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PubMed1997

Improved bioavailability and clinical response in patients with chronic liver disease following the administration of a spironolactone: beta-cyclodextrin complex.

AIMS: To compare the absorption and clinical effect of spironolactone from an inclusion complex with beta-cyclodextrin (SP-COMP) to Aldactone tablets (ALD) in chronic liver disease. METHODS: Patients, admitted with chronic liver disease, completed a randomized crossover steady state study. They received their spironolactone dose as either daily SP-COMP or ALD for 7 days. Serial blood samples were drawn over a 24 h period from day 7 of each therapy. Accurate fluid balance was recorded on days 5-7 and 12-14. Thirteen (six females) whose mean (s.d.) age and weight was 58.4(9.3) years and 74.3(19.0) kg completed the study. RESULTS: The mean (95% confidence limits) relative bioavailability for SP-COMP (compared with ALD) from steady state serum concentrations of canrenone, 6beta-hydroxyl 7alpha-thiomethyl spironolactone and 7alpha-thiomethyl spironolactone was 310.0 (265.4, 336.7), 233.4(212.9, 250.8) and 254.8(230.8, 279.0)%, respectively. Improvements in clinical status and fluid balance occurred over the last 3 days of SP-COMP with a mean (s.d.) net loss, in fluid balance, of 1370(860)ml compared with a gain of 228(936)ml during ALD. CONCLUSIONS: Better absorption of spironolactone from the spironolactone: beta-cyclodextrin complex formulation should lead to a reduction in dosage and perhaps a more consistent effect in patients with chronic liver disease.

Biological Availability↗
PubMed2000

Effects of spironolactone on systolic blood pressure in experimental diabetic rats.

BACKGROUND: Mineralocorticoid hormones, which maintain electrolyte balance and blood pressure, are thought to be associated not only with the expression of renal 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), but also with that of intracellular mineralocorticoid receptors (MRs). The present study was designed to test whether the mineralocorticoid action of glucocorticoid corticosterone on renal MR is involved in the development of diabetes-associated hypertension by measuring the alterations of renal 11beta-HSD2. METHOD: We measured the mean systolic blood pressure, renal 11beta-HSD1, and mRNA levels in streptozotocin (STZ)-induced diabetic rats that received spironolactone, insulin, or no treatment, and in nondiabetic controls that received spironolactone. RESULTS: Four weeks after an injection of STZ, the renal 11beta-HSD2 and mRNA levels were significantly lower in diabetic rats than in control rats, and the mean systolic blood pressure was 14.8% higher in diabetic rats than in controls. Subcutaneous injections of spironolactone into diabetic rats for three weeks partially reversed the decrease in renal 11beta-HSD2 activity and gene expression, and prevented the mean systolic blood pressure elevation. Spironolactone treatment for one week also resulted in a significant reduction in mean systolic blood pressure during the development of diabetic hypertension. However, treatment with STZ did not significantly decrease the renal 11beta-HSD1 activity and mRNA expression, and spironolactone treatment did not exert a significant effect on this enzyme in STZ-induced diabetic rats. CONCLUSION: In the development of diabetes-induced hypertension, the effect of spironolactone on mean systolic blood pressure may be associated with the mineralocorticoid effects of corticosterone on renal MR, as well as an alteration of renal 11beta-HSD2 activity and its mRNA expression in insulin-dependent diabetic rats.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2005

Effect of spironolactone on blood pressure and the renin-angiotensin-aldosterone system in oligo-anuric hemodialysis patients.

BACKGROUND: Through its actions on nonepithelial tissues, including brain, blood vessels, and heart, aldosterone may mediate hypertension, cardiac hypertrophy, and fibrosis. Whether aldosterone has a direct pathogenic role in the development of cardiovascular complications in patients with end-stage renal disease is unknown. Oligo-anuric dialysis patients provide a clinical setting to study the effects of the mineralocorticoid receptor blocker spironolactone that are independent of the diuretic properties of the drug. We performed a randomized, double-blinded, placebo-controlled, crossover study to assess the effect of spironolactone on blood pressure and the renin-angiotensin-aldosterone system in oligo-anuric hemodialysis patients. METHODS: Eight hemodialysis patients were administered either spironolactone, 50 mg, or placebo orally twice daily for 2 weeks, followed by a 3-week washout period, after which patients crossed over in their treatment arms for 2 more weeks. RESULTS: Administration of spironolactone for 2 weeks decreased predialysis systolic blood pressure from 142.0 +/- 19.6 to 131.4 +/- 18.2 mm Hg (P < 0.05). Compared with placebo, a 2-week course of spironolactone had no effect on predialysis and postdialysis plasma potassium or aldosterone concentrations or renin activity. CONCLUSION: When administered for 2 weeks, spironolactone, 50 mg twice daily, reduced predialysis systolic blood pressure, but did not produce hyperkalemia in oligo-anuric hemodialysis patients.

