Role of atrial natriuretic peptide in mineralocorticoid escape phenomenon in patients with primary aldosteronism

The withdrawal effect of spironolactone treatment on natriuresis was studied in relation to atrial natriuretic peptide (ANP) in five patients with primary aldosteronism due to adenoma. The patients had been treated with spironolactone for 2-3 months before they were admitted. After admission, blood pressure, body weight, and urinary excretion of sodium were measured daily. Venous samples were obtained twice a week for measurements of plasma levels of ANP, plasma renin activity (PRA), and plasma concentrations of aldosterone (PAC), cortisol, and deoxycorticosterone. The study was performed for 7 days during the treatment with spironolactone and for 18 days after stopping the administration. Plasma volume was determined two times, during the control period and on the 13th day after stopping spironolactone. Urinary sodium excretion decreased initially and returned to the control levels successively. Body weight and plasma volume increased, and blood pressure rose steadily. PRA and the plasma concentrations of cortisol and deoxycorticosterone decreased significantly (P less than 0.05); however, high levels of PAC did not alter significantly. Plasma ANP levels increased significantly (P less than 0.05) from 26 +/- 4 pg/ml during the control period to 195 +/- 47 pg/ml on the 13th day after stopping spironolactone. The data of the urinary sodium excretion showed the escape from sodium-retaining effect of aldosterone, and this escape could be explained by the increase in plasma ANP. Furthermore, ANP might contribute to the decrease in cortisol and deoxycorticosterone in plasma because of the direct inhibitory action of ANP on steroidogenesis.     

Effect of metformin and spironolactone therapy on OGTT in patients with polycystic ovarian syndrome - a retrospective analysis

Background: Metformin (an insulin sensitizer) and spironolactone (an antiandrogen) are both used for treatment of polycystic ovary syndrome. We analyzed the effect of 6 months of therapy with these drugs on body weight and glucose tolerance. Results: This was a retrospective analysis of polycystic ovarian syndrome (PCOS) cases on treatment. There were 88 patients with PCOS-42 were on metformin 1 g daily and 46 were taking spironolactone 50-75 mg daily. 21 of 42 had abnormal glucose tolerance (AGT) in the metformin group and 13 of 46 had AGT in the spironolactone group. Patients on metformin reported a greater reduction in body weight, whereas there was no change in body weight with spironolactone therapy (67.6-63.7 versus 59.6-59.2 kg). There was a significant reduction in the 1 and 2 h glucose and insulin levels with metformin therapy in those with AGT. However, fasting glucose increased in those with normal glucose tolerance. There was no change in either body weight or insulin levels with spironolactone. But, there was a significant reduction in both the 0 and 2 h glucose with spironolactone also in those with AGT. Conclusion: Spironolactone and metformin had similar effect in reducing the glucose levels in PCOS patients with AGT. PCOS patients with normal glucose tolerance had higher fasting plasma glucose at the end of 6 months of metformin therapy inspite of weight reduction.     

Metabolic Studies on Patients with Resistant Heart Failure Treated by Spironolactone

Metabolic balance studies were carried out on five patients with resistant heart failure treated with spironolactone and other diuretics. Spironolactone alone had little effect. When it was used in a daily dose of 400-600 mg. in combination with hydrochlorothiazide 100 mg. daily, the results were excellent in two patients. One of these was still free of failure after 12 months on combined therapy. In the other patient the serum potassium became elevated after a good diuresis, though on subsequent intermittent therapy with the drug the patient remained well for 12 months. In two other patients administration of spironolactone had to be discontinued because of elevation of the serum potassium before a good diuresis could take place. The fifth patient died.Spironolactone can be a useful adjunct to the therapy of resistant heart failure, but there appears to be a real danger of causing the serum potassium to rise to toxic levels in patients so treated.     

Influence of spironolactone on urinary prostaglandin E2 and kinin excretion in rats

Spironolactone was administered to spontaneously hypertensive rats (SHRs) in order to examine the urinary excretions of prostaglandin E2 (PGE2) and kinin. Thirteen SHRs were divided into 2 groups: 0.1 ml of sesame oil was administered to one group (the spironolactone-lactone-untreated group, n = 6) and 20 mg of spironolactone in 0.1 ml of sesame oil was administered to the other group (the spironolactone-treated group, n = 7) by the subcutaneous route for 10 days in succession. Determinations were then made of the body weight, blood pressure, urine volume, and excretion levels of Na, K, kinin and PGE2 in the 24-hour urine. After the animals had been killed by decapitation, blood samples were drawn for determination of the plasma renin activity (PRA). The results obtained indicated decreased blood pressure and increased urinary Na excretion in the spironolactone-treated group. On the other hand, the PGE2 excretion level in the 24-hour urine decreased markedly immediately after administration of spironolactone (p less than 0.05) and was maintained at lower levels up to the end of the experiment. However, the 24-hour urinary kinin levels showed similar changes in both the spironolactone-treated group and the untreated group with no significant difference between them. These findings suggest that spironolactone has a suppressive effect on urinary PGE2 excretion, the activity of which is not mediated by kinin production in the kidneys but is the result of a direct action of spironolactone itself.     

Effect of prostaglandin E1 on renin and aldosterone in hypertensive patients.

The effect of prostaglandin E1 (PGE1) on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was studied in the hypertensive subjects treated with or without 75 mg indomethacin or 60 mg propranolol for a week. Subsequent to the treatment with indomethacin for a week, PRA and PAC levels were decreased as compared to the control, without changes in the blood pressure and heart rate. During the infusion of PGE1, the blood pressure was decreased and the pulse rate was increased. PRA and PAC levels were also elevated. These changes of parameters were not different between the control and the indomethacin-treated subjects. PRA and PAC were suppressed after the treatment with propranolol. With the infusion of PGE1, the level of PRA was not significantly elevated, while, PAC was significantly increased by the infusion of 100 ng/Kg/min of PGE1. During the infusion of PGE1, the blood pressure was decreased while the pulse rate was increased in the subjects treated with propranolol. However, the elevation of the pulse rate was less remarkable than the control. These data indicate that PGE1 have important roles in the regulation of the release of renin and aldosterone. These findings also suggest that PGE1 may act to stimulate the secretion of aldosterone in man.     

Comparison of chlorthalidone and spironolactone in low--renin essential hypertension.

Nineteen patients with uncomplicated essential hypertension and low activity of plasma renin in response to a change from recumbency to an upright posture along with furosemide administration were given spironolactone, 400 mg/d, or chlorthalidone, 100mg/d, in a double-blind, random-sequence, crossover trial. The sequence of treatments was placebo for 2 months, one active drug for 2 months, placebo again for 1 month and the other active drug for 2 months. With both active treatments the average systolic, diastolic and mean arterial pressures decreased significantly. The two agents were equally efficacious in lowering the blood pressure regardless of the severity of hypertension during placebo treatment. Body weight, 24--hour urinary excretion of sodium, the plasma renin activity and the plasma aldosterone level at the end of the initial placebo period did not allow us to predict the response to either drug. Both drugs reduced the body weight and increased the stimulated plasma renin level activity. Chlorthalidone significantly increased the serum uric acid level and significantly reduced the serum potassium level. Three patients experienced orthostatic dizziness during spironolactone therapy, but no adverse symptoms were observed with chlorthalidone therapy. Thus, spironolactone is an effective alternative to thiazide-type drugs in patients with low-renin essential hypertension.     

Methyldopa and propranolol or practolol in moderate hypertension.

The effect of a low dose of methyldopa combined with (a) a non-selective and (b) a selective beta-adrenoceptor antagonist was studied in a double-blind crossover trial in 24 carefully selected patients with moderate hypertension (mean initial lying blood pressure 189/117 mm Hg). Each patient received methyldopa 750 mg/day, propranolol 240 mg/day, practolol 600 mg/day, methyldopa 750 mg/day combined with propranolol 240 mg/day, methyldopa 750 mg/day combined with practolol 600 mg/day, and placebo for four weeks each according to a random sequence. After four weeks of therapy the most effective treatment, methyldopa combined with propranolol, reduced lying and standing blood pressures by 36-5/21-4 mm Hg and 44-7/25 mm Hg respectively. Thic combination had similar effects to those of the combination of methyldopa with the cardioselective agent practolol except that it reduced lying diastolic pressure further. The combination was more effective than either treatment alone. No significant differences were found between the effects of propranolol, practolol, or methyldopa at the doses used.     

Sex-specific effects of spironolactone on blood pressure in gonadectomized male and female Wistar rats

A low-salt diet is known to decrease and salt excess to increase blood pressure in humans and rodents. Sex steroids seem to play a role in salt dependent hypertension. However, little is known about sex differences in mineralocorticoid receptor blockade between male and female rats. The objective of the work was at first to investigate the effects of a low-salt vs. a high-salt diet on blood pressure without the influence of gonadal steroids in male and female rats. Second, to determine the sex-specific effects of mineralocorticoid receptor blockade by spironolactone in high-salt and low-salt fed gonadectomized male and female animals. Normotensive male and female Wistar rats were gonadectomized and put on a low (NaCl<0.03%) or high (NaCl=4%) salt diet. On each diet animals received spironolactone or placebo. Blood pressure was measured by tail-cuff-method; 24-h urine samples were collected in metabolic cages and blood was collected for hormonal measurements. High-salt diet significantly increased systolic blood pressure in both sexes. This effect could be blocked effectively by spironolactone only in male rats. Spironolactone treatment significantly increased aldosterone levels in males and females independent of the sodium content of the diet. High sodium diet significantly increased relative kidney weight, which was not altered by spironolactone treatment. Independently of gonadal steroids a high-salt diet increased blood pressure in gonadectomized male and female rats. Spironolactone lowered blood pressure only in male not in female rats on a high-salt diet clearly indicating sex-specific effects of the mineralo-corticoid antagonist spironolactone.     

Beta-adrenoreceptor blockade in the conscious rabbit: effects on plasma renin activity and blood pressure.

The administration of a single dose of dl-propranolol, 1 mg/kg i.v., in the conscious unstimulated rabbit produced effective beta-adrenoreceptor blockade (inhibition of isoprenaline tachycardia) for 150 min. During this period there was a positive correlation between plasma concentrations of propranolol and the degree of beta-blockade observed. In a further group of animals treated with propranolol, plasma renin activity (PRA) fell to 50% of control (P < 0.001) within 60 min, the rate of change of PRA also correlating with plasma propranolol levels. Similarly, there were reductions in mean blood pressure (P < 0.025) and heart rate (P < 0.025). Statistical relationships between the fall in blood pressure and either pre-treatment PRA or the change in PRA were consistent with the hypothesis that the hypotensive effect of propranolol was dependent upon its suppression of renin release. However, an alternative possibility that the fall in blood pressure was due to an acute reduction in cardiac output could not be excluded.     

Spironolactone in essential hypertension: evidence against its effect through mineralocorticoid antagonism