in normal volunteers caused increases in plasma active and total renin, angiotensin II and aldosterone; a slight but significant fall in inactive renin accompanied these changes. 2 The alterations in the renin-angiotensin-aldosterone system on tilting took up to 1 h upright to become fully established. 3 Large intravenous doses of propranolol or metoprolol attenuated, without abolishing, the rises in active renin, angiotensin II, and aldosterone; the attenuation was most evident soon after tilting and was largely overcome by 1 h upright. Inactive renin did not fall significantly after beta-adrenoceptor blockade. 4 Intravenous frusemide caused immediate rises in plasma active, total and inactive renin, angiotensin II, and aldosterone, which then declined over 2 h despite increasing cumulative sodium losses. 5 Intravenous propranolol or metoprolol attenuated, without abolishing, these early increases in the components of the renin-angiotensin-aldosterone system after frusemide. 6 Prior oral metoprolol or propranolol, while significantly slowing the heart, did not limit the early rise in plasma angiotensin II following intravenous frusemide. 7 Thus in contrast to previous workers, we did not find that propranolol eliminated the response of the renin-angiotensin system to upright tilting; in part this difference appeared to be due to the longer tilt we employed. 8 Also in contrast to earlier work, we found attenuation by both intravenous propranolol and metoprolol of the immediate rise in renin after intravenous frusemide.     

A comparative study of the action of frusemide and methyclothiazide on renin release by rat kidney slices and the interaction with indomethacin.

1 The effects of frusemide (a diuretic acting on the loop of Henle) and methyclothiazide (a thiazide diuretic) on renin release were studied on rat kidney slices. 2 Frusemide at concentrations of 1.5 and 7.5 mmol/l produced significant increases in renin release but had no effect at 0.15 mmol/l. 3 Methyclothiazide in a similar concentration range did not increase renin release; instead, at the highest concentration used, methyclothiazide (3.5 mmol/l) inhibited renin release. 4 Indomethacin (25 mumol/l) did not inhibit the increase of renin induced by frusemide. 5 Our limited study in vitro is consistent with the findings of other workers who have shown in vivo, in the absence of systemic electrolyte depletion, that only "loop diuretics" increase renin secretion. Under our experimental conditions, it is suggested that frusemide exerts a direct action either upon the epithelioid cells or upon the macula densa since the renal prostaglandin system does not intervene.     

Comparison of the acute renal and peripheral vascular responses to frusemide and bumetanide at low and high dose.

1. The effects of equipotent doses of frusemide (10 mg and 100 mg) and bumetanide (250 micrograms and 2.5 mg) upon renal and peripheral vascular responses, urinary prostaglandin excretion, plasma renin activity, angiotensin II and noradrenaline were compared in nine healthy volunteers. 2. Frusemide (10 mg and 100 mg) and bumetanide (2.5 mg) increased renal blood flow acutely compared with placebo but bumetanide (250 micrograms) had no effect. The changes in peripheral vascular responses were not significantly different from placebo. 3. Urinary prostaglandin metabolite excretion was acutely increased by all treatments, with no inter-treatment difference. Plasma renin activity was increased acutely by both doses of frusemide and by bumetanide (2.5 mg) compared with placebo and to bumetanide (250 micrograms). There were no differences between the latter two treatments. Angiotensin II was increased significantly 30 min after frusemide 100 mg and bumetanide 2.5 mg, and by all four treatments at 50 min when compared with placebo. There were no significant differences between either of the low doses or the higher doses. Plasma noradrenaline was unchanged by all treatments. 4. Frusemide 100 mg and bumetanide 2.5 mg have the same effects on the renal vasculature and the renin-angiotensin-prostaglandin system. Under the conditions of this study, frusemide 10 mg had different effects on plasma renin activity than bumetanide 250 micrograms.     

Effect of Penicillin on the clinical course of streptococcal pharyngitis in general practice

Summary The diuretic and natriuretic response to an intravenous dose of frusemide 40 mg was assessed in the erect and supine positions in 10 patients with cardiac failure who were being treated with enalapril 10 mg twice daily in addition to diuretics (Enalapril group) and in 10 patients with cardiac failure taking diuretics alone (Control group).Total 4 h diuresis in the erect position was 728 ml and in the supine position was 824 ml in the patients taking enalapril compared to 655 ml in the erect position and 1166 ml in the supine position in those patients taking diuretics alone. Total 4 h natriuresis in the erect positions was 78 mmol and in the supine position was 85 mmol in patients taking enalapril 10 mg twice daily but in those patients taking diuretics alone total 4 h natriuresis in the erect position was 67 mmol increasing to 120 mmol in the supine position.Measurements of plasma renin activity and plasma angiotensin II concentration confirmed effective converting enzyme inhibition, in the group of patients taking enalapril, but in those patients taking diuretics alone the erect position was associated with an increase in plasma renin activity, and plasma concentrations of angiotensin II and aldsterone.We conclude that the renin angiotensin system is a major factor in mediating the effect of posture on loop diuretic drugs.     

The effects of ibuprofen and indomethacin on renal function in the presence and absence of frusemide in healthy volunteers on a restricted sodium diet.

1. Since salt depletion stimulates the renal prostaglandin system to maintain renal function, the effects of indomethacin and ibuprofen upon renal haemodynamics, electrolyte excretion and renin release were examined in eight healthy male volunteers on a salt restricted diet, before and after frusemide administration. 2. Neither indomethacin (50 mg) nor ibuprofen (400 mg and 800 mg) affected renal blood flow, glomerular filtration rate or electrolyte excretion before frusemide. 3. Renal blood flow and glomerular filtration rate were significantly increased in the first 20 min after frusemide. These changes were significantly attenuated by indomethacin compared with placebo and ibuprofen 400 mg. Frusemide-induced diuresis but not natriuresis was inhibited by all treatments. 4. Both nonsteroidal agents inhibited equally the rise in renin activity seen after frusemide. 5. In this group of healthy volunteers on a salt restricted diet, ibuprofen and indomethacin had no detrimental effects on renal function in the absence of frusemide. The changes in renal haemodynamics due to frusemide were suppressed more by indomethacin than by ibuprofen, probably reflecting the more potent nature of indomethacin as an inhibitor of prostaglandin synthesis.     

A comparison of the effects of ibuprofen and indomethacin upon renal haemodynamics and electrolyte excretion in the presence and absence of frusemide.

1. This study has compared the effects of ibuprofen and indomethacin upon renal haemodynamics, electrolyte excretion and renin release in the presence and absence of frusemide under sodium replete conditions in eight healthy volunteers. 2. Neither ibuprofen (400 mg and 800 mg) nor indomethacin (50 mg) affected renal blood flow, glomerular filtration rate or electrolyte excretion in the basal state. 3. Frusemide had no effect on renal blood flow, but significantly increased glomerular filtration rate. This latter change was suppressed significantly only by ibuprofen 400 mg. Frusemide-induced diuresis was inhibited by all treatments, while natriuresis following frusemide was inhibited by indomethacin only. 4. Significant increments in plasma renin activity, which were suppressed by all treatments, were observed after frusemide. The degree of inhibition of the renin responses was significantly greater in the presence of indomethacin than with either dose of ibuprofen. 5. In a sodium replete setting in healthy volunteers, indomethacin and ibuprofen had no detrimental effects on basal renal function. In the presence of frusemide, indomethacin had more anti-natriuretic and renin-suppressing effect than ibuprofen. There was no evidence for a dose-related effect of ibuprofen.     

The influence of frusemide formulation on diuretic effect and efficiency

AIMS: Changes in drug delivery rate may result in clinically important changes in drug effects. For the loop diuretic frusemide, it would be desirable to develop controlled release preparations, that could maintain an effective urinary excretion rate over a prolonged period of time. The aim of this study was to investigate the influence of frusemide formulation on frusemide recovery, diuretic effect and efficiency. METHODS: Twelve subjects were given 60 mg of four different frusemide controlled release formulations in a single-dose, double-blind, randomized 4-way cross-over design. The formulations were three study drugs with different extended dissolution rates (ER1Tab, ER2Tab and ER3Caps ) and one reference drug (LR). Urinary volume and contents of frusemide in urine were measured in samples collected over 24 h. RESULTS: Substantial differences in frusemide recovery and diuretic efficiency were observed between LR and all other formulations. At 24 h, mean total frusemide recoveries of ER1Tab, ER2Tab and ER3Caps were 52%, 36% and 57% lower, respectively, compared with LR (P<0.01). Also at 24 h, mean total diuretic efficiency for ER1Tab, ER2Tab and ER3Caps was 83%, 31% and 135% higher, respectively, compared to LR. The rapid dissolution and absorption of LR resulted in a high diuretic response from 0 to 3 h after dosing. However, from 0 to 24 h, there were no differences in diuretic response between the formulations. CONCLUSIONS: Controlled release formulations of frusemide with a low and extended rate of dissolution lead to a more prolonged absorption and subsequent diuresis, but still maintain a similar cumulative response, due to their higher diuretic efficiency.     

Xipamid, a potent new diuretic.

The effects of xipamid and frusemide were comapred in 9 oedematous patients. Xipamid was found to be equipotent with frusemide in doses of 40 mg. and 80 mg., with respect to its effect on sodium and water excretion. The time course of action of xipamid was observed to be more prolonged than that of frusemide. It is concluded that xipamid is a potent and safe diuretic.     

Effects of frusemide and hypoxia on the pulmonary vascular bed in man

Aims Diuretic therapy is conventionally used to treat oedema in patients with hypoxic cor pulmonale. This condition is associated with activation of the renin angiotensin system (RAS) with elevated levels of angiotensin II (ANG II), a potent pulmonary pressor agent. We explored the hypothesis that RAS activation by diuretic therapy might therefore worsen hypoxic pulmonary vasoconstriction via the effects of ANG II on the pulmonary vascular bed. Methods Eight normal volunteers were studied on 2 separate days. They either received 40 mg frusemide daily or placebo for 4 days and were then rendered hypoxaemic, by breathing an N₂/O₂ mixture for 20 min to achieve an SaO₂ of 85–90% adjusted for a further 20 min to achieve an SaO₂ of 75–80%. Pulsed wave doppler echocardiography was used to measure mean pulmonary artery pressure, cardiac output and hence pulmonary vascular resistance (PVR). Results Plasma renin activity (PRA) was significantly (P<0.01) increased after prior treatment with frusemide compared with placebo at all time points. Prior treatment with frusemide significantly (P<0.05) increased PVR compared with placebo at baseline: 185±17 vs 132±10 dyn s cm⁻⁵ at an SaO₂ of 85–90%: 291±18 vs 229±16 dyn s cm⁻⁵ and at SaO₂ of 75–80%: 356±12 vs 296±17 dyn s cm⁻⁵ respectively. However, the delta-PVR response to hypoxaemia was not significantly altered by frusemide compared with placebo. In contrast to its effect on the pulmonary vasculature prior treatment with frusemide did not significantly alter systemic haemodynamic parameters either at baseline or during hypoxia.. Conclusions Thus, prior treatment with frusemide increased baseline pulmonary vascular resistance and significantly augmented the hypoxaemic pulmonary vascular response in additive fashion. It is hypothesised that this effect of frusemide may be due to RAS activation with ANG II mediated pulmonary vasoconstriction.     

The influence of drug input rate on the development of tolerance to frusemide

Aims Understanding the impact of drug input rate on its pharmacokinetic-pharmacodynamic relationship may lead to a more optimal drug therapy. The aim of the present study was to investigate the influence of the rate of administration on tolerance development to frusemide, by giving the drug at four different infusion rates.
Methods Eight healthy volunteers were given 10  mg of frusemide on four different occasions, as a constant-rate intravenous infusion during 10, 30, 100 and 300  min, respectively. Urinary volume and contents of frusemide and sodium were measured in samples collected over 8  h.
Results The four different infusion rates systematically influenced the frusemide excretion rate versus diuretic and natriuretic response relationship. Counter-clockwise hysteresis occurred for the most rapid infusion rate, whereas a progressive clockwise hysteresis was observed for the slower infusions, indicating development of tolerance. For each subject, diuresis and natriuresis were modeled for all four treatments simultaneously, using a feedback tolerance model. It was not possible to describe the data using a model without tolerance. The time course of tolerance development showed remarkable differences between the infusion rates. The intensity of maximum tolerance development was significantly less for the slowest infusion rate compared with the more rapid infusions and it appeared significantly later. However, no differences in diuretic or natriuretic response were found between the treatments.
Conclusions The direction of the hysteresis loop is dependent on the input rate of frusemide. After the administration of a single low dose of frusemide, the time course of tolerance, rather than the integrated time course of tolerance, is influenced by the drug input rate.     

A study of the potential interactions between azapropazone and frusemide in man.

Ten healthy individuals received frusemide 40 mg orally for 7 days. Following a drug free period of 7 days they received azapropazone 600 mg twice daily for 7 days and then both treatments for a further 7 days. Sodium excretion fell from 141 +/- 16.8 mmol/day to 84.3 +/- 6.8 mmol/day (P less than 0.01) on initiation of azapropazone treatment. The natriuretic response to frusemide was unchanged by premedication with azapropazone. Urate excretion rose from 3.35 +/- 0.249 mmol/day to 4.98 +/- 0.365 mmol/day on initiation of azapropazone therapy but subsequently returned to baseline values. Plasma uric acid fell from 0.289 +/- 0.024 mmol/l to 0.167 +/- 0.0125 mmol/l (P less than 0.001) on azapropazone but rose to 0.186 +/- 0.0116 mmol/l (P less than 0.001) with the addition of frusemide. Azapropazone may cause sodium retention but after repeated administration frusemide still has a marked diuretic action. The hypouricaemic effect of azapropazone is only slightly antagonised by frusemide at the doses studied.     

Xipamid,a potent new diuretic

Summary

The effects of xipamid and frusemide were compared in 9 oedematous patients. Xipamid was found to be equipotent with frusemide in doses of 40?mg. and 80?mg., with respect to its effect on sodium and water excretion. The time course of action of xipamid was observed to be more prolonged than that of frusemide. It is concluded that xipamid is a potent and safe diuretic.     

A method for screening diuretic agents in the mouse: an investigation of sexual differences.

Acetazolamide, aminophyline, frusemide, ethacrynic acid and triamterene were tested for diuretic action at dosages of 3, 10 and 30 mg kg-1 (s.c.) in male and female mice. Each drug significantly raised sodium excretion and all but acetazolamide elevated urine volume and chloride excretion. Potassium excretion was significantly raised by acetazolamide and frusemide. Acetazolamide and triamterene evoked urinary alkalinization whereas frusemide and ethacrynic acid reduced urinary pH. Female mice were markedly more sensitive than males to the diuretic, natriuretic, chloruretic and urinary acidfying actions of ethacrynic acid.     

The effect of nitric oxide inhibition on the renin response to frusemide, in man

AIMS: We wished to see if renin release in man was inhibited by nitric oxide blockade, suggesting a role for nitric oxide in renin release. Evidence from animal studies has shown variable effects on renin release depending on the model and stimulus used. METHODS: Ten normal male volunteers, received either L-NMMA as a front loaded infusion (4 mg kg-1 bolus, with 4 mg kg-1 infusion), or placebo, followed by an intravenous bolus of 5 mg frusemide to stimulate renin. To investigate whether any alteration in renin release was due to the pressor effect of the L-NMMA, the experiment was repeated using an equipressor dose of phenylephrine (0.5 microg kg-1 min-1 ). RESULTS: L-NMMA caused the expected increase in mean arterial pressure (96+/-2.6 vs 89+/-3.3 mmHg P<0.05 [mean+/-s.e.mean]), and a reduction in heart rate (59+/-3.6 vs 67+/-2.5 beats min-1 P<0.05). L-NMMA completely blocked the renin rise following the bolus of frusemide (1.18+/-0.196 vs 1.96+/-0.333 ng ml-1 h-1 P<0.01). Phenylephrine 0.5 microg kg-1 min-1 produced very similar haemodynamic effects to L-NMMA, and also suppressed the renin response to frusemide (1.43+/-0.290 vs 2.67+/-0.342 ng ml-1 h-1 P<0. 01). CONCLUSIONS: In man, the renin inhibition seen with NO synthesis inhibition is similar to that seen with a standard pressor stimulus, hence inhibition of renin in man by L-NMMA, may be due to both direct effects on macula densa cells and indirect haemodynamic effects.     

A comparative study on the effects of pindolol and propranolol on systemic and cardiac haemodynamics in hypertensive patients

Eight out-patients with essential hypertension participated in a comparative, placebo-controlled study with a cross-over design. Pindolol and propranolol were administered orally in doses of 20.0 +/- 3.13 mg/d (mean +/- SEM) and 125.0 +/- 19.17 mg/d respectively. Pindolol reduced mean blood pressure by 11.9 mmHg; pre-ejection period index by 8.1 msec; total peripheral resistance by 3.1 mmHg min/L; and limb vascular resistance by 3.28 mmHg min 100 g/ml. Heart rate, cardiac output, plasma renin activity and urinary norepinephrine excretion rate were not altered by pindolol. Propranolol reduced mean blood pressure by 14.0 mmHg; heart rate by 9.1 beats/min; cardiac output by 0.57 L/min; limb blood flow by 1.06 ml/100 g.min; and plasma renin activity by 1.44 ng/ml/h; and increased pre-ejection period index by 8.7 msec. Total peripheral resistance, limb vascular resistance and urinary norepinephrine excretion rate were not altered by propranolol. It was concluded that: (1) the drugs, pindolol and propranolol, are equally effective as antihypertensive agents; (2) heart function and plasma renin activity are decreased by propranolol and unaltered by pindolol; (3) total peripheral resistance is decreased by pindolol and unaltered by propranolol; and (4) these findings may be explained by the intrinsic sympathomimetic activity exhibited by pindolol only.     

Discrepancy between bioavailability as estimated from urinary recovery of frusemide and total diuretic effect.

1. Frusemide was given at a dose of 60 mg as two oral controlled release (CR) formulations and as plain tablets in a randomised, balanced, three way cross over design to 26 healthy volunteers. Urinary volume, and contents of frusemide, sodium, chloride and potassium were measured in samples taken over 24 h. 2. There was a marked difference between the CR formulations on one hand and the plain tablets on the other, in excretion of frusemide and diuresis vs time. The total diuretic/saluretic effect was only marginally lower (19 and 28% respectively, P less than 0.05) after CR compared with plain tablets although the fraction absorbed was markedly decreased (39 and 51% lower, respectively, P less than 0.05), estimated as urinary recovery of frusemide. The total diuresis of the two CR formulations did not differ although the urinary recovery was significantly different (P less than 0.05). 3. The diuretic effect vs frusemide excretion rate showed minimal counter-clockwise hysteresis after plain tablets while the CR formulations produced clockwise hysteresis indicating tolerance. 4. In agreement with the concept of efficiency, the higher diuretic/saluretic effect per amount of excreted frusemide may be a consequence of the slower output of frusemide in urine with the CR formulations compared with plain tablets. The major part of the pharmacological effect was produced with a higher efficiency after CR compared with plain tablets. It should be noted that the pharmacokinetics of a drug and its pharmacodynamic potency independently determine the total response.(ABSTRACT TRUNCATED AT 250 WORDS)