Adult↗
PubMed1975

[Spironolactone and thiabutazide in the treatment of essential hypertension (author's transl)].

The anti-hypertensive effect of spironolactone and thiabutazide was tested on 47 unselected patients with primary hypertension. They were divided into two groups according to the change in plasma-renin activity in response to furosemide administration: those with and those without response to stimulation, and sub-groups with low, normal or high plasma-renin activity (low renin hypertension; normal renin hypertension; high renin hypertension). During both 4-week treatment periods there was a distinct fall in systolic blood pressure, most marked in the patients without plasma renin stimulation (after spironolactone of about 26.2 mm Hg, after thiabutazide 29 mm Hg), the diastolic pressure fall being only slight in all groups (about 5-10 mm Hg). The plasma-renin activity and plasma-aldosterone concentration increased in all groups, after both spironolactone and thiabutazide three-to fourfold compared with the basal value, even in patients without change in plasma-renin activity after furosemide injections. Serum sodium content decreased after administration of spironolactone, increasing again after subsequent thiabutazide administration. Serum potassium content increased after spironolactone, decreasing after thiabutazide. There was no significant difference between either individual groups or different treatment periods with spironolactone or thiabutazide as far as weight, urine volume or electrolyte excretion in 24-hour urine was concerned.

Aldosterone↗
PubMed2002

Furosemide and spironolactone reduce transmigration of leukocytes through endothelial cell monolayers.

Furosemide and spironolactone reduce transmigration of leukocytes through endothelial cell monolayers. Leukocytes play a tremendous role during inflammation. Leukocytes migrate from intravascular space into the tissue to attack microorganisms. Various agents are able to influence leukocyte recruitment. The influence of diuretics, such as furosemide and spironolactone, on inflammatory processes is not well known. The aim of our study was to examine the influence of furosemide and spironolactone on leukocyte migration through endothelial cell monolayers (ECM). Human umbilical vein endothelial cells were cultured on microporous membranes achieving a monolayer. Polymorphonuclear leukocytes (PMNL) were used in a currently described migration assay. PMNL and/or ECM were pretreated with furosemide and spironolactone using therapeutic, as well as higher and lower, concentrations. Furosemide (76 +/- 7.2%) and spironolactone (70 +/- 7.7%) were able to inhibit PMNL migration through ECM significantly, when both cell types were treated simulating the situation after an iv injection. Furosemide and spironolactone were identified as potent inhibitors of leukocyte migration through ECM.

Cell Adhesion↗
PubMed1993

Spironolactone directly inhibits proliferation of cultured human facial sebocytes and acts antagonistically to testosterone and 5 alpha-dihydrotestosterone in vitro.

Spironolactone produces antiacne effects and has recently been shown to inhibit 5 alpha-dihydrotestosterone (5 alpha-DHT) receptors in human sebaceous glands. We applied spironolactone alone and combined with testosterone and 5 alpha-DHT to investigate its effects on the proliferation of human sebocyte cultures derived from facial skin. Secondary human facial sebocytes in 96-well culture plates were treated for 10 d by a single or combined application of testosterone (10(-8)-10(-5) M), 5 alpha-DHT (10(-8)-10(-5) M), and spironolactone (10(-12)-10(-7) M) in serum-free basal medium. Cell proliferation was assessed in six wells using a fluorometric assay. Testosterone and 5 alpha-DHT significantly stimulated sebocyte proliferation in a dose-dependent manner, the effect being strongest with 5 alpha-DHT. Spironolactone, on the other hand, caused a dose-dependent inhibition (25% and 50% at 10(-9) and 10(-7) M, respectively). Combined treatment of human facial sebocytes with spironolactone and testosterone or 5 alpha-DHT resulted in a lower proliferation than with androgens alone. The fact that spironolactone directly and dose dependently inhibits the proliferation of cultured human facial sebocytes and acts antagonistically to testosterone and 5 alpha-DHT at the cellular level is indicative of a receptor-mediated effect.

Cell Division↗
PubMed1983

Use of a bioassay in healthy men to evaluate diuretic-spironolactone combinations.

The plasma potassium responses to 1 week's treatment with metolazone 0.625 mg, 1.25 mg and 2.5 mg in combination with spironolactone 50 mg, and metolazone 2.5 alone were examined in a double-blind, crossover study in twelve healthy subjects. Spironolactone attenuated the hypokalaemia induced by metolazone--addition of spironolactone 50 mg to metolazone 2.5 mg raised plasma potassium by 0.18 mmol/l (P less than 0.025). In the presence of spironolactone, a linear log metolazone dose-plasma potassium response relationship (P less than 0.01) was demonstrated. Spironolactone was unable to compensate fully for metolazone's hypokalaemic effect although in combination with metolazone 0.625 mg and 1.25 mg, plasma potassium concentration was maintained close to pretreatment levels. The human bioassay employed provided conveniently quantitative information which allows the rational development of a fixed dose diuretic-spironolactone combination tablet.

Adult↗
PubMed1984

Metabolic effects of high dose amiloride and spironolactone: a comparative study in normal subjects.

Amiloride (75 mg daily) and spironolactone (300 mg daily) were given to five normal subjects for 7 days in order to compare metabolic effects at maximal doses. Blood pressure, body weight, Na+ and K+ balance, and plasma concentrations of Na+, K+, active and total renin, angiotensin II, aldosterone, 11-deoxycorticosterone (DOC), 18-hydroxydeoxycorticosterone (18-OH DOC), corticosterone (B), 18-hydroxycorticosterone (18-OH B) and cortisol were measured before and on each day of treatment. Natriuresis and K+ retention were significantly greater with amiloride. Plasma K+ increased from 4.1 +/- 0.2 to 4.9 +/- 0.2 mmol/l (mean +/- s.d.) on amiloride and from 4.0 +/- 0.2 to 4.4 +/- 0.2 mmol/l with spironolactone. Stimulation of renin, angiotensin II, aldosterone and 18-OH B occurred with both drugs but was greater with amiloride in each case. A transient decrease in systolic and diastolic blood pressure was observed after 2 days of spironolactone treatment but not with amiloride. The slope of the regression of aldosterone on angiotensin II during spironolactone treatment was less than that with amiloride, consistent with partial blockade of aldosterone synthesis by spironolactone. These data suggest that the maximum metabolic effects of amiloride exceed those of spironolactone.

Adult↗
PubMed1993

A comparison of the potassium and magnesium-sparing properties of amiloride and spironolactone in diuretic-treated normal subjects.

1. The relative potencies of amiloride (5 and 20 mg) and spironolactone (25 and 100 mg) for plasma and erythrocyte electrolytes were investigated in a double-blind, randomised, balanced, crossover study in 12 normal men treated concomitantly with hydrochlorothiazide 100 mg daily for 1 week. 2. Participants satisfied an a priori requirement for a fall in plasma potassium concentration of at least 0.5 mmol l-1 after 7 days of treatment with hydrochlorothiazide alone. 3. After hydrochlorothiazide alone, plasma potassium and sodium concentrations fell (P < 0.001). There were associated reductions in erythrocyte sodium (P < 0.01). Plasma magnesium concentration did not change, although erythrocyte magnesium decreased (P < 0.001). 4. Both amiloride and spironolactone attenuated the thiazide-induced fall in plasma potassium (relative potency, amiloride:spironolactone 10:1, 95% confidence interval 6.3-16.2:1). Amiloride but not spironolactone was associated with a dose-related increase in plasma magnesium; a relative potency estimation was precluded. There was little evidence of influences of amiloride or spironolactone on erythrocyte electrolytes. 5. On a weight basis, amiloride is ten times more potent than spironolactone as a potassium-sparing agent in diuretic-treated subjects but neither agent had major effects on erythrocyte potassium. The drugs may have divergent actions on magnesium handling; hydrochlorothiazide alone had no influence on plasma magnesium.

Adult↗
PubMed2006

Carvedilol accelerate elevation of serum potassium in chronic heart failure patients administered spironolactone plus furosemide and either enalapril maleate or candesartan cilexetil.

OBJECTIVE: To retrospectively investigate the effect of carvedilol and spironolactone plus furosemide, administered concomitantly with an angiotensin II converting enzyme inhibitor (ACE-I) or an angiotensin II receptor blocker (ARB) to patients with chronic heart failure (CHF). METHODS: Patients with CHF, who visited Departments of Cardiovascular Internal Medicine at the National Hospital Organization Osaka Medical Center, were enrolled for this study. Serum potassium, blood urea nitrogen (BUN), serum creatinine (Scr) and serum sodium were measured in every patient at the time of start of treatment and after 3 and 12 months of treatment. Data from patients in groups A (20 mg/day carvedilol + 25 mg/day spironolactone + 40 mg/day furosemide + an ACE-I) and B (20 mg/day carvedilol + 25 mg/day spironolactone + 40 mg/day furosemide + ARB) were compared. RESULTS: When 20 mg/day carvedilol plus 25 mg/day spironolactone plus 5 mg/day enalapril maleate (enalapril, group A) or 8 mg/day candesartan cilexetil (candesartan, group B) plus 40 mg/day furosemide were used concomitantly, the mean serum potassium increased significantly in both groups of patients. Seven of 59 (11.9%) patients had hyperkalemia (>5.5 mEq/L) during 12 months of treatment whereas 8.5% of patients (five of 59) had hypokalemia (< or =3.5 mEq/L). CONCLUSION: When carvedilol is used concomitantly with spironolactone, furosemide and enalapril or candesartan, it is necessary to monitor serum potassium concentration, even if spironolactone is administered at a low dose of 25 mg/day.

Adult↗
PubMedDate not supplied

Spironolactone further reduces urinary albumin excretion and plasma B-type natriuretic peptide levels in hypertensive type II diabetes treated with angiotensin-converting enzyme inhibitor.

1. Over the course of treatment with angiotensin-converting enzyme inhibitor (ACEI), plasma levels of aldosterone have been shown to increase and this increase would blunt the effectiveness of the ACEI (aldosterone escape phenomenon). 2. In the present study, we assessed a potential renal benefit of additional aldosterone blockade with spironolactone in hypertensive diabetic patients treated with ACEI showing the phase of aldosterone escape. 3. The present clinical study was a randomized prospective study to assess difference between the clinical effects of spironolactone and furosemide. Thirty hypertensive type II diabetics (DM2) with a urinary alubumin:creatinine ratio (ACR) above 30 mg/g creatinine (showing albuminuria) and plasma B-type natriuretic peptide (BNP) levels above 100 pg/mL (showing mild heart failure) were treated with an ACEI (imidapril 5 mg/day) for 1 year and then randomly divided into two groups, one group receiving additional spironolactone (25 mg/day) treatment and the other receiving furosemide (20 mg/day) treatment. Blood pressure, ACR and plasma BNP levels were monitored in both groups. 4. Treatment with the ACEI reduced ACR initially but, in 1 year, ACR tended to increase. Additional spironolactone treatment progressively reduced ACR, whereas furosemide treatment did not show any effect. Plasma BNP levels were reduced by ACEI and were further reduced by additional spironolactone treatment, but not furosemide treatment. Blood pressure levels in both groups were comparable. 5. In conclusion, additional therapy with spironolactone in ACEI treatment exerts a renoprotective, as well as cardioprotective, effect in hypertensive diabetes.

Albuminuria↗
PubMed2004

Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats.

BACKGROUND: Glomerular and tubulointerstitial injury leads to chronic impairment of renal function, and thus, reversal of the injury may improve renal function and survival. The present study investigated whether and how mineralocorticoid receptor antagonist spironolactone ameliorates early renal injury in streptozotocin-induced diabetic rats. METHODS: Streptozotocin (65 mg/kg, single intraperitoneal injection)- or vehicle-administered rats were used as diabetic or control rats, respectively. The streptozotocin-administered rats were treated with spironolactone (50 mg/kg/day sc) for 3 weeks. Among the 3 groups of rats, we compared renal fibrosis and renal hypertrophy, using picro-sirius red staining and immunohistochemistry of ED-1 macrophage marker, plasminogen activator inhibitor-1 (PAI-1), and transforming growth factor (TGF)-beta1. RESULTS: Three weeks after administration of streptozotocin, rats exhibited increased collagen deposition in glomerular, tubulointerstitial, and perivascular areas in the kidney, which was completely attenuated by spironolactone treatment. In rats given streptozotocin alone, there were increases in ED-1-positive cell, PAI-1 expression, and TGF-beta1 expression in glomeruli and tubulointerstitiums, which were also suppressed by spironolactone treatment. Maximal glomerular and proximal tubular areas were not significantly different among the 3 groups. Rats given streptozotocin alone revealed an increase in proximal tubule wall-to-lumen ratio that was not influenced by treatment with spironolactone. CONCLUSION: Streptozotocin-induced renal fibrosis, PAI-1 expression, TGF-beta1 expression, and macrophage infiltration occur via mineralocorticoid receptor, and spironolactone ameliorates renal fibrosis presumably via the inhibition of macrophage infiltration, PAI-1 expression, and TGF-beta1 expression in streptozotocin-induced early diabetic injury.

Animals↗
PubMed2005

Beneficial impact of spironolactone in diabetic nephropathy.

BACKGROUND: Aldosterone has been suggested to play a role in the initiation and progression of diabetic nephropathy. Currently recommended treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers [renin-angiotensin system (RAS) blockade] does not suppress circulating aldosterone sufficiently. We therefore aimed to evaluate the short-term effect of aldosterone antagonism with spironolactone on albuminuria and blood pressure in diabetic nephropathy. METHODS: Twenty Caucasian type 1 diabetic patients with persistent macroalbuminuria despite antihypertensive treatment, including RAS blockade, completed this double-masked, randomized cross-over trial. Patients were treated in random order with spironolactone 25 mg once daily and matched placebo for two months, respectively, on top of usual antihypertensive treatment. After each treatment period albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were determined. RESULTS: Spironolactone on top of usual antihypertensive treatment induced a 30% (95% CI 17 to 41) reduction in albuminuria from [geometric mean (95% CI)] 831 (624 to 1106) mg/24-hour on placebo treatment (P < 0.001), and a reduction in fractional albumin clearance of 35% (20 to 46, P < 0.001). Twenty-four-hour blood pressure showed an insignificant reduction of [mean reduction (95% CI)] 8 (-1 to 17)/3 (-0.2 to 7) mm Hg (P < 0.10). There was an insignificant reversible reduction in GFR during treatment with spironolactone. On spironolactone treatment, one patient was excluded due to hyperkalemia (plasma potassium 5.7 mmol/L) and one due to orthostatic dizziness. Otherwise treatment was well tolerated. CONCLUSION: Our results suggest that spironolactone treatment on top of recommended antihypertensive treatment reduces blood pressure and may offer additional renoprotection in type 1 diabetic patients with diabetic nephropathy.

Adult↗
PubMed2004

Influence of spironolactone treatment on gentamicin-induced nephrotoxicity in rats.

The effect of treatment of rats with gentamicin (80 mg/kg/day for 6 days), oral doses of spironolacatone (20 mg/kg/day for 6 days), and the combined treatment (spironolactone + gentamicin) on renal histology and reduced glutathione (GSH) concentration, and some serum constituents indicative of kidney function were studied. The serum concentrations of creatinine and urea were not significantly affected by spironolactone treatment, but were significantly elevated (P<0.05) by gentamicin administration. The antibiotic treatment also reduced GSH concentration and caused a moderate renal cortical necrosis. However, rats exposed to spironolactone + gentamicin revealed drastic increases in the serum urea and creatinine concentrations amounting to about 1.8 and 2.1 times those of rats treated with gentamicin alone, respectively. The histological examination of slides of the renal cortex of rats exposed to the combined drugs exhibited more extensive necrosis in the tubules when compared to those treated with gentamicin alone. The reduction in GSH induced by gentamicin was unaffected by the concomitant treatment of gentamicin and spironolactone. The concentration of gentamicin accumulated in the renal cortex was significantly larger (twofold) in rats treated concomitantly with spironolactone + gentamicin than in rats treated with gentamicin alone. The present results indicate that spironolactone aggravates gentamicin-induced nephrotoxicity in the rat.

Administration, Oral↗
PubMed1992

Absence of hepatic p-nitrophenol UDP-glucuronosyltransferase induction by spironolactone in male rats: possible involvement of testosterone.

This study was performed to determine whether the lack of spironolactone induction of hepatic p-nitrophenol UDP-glucuronosyltransferase in male rats could be attributed to a presumed interaction between spironolactone and testosterone. The effect of spironolactone was evaluated in four experimental groups: normal females, normal males, castrated males, and castrated males that received testosterone. Enzyme activity was measured in native microsomes and in microsomes activated with UDP-N-acetylglucosamine or Triton X-100. When the nucleotide was included in the incubations, it was observed that enzyme activity in castrated male rats decreased to values approaching those obtained in normal females. Treatment of castrated animals with testosterone enhanced enzyme activity so that no significant difference existed between this group and normal males. This suggests that testosterone may act as an endogenous inducer of hepatic p-nitrophenol glucuronidation. It was also found that only females and castrated males showed an increase in enzyme activity in response to spironolactone treatment. Thus, the absence of an additive effect of endogenous or exogenous testosterone and spironolactone on UDP-glucuronosyltransferase activity suggests that these compounds could share a common induction mechanism, which appears to reach its maximal capacity in male rats. Possible explanations of this observation are discussed. From the analysis of enzyme activity in native and Triton X-100 activated microsomes, it can be postulated that spironolactone enzyme induction in female and castrated male rats could be attributed to an enhancement in the transferase synthesis rather than to an alteration of the membrane environment.

Animals↗
PubMed1988

Effect of spironolactone on glucocorticoid-induced colonic cation transport.

Glucocorticoids stimulate colonic sodium absorption. Whether this stimulation is mediated by crossover binding to the aldosterone receptor has not been established. The effect of the aldosterone receptor antagonist, spironolactone, on dexamethasone-mediated transport was investigated in proximal and distal colon of adrenalectomized rats. In adrenal-intact control rats spironolactone minimally affected sodium absorption but markedly decreased the transmural potential difference (PD). In adrenalectomized, aldosterone-replaced rats spironolactone clearly decreased sodium absorption and transmural PD in both proximal and distal colon. In adrenalectomized rats treated with 5 micrograms/100 g body wt of dexamethasone twice daily spironolactone did not decrease sodium absorption or transmural PD. However, when adrenalectomized rats were treated with 25 micrograms/100 g body wt of dexamethasone, a dose estimated from plasma levels to occupy 80% of colonic aldosterone receptors, spironolactone inhibited 20% of proximal colon and 47% of distal colon sodium absorption. Thus lower doses of glucocorticoid which predominantly occupy glucocorticoid receptors stimulate sodium absorption by a spironolactone independent mechanism. When the levels of glucocorticoid are high enough to also occupy the majority of aldosterone receptors, sodium absorption is stimulated by an aldosterone receptor mediated mechanism.

Adrenalectomy↗
PubMed2000

Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure.

BACKGROUND: The RALES study showed that spironolactone, added to conventional therapy for chronic heart failure, dramatically reduced mortality. We tested the hypothesis that this benefit was partially due to improvement in endothelial function and/or to amplified suppression of the vascular renin-angiotensin axis. METHODS AND RESULTS: We performed a randomized, placebo-controlled, double-blind crossover study on 10 patients with NYHA class II to III chronic heart failure on standard diuretic/ACE inhibitor therapy, comparing 50 mg/d spironolactone (1 month) versus placebo. Forearm vasculature endothelial function was assessed by bilateral forearm venous occlusion plethysmography using acetylcholine and N-monomethyl-L-arginine (L-NMMA), with sodium nitroprusside as a control vasodilator. Also, vascular ACE activity was assessed by use of angiotensin (Ang) I, with Ang II as a control vasoconstrictor. Spironolactone significantly increased the forearm blood flow response to acetylcholine (percentage change in forearm blood flow [mean+/-SEM], 177+/-29% versus 95+/-20%, spironolactone versus placebo; P<0.001), with an associated increase in vasoconstriction due to L-NMMA (-35+/-6% versus -18+/-4%; P<0.05). The Ang I response was also significantly reduced with spironolactone (P<0.05), with Ang II responses unaltered. CONCLUSIONS: Spironolactone improves endothelial dysfunction, increases NO bioactivity, and inhibits vascular Ang I/Ang II conversion in patients with heart failure, providing novel mechanisms for its beneficial effect on cardiovascular mortality.

Aged↗
PubMed1996

New activity of spironolactone. Inhibition of angiogenesis in vitro and in vivo.

BACKGROUND: The formation of new blood vessels (angiogenesis) is a critical component in a variety of pathological settings, including solid tumor growth, macular degeneration, and atherosclerosis. METHODS AND RESULTS: We have found that orally administered spironolactone inhibited the area of angiogenesis induced by basic fibroblast growth factor (bFGF) in a rabbit corneal micropocket assay. Additionally, spironolactone inhibited bFGF- and vascular endothelial growth factor-stimulated capillary endothelial cell proliferation in vitro, inhibited bFGF-stimulated capillary endothelial cell chemotaxis in vitro, and caused avascular zones when placed on the chick chorioallantoic membrane. Experiments analyzing spironolactone metabolites revealed that the major human metabolites 6 beta-hydroxy-7 alpha-thiomethyl spironolactone and canrenoic acid retained antiangiogenic activity. The antiangiogenic activity appears to be unrelated to the antiandrogenic and antimineralocorticoid effects of spironolactone. CONCLUSIONS: These experiments hold promise for the potential use of spironolactone as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.

Animals↗