Administration Of Spironolactone Research Articles

Gender differences in urinary kallikrein excretion in man: variation throughout the menstrual cycle.

1. Urinary kallikrein excretion was measured in healthy male subjects and in healthy pre- and post-menopausal females. 2. Urinary kallikrein excretion was shown to be constant throughout a 24 h period. Individual male subjects showed little fluctuation in urinary kallikrein excretion; within-subject variance accounted for 1.65% of the total. 3. Female subjects with ovulatory menstrual periods excreted significantly more kallikrein than post-menopausal females and males. 4. Pre-menopausal females showed a much greater within-subject variation in urinary kallikrein excretion and this could be related to the stage of the menstrual cycle, with significantly greater urinary kallikrein excretion in the luteal phase than in the follicular phase. 5. Plasma renin activity and plasma aldosterone concentration also showed a menstrual variation, with concentrations in the luteal phase being significantly higher than those in the follicular phase. 6. The rise in urinary kallikrein excretion in the luteal phase could be abolished by oral administration of the aldosterone antagonist spironolactone. 7. Urinary kallikrein excretion in post-menopausal females was similar to the range found in males, and showed no cyclic changes over a 4 week period. 8. Gender and menstrual status should be taken into account in studies of the physiological role of tissue kallikreins.

Suppression of prostaglandin F 2α and oxytocin release after inhibition of testosterone synthesis in the goat

Increased peripheral plasma concentrations of testosterone were detected in goats on days 13 and 14 of the oestrous cycle (oestrus = day 0), at the onset of luteolysis. Subcutaneous administration of spironolactone (10 mg kg −1 day −1) on days 10 to 19 inhibited the increases in testosterone, delayed luteolysis and suppressed plasma concentrations of 13,14-dihydro-15-ketoprostaglandin F 2α and oxytocin. These results suggest that testosterone of follicular or luteal origin, possibly via aromatisation to oestrogens, is needed to expedite luteolysis and induce oestrus in the goat.

Role of glucocorticoid in the development of glycyrrhizin-induced hypertension.

Role of alterations of corticosterone metabolism in the expression of the mineralocorticoid activity of glycyrrhizin was explored in rats. While the mineralocorticoid actions of oral glycyrrhizin were not observed in bilaterally adrenalectomized rats and dexamethasone treated rats, the mineralocorticoid actions of glycyrrhizin were fully expressed in bilaterally adrenalectomized rats supplemented with physiological doses of corticosterone. Similar mineralocorticoid actions were observed in rats given glycyrrhizin, deoxycorticosterone and pharmacological doses of corticosterone. Although increases in mean blood pressure were suppressed only by concurrent administration of spironolactone to glycyrrhizin- and deoxycorticosterone-treated rats, increases in mean blood pressure were attenuated by both the glucocorticoid antagonist RU 38486 and spironolactone in pharmacological doses of corticosterone administered rats. Pressor responses to norepinephrine and angiotensin II infusions in rats given deoxycorticosterone and pharmacological doses of corticosterone were significantly higher than in glycyrrhizin-treated rats. These results confirmed the functional significance of 11-beta-hydroxysteroid dehydrogenase in expression of the mineralocorticoid activity of glycyrrhizin.

Differential Effects of Angiotensin II and Aldosterone on Cardiovascular Hypertrophy.

The objective of this study was to determine the relative importance of angiotensin II (Ang II) and aldosterone in cardiovascular hypertrophy. Rats were given an infusion of Ang II (200ng/kg/min) subcutaneously for 8 weeks with a mini-osmotic pump, with or without oral spironolactone (200mg/kg) or MK-954 (30mg/kg) daily. Ang II infusion resulted in marked hypertension of around 207mmHg, which was associated with cardiac hypertrophy, with a heart-to-body-weight ratio of 0.35±0.005% and thoracic aorta medial thickness of 0.166±0.005mm (vs. 0.285±0.002% and 0.113±0.003mm, respectively, in control rats). Concomitant administration of spironolactone or MK-954 reduced the blood pressure in rats given Ang II to the same degree (164 and 171mmHg, respectively). Aldosterone receptor blockade by spironolactone prevented Ang II-induced cardiac hypertrophy heart-to-body-weight ratio= 0.307±0.009%, but the Ang II-receptor antagonist MK-954 did not (heart-to-body-weight ratio=0.331 ±0.007%), although aortic vascular wall thickening in rats given Ang II was attenuated by both drugs. Renal hypertrophy induced by Ang II was not completely normalized by either drug. These results suggest that blockade of mineralocorticoid receptors is more effective than antagonism of Ang II receptors in preventing cardiac hypertrophy, and is as effective as antagonism of Ang II receptors in reducing vascular medial hypertrophy. They also indicate that, in addition to Ang II, aldosterone may play a pivotal role in regulating the growth of cardiac myocytes and vascular smooth muscle cells during Ang II-dependent hypertension. (Hypertens Res 1994; 17 233-237)

Binding of spironolactone metabolites in vivo to renal mineralocorticoid receptors in guinea pigs.

Spironolactone (SL) is a mineralocorticoid antagonist used clinically to treat hypertension and congestive heart failure. Its mechanism of action involves competitive binding to aldosterone receptors in the kidneys, resulting in diuresis. It is known that the actions of SL are mediated by metabolites of the drug, but the active metabolites have not been definitively identified. Accordingly, studies were done to determine which metabolites bind to renal mineralocorticoid receptors after SL administration to guinea pigs. The major metabolite found in the steroid receptor fraction of kidney cytosol was 7 alpha-thiomethyl-SL (TM). Incubation of kidney cytosol with varying concentrations (0-100 pmol/l) of aldosterone resulted in the concentration-dependent displacement of TM from the steroid receptor fraction. The steroid receptor fraction from renal nuclei of SL-treated animals contained approximately equal concentrations of TM, 7 alpha-thio-SL (TH), and canrenone (CAN). Incubation of kidney nuclei with aldosterone caused a concentration-dependent displacement of all three metabolites. The results indicate that TM is the major SL metabolite that interacts with cytosolic mineralocorticoid receptors in kidneys, but that TH and CAN may contribute to nuclear receptor binding.

Renal sodium handling and neurohumoral systems in patients with cirrhosis in sitting posture: effects of spironolactone and water immersion

Renal sodium handling, neurohumoral systems, and systemic hemodynamics were investigated under baseline conditions in sitting posture in 10 healthy subjects, 11 patients with cirrhosis without, and 10 patients with cirrhosis with ascites. Furthermore, the effects of head-out water immersion, 1-week spironolactone administration, or their combination was assessed in the two groups of patients. Patients without ascites exhibited a significant increase in plasma norepinephrine concentration and a tendency toward an increase in plasma aldosterone concentration. Patients with ascites had a significantly lower mean arterial blood pressure despite significant reduction of urinary sodium excretion and fractional sodium excretion as well as an increase of plasma renin activity, plasma aldosterone, and norepinephrine concentration. In patients with ascites, the increase in renal sodium excretion and fractional sodium excretion following water immersion or spironolactone was clearly augmented by the combination of the two maneuvers. The same pattern was observed in patients without ascites. Our findings (a) underscore the importance of studying hemodynamics, renal function, and neurohumoral systems also in upright posture, (b) suggest a role of sympatico-adrenergic activation and proximal sodium retention in preascitic patients, and (c) are compatible with the vasodilation hypothesis of ascites formation.

Dose-related cardiovascular effects of spironolactone

The aim of this study was to assess the shortterm hemodynamic effects of increasing doses of spironolactone (25, 50, and 75 mg/day) on oligurie patients (5 men, mean age 47 ± 12 years) undergoing hemodialysis for chronic renal impairment. Parameters of interest included heart rate (HR), cardiac output, systemic vascular resistance (SVR), arterial pressure, right atrial pressure, and pulmonary capillary wedge pressure (PCWP). The study also evaluated how spironolactone modified the effects on arterial and right atrial pressures and PCWP of infusion of increasing doses of norepinephrine (20, 40, and 100 ng/ kg/min) and angiotensin II (2, 4, and 10 ng/kg/ min). Compared with placebo, the lowest dose of spironolactone (25 mg/day) produced statistically significant (p < 0.05) modifications in systemic arterial pressures without a compensatory increase in cardiac output. The modifications were more pronounced at 50 and 75 mg/day, and the latter had a significant dose-dependent effect. Moreover, doses of 50 and 75 mg/day produced significant (p < 0.05) decreases in right atrial pressure and PCWP. Spironolactone administration caused the curve expressing the relation between an infused norepinephrine or angiotensin II dose and the blood pressure response to shift significantly (p < 0.05 to <0.01) to the right, and the pressor doses of norepinephrine or angiotensin II showed a significant (p < 0.05 to <0.01) dose-related increase, suggesting that treatment with spironolactone inhibited cardiovascular reactivity. This effect was observed on both the capacitance (i.e., low-pressure) and resistance (i.e., high pressure) vessels. Thus, an important dose-related effect of spironolactone on both the high- and low-pressure systems appears to play a major role in the drug's vascular and antihypertensive effects.

Effect of spironolactone on cytosolic free sodium concentration in platelets from hypertensive patients with primary aldosteronism

Cytosolic free sodium concentration ([Na+]i) was investigated in intact platelets from 5 hypertensive patients with primary aldosteronism (unilateral adenoma in 3 patients, and adrenal hyperplasia in 2 patients) and 21 normotensive control subjects. [Na+]i was measured using a novel sodium-sensitive fluorescent dye technique. [Na+]i was significantly decreased in platelets from patients with primary aldosteronism compared to control subjects (21.9 +/- 4.1 mM vs 35.8 +/- 2.2 mM, mean +/- SEM, P < 0.05). After administration of the mineralocorticoid antagonist spironolactone in 4 patients [Na+]i tended to be higher in platelets although the differences did not reach statistical significance (26.3 +/- 7.2 mM vs 18.2 +/- 2.4 mM, P = 0.125). From the present results it may be concluded that intracellular sodium is decreased by aldosterone-induced activation of Na-K-ATPase. That activation may be partly blocked by spironolactone.

Plasma volume contraction in portal hypertension

The effect of blood volume contraction induced by a 4-week regimen of spironolactone (100 mg/day) or furosemide (40 mg/day) on the hepatic venous pressure gradient (HVPG), an indicator of portal hypertension, was evaluated in patients with cirrhosis and no ascites. In the spironolactone group (n = 15), HVPG decreased significantly from 16.5 +/- 0.9 mmHg (mean +/- S.E.M.) to 12.9 +/- 1.0 mmHg (P < 0.005) and total blood volume contracted significantly from 4338 +/- 231 ml to 4006 +/- 203 ml (n = 14, P < 0.01). Although the HVPG changes did not correlate significantly with changes in measured total blood volume or in simultaneously determined systemic haemodynamics, a significant inverse correlation (r = -0.74, P < 0.01, n = 12) was found between the HVPG change and posttreatment plasma aldosterone levels, attesting to the effectiveness of spironolactone therapy in lowering HVPG. In the furosemide group (n = 10), neither HVPG (13.7 +/- 0.3 mmHg vs. 13.6 +/- 0.9 mmHg) nor total blood volume (4961 +/- 153 ml vs. 4964 +/- 162 ml) declined significantly. These results show that long-term administration of spironolactone to patients with cirrhosis and no ascites produced a significant reduction in HVPG that may have been due to gradual, sustained volume contraction. Thus, spironolactone may prove to be an effective treatment for portal hypertension in cirrhosis without ascites.

Dietary restriction sensitizes the rat distal colon to aldosterone.

1. The effects of starvation and undernutrition were assessed on rat colonic electrogenic Na+ absorption in fed controls, 72 h starved and acute undernourished (fed one-third of the control group's daily food intake for up to 9 days). The basal short-circuit currents (Isc) of three segments of rat colon (proximal, mid- and distal), stripped of their external muscle layers were monitored before and during addition of 0.1 mM-mucosal amiloride. The decrease in Isc was used as the measure of the electrogenic Na+ absorption. 2. Acute undernutrition and to a lesser extent 72 h starvation elevated the basal Isc only in the distal colon. The increase was inhibited by amiloride (0.1 mM, mucosal) indicating that it was due to electrogenic Na+ transport. 3. Allowing the 9 days acute undernourished rats to drink 0.9% NaCl failed to prevent the increase in the basal Isc in the distal colon but it was reduced by administration of spironolactone. 4. Adrenalectomy completely abolished the increased basal Isc in the distal colon induced by the 9 day undernutrition. However, the plasma aldosterone levels in the fed and 9 day undernutrition groups were not significantly different. 5. Injection of aldosterone into adrenalectomized rats drinking 0.9% NaCl and which were undernourished for 9 days induced a large increase in their distal colonic Isc which was inhibited by mucosal amiloride. Similar treatment of sham-operated rats on 0.9% NaCl or adrenalectomized control fed rats on 0.9% NaCl had no effect on the distal colonic Isc. 6. The results indicate that acute undernutrition for 9 days makes the distal colonic epithelium more sensitive to the prevailing plasma aldosterone level allowing an enhanced electrogenic Na+ absorptive capacity to be induced.

Are Angiotensin Converting Enzyme Inhibition and Aldosterone Antagonism Equivalent in Hypertensive Patients Over Fifty?

The effects of inhibiting angiotensin converting enzyme with perindopril and aldosterone with spironolactone were tested in hypertensive patients over fifty. Accordingly, 75 patients with mild hypertension aged 50 to 70 were randomly divided into three groups for a double-blind 8 week comparison of the actions of placebo, 4 to 8 mg/day perindopril, and 37.5 to 75 mg/day spironolactone. Side-effects caused one patient to withdraw from placebo and one from spironolactone treatment. Mean blood pressure rose by 2.4 mm Hg after placebo but dropped by 7.4 and 8.6 after perindopril and spironolactone (P less than .01). Placebo, perindopril, and spironolactone did not alter blood glucose or plasma potassium, but induced, respectively, variations of -0.09, 0, and +0.34 mmol/L in cholesterol (P = .04), and -0.02, -0.05, and +0.27 mmol/L in triglycerides (P less than .01). After the three treatments, changes in angiotensin converting enzyme activity averaged -1, -6, and -1 mU/mL (P less than .01), in active renin -2, +18, and +28 pg/mL (P less than .01), and in aldosterone, +15, +8, and +95 pg/mL (P less than .01). Placebo, perindopril, and spironolactone did not alter microalbuminuria, but reduced urinary kallikrein activity by 0.9, 1.8, and 5.4 mU/mmol creatinine (P = .04). Although short-term administration of spironolactone raised renin and aldosterone markedly and lipids moderately (possibly because of volume contraction), the present results show that perindopril and spironolactone are both safe and effective for treating hypertension at the age of 50 or older.

Effect of spironolactone and phenobarbital administration on bilirubin glucuronidation in hepatic and extrahepatic rat microsomes

We compared bilirubin glucuronidation in liver, renal cortex and intestinal mucosa rat microsomes in order to investigate the effect of individual and combined administration of PB and SP on the formation of bilirubine monoglucuronide (BMG) isomers and bilirubine diglucuronide (BDG)

Aldosterone in Congestive Heart Failure: Analysis of Determinants and Role in Sodium Retention

In patients with congestive heart failure (CHF), the role of aldosterone in the abnormal sodium (Na+) retention and the determinants of plasma aldosterone (PA) including plasma atrial natriuretic factor (hANF), plasma renin activity (PRA), and plasma potassium (K+) have not been fully elucidated. We therefore studied the effect of the specific aldosterone antagonist, spironolactone, on urinary Na+ and K+ excretion and plasma hormone responses in 6 Na(+)-retaining CHF patients. After withdrawal of diuretics 4 days prior to the study, the CHF patients were placed on a Na+ intake of 100 mmol/day for 9 days. Spironolactone, 200 mg p.o. bid, was administered for the last 4 days of the 9-day study period. PRA and norepinephrine increased with spironolactone treatment (both p less than 0.05). Plasma hANF before spironolactone was significantly elevated and decreased during spironolactone therapy (p less than 0.05). Urinary Na+ excretion significantly increased during spironolactone administration and the positive Na+ balance was reversed in the CHF patients. Moreover, the urine Na+:K+ concentration ratio significantly increased during spironolactone administration. Analysis of the relationship between PA, plasma K+, PRA, and plasma hANF indicated that PRA is the primary determinant of PA in patients with CHF. Thus, the present results indicate that the renin-angiotensin-aldosterone system is an important mediator of Na+ retention in CHF, as evidenced by the reversal of the positive Na+ balance with a specific aldosterone antagonist. This natriuretic effect can be demonstrated in the presence of potential antinatriuretic influences including stimulation of the renin-angiotensin and sympathetic nervous systems and a decrease in plasma hANF.

Effect of Chronic Treatment with Clonidine and Spironolactone on Cold-Induced Elevation of Blood Pressure

The present study was designed to determine whether antihypertensive agents known to affect the renin-angiotensin-aldosterone (RAA) system might affect the elevation of blood pressure induced by chronic exposure to cold. Spironolactone, a mineralocorticoid receptor blocker, was added to the food and administered to rats chronically exposed to cold. In addition, clonidine, and alpha 2-adrenergic agonist and inhibitor of renin secretion, was administered to another group of cold-exposed rats by daily intraperitoneal injection. A warm-adapted and a cold-treated control group were also used. Chronic administration of spironolactone prevented the development of hypertension but failed to prevent other adaptive physiological changes characteristically occurring during exposure to cold and seen in the cold-treated control rats. Thus, increased weight of the heart, kidneys, adrenals and brown adipose tissue, increased dipsogenic responsiveness to angiotensin II, increased urinary outputs of norepinephrine and epinephrine, and increased food and water consumption were observed in all rats, treated and untreated, during exposure to cold. Similarly, daily injection of clonidine attenuated the elevation of blood pressure but also failed to prevent the other adaptive physiological changes characteristic of cold. These results are consistent with the hypothesis that the RAA system plays a role in the development of the cold-induced elevation of blood pressure.

Sex differences in spironolactone induction of rat intestinal and hepatic p-nitrophenol UDP-glucuronyltransferase

In the present study we analyzed the effect of spironolactone administration on hepatic and intestinal p-nitrophenol-UDP-glucuronyltransferase activity. We used microsomal preparations from male and female Wistar rats to establish whether or not this effect was sex dependent. Enzyme activity was measured in the presence of UDP-N-acetylglucosamine, a presumed physiological activator of the enzyme. Female but not male microsomes showed an increase in enzyme activity of both hepatic and intestinal tissue preparations in response to the inducer pretreatment. In addition, the inducer effect observed in female rats showed a tissue-related difference, since percent increase in the intestinal enzyme activity was greater than that in the liver (127 and 52%, respectively). These results suggest that factors regulating enzyme activity or mechanisms involved in the inducer effect of spironolactone could be different in the intestinal mucosa in comparison to the liver. A possible explanation of sex-related response to spironolactone administration was discussed.

Peripheral action of spironolactone: Improvement in arterial elasticity

Arterial elasticity, which can be assessed by means of a piezogram, is thought to be involved in the development of hypertension. In hypertensive patients (and with aging in normal subjects), arterial elasticity is reduced. Long-term administration of spironolactone, β blockers, or a β-blocker/dihydralazine combination to hypertensive patients sufficiently reduced systolic and diastolic blood pressure to about the same extent; however, only spironolactone had any effect on piezoelectric indexes of arterial elasticity.

Aldosterone and glucocorticoid receptor-specific agonists regulate ion transport in rat proximal colon

Dietary sodium depletion increases electroneutral Na-Cl absorption and potassium secretion in the proximal colon of the rat. Although sodium depletion results in secondary hyperaldosteronism, the stimulation of electroneutral Na-Cl absorption is not a typical mineralocorticoid-mediated event. These studies were performed to determine whether the aldosterone or glucocorticoid receptor mediates these changes in electrolyte transport. Continuous infusion of aldosterone at 70 micrograms.100 g body wt-1.day-1 for 7 days resulted in a significant increase in net Na+ and Cl- absorption (5.5 +/- 0.8 and 5.9 +/- 1.0 mueq.h-1.cm-2, respectively). A 7-day infusion of RU 28362, a glucocorticoid receptor-specific agonist, at 70 micrograms.100 g body wt-1.day-1 similarly increased net Na+ and Cl- absorption (5.4 +/- 1.3 and 4.1 +/- 0.5 mueq.h-1.cm-2, respectively). Both aldosterone and RU 28362 produced a minimal increase in Isc (0.4 +/- 0.2 and 0.8 +/- 0.2, respectively). Administration of spironolactone prevented the stimulation of Na+ absorption induced by aldosterone but not that by RU 28362, and aldosterone but not RU 28362 stimulated active potassium secretion. These studies indicate that aldosterone mediates the stimulation of both electroneutral Na-Cl absorption and K+ secretion produced by dietary sodium depletion and that both aldosterone and glucocorticoid agonists each stimulate electroneutral Na-Cl absorption as a result of interacting with the mineralocorticoid and glucocorticoid receptors, respectively.

A CASE OF ADVANCED BREAST CANCER WITH SEVERE FUNNEL CHEST AND OPERATED AORTIC DISSECTION (TYPE I)

A 40-year-old single woman being suffered from severe funnel chest from her childhood had Bentall's operation for aortic dissection (DeBakey type I) 2 years before. After that the patient had been administered spironolactone, a diuretic, orally for 2 years. This time, the patient underwent standard radical masatectomy for right breast cancer. Histological examination revealed a papillotubular carcinoma with extensive lymphatic invasion and metastasis, and it was classified into stage III (t2, n2, M0). The patient is doing well 2 years after mastectomy. Two interesting problems in this case were: how to make the skin incision for the breast cancer complicated with severe funnel chest; and that the long-term administration of spironolactone might somewhat contribute to the occurrence of breast cancer etiologically because of its histological features.

Identification and implications of new types of mineralocorticoid hypertension

200 patients with mineralocorticoid hypertension were studied at the Clinical Study Center. The study of 150 patients with primary aldosteronism revealed five distinct subsets based on their responses to the upright posture, after administration of intravenous saline, deoxycorticosterone acetate, and spironolactone. Two new types were identified—aldosterone producing responsive adenoma (AP-RA) and primary adrenal hyperplasia (PAH). Patients with AP-RA maintained normal physiologic responses to the above maneuvers. Patients with PAH had responses similar to patients with an aldosterone producing adenoma (APA) but no tumor was identified. Both types were cured by unilateral adrenalectomy. There has been no change in subtype in up to 20 years of follow-up. The notion of a continuum from low renin hypertension to APA is not supported. Primary deoxycorticosteronism caused by a benign adrenal adenoma, malignancy and hyperplasia is described. Uniquely, overproduction of the 17-deoxysteroids of the zona fasciculata occurs with normal 17-hydroxy function. After the removal of a benign adenoma the contralateral adrenal gland revealed a delay in the 17-deoxysteroid responses to ACTH in the face of normal cortisol increases. This suggests that an independent pituitary regulator of the 17-deoxypathway may exist. Other hypertensive disorders with excessive deoxycorticosterone production are linked with increases of ACTH and cortisol levels. The hallmarks of primary deoxycorticosteronism are hypertension with hypokalemia, suppression of renin and aldosterone, and overproduction of the 17-deoxysteroids.

A possible role for testosterone during luteolysis in the ewe

Increased peripheral plasma concentrations of testosterone were detected at the commencement of luteolysis and at oestrus in sheep. Daily subcutaneous administration of spironolactone (10 mg kg-1) between days 10 and 16 of the oestrous cycle suppressed testosterone secretion and delayed luteolysis and oestrus. In pregnant ewes no increases in testosterone concentrations occurred between days 10 to 16 after mating and luteal regression, monitored by peripheral progesterone concentrations, was inhibited. It is suggested that aromatisation of testosterone to oestrogens is needed for luteolysis in sheep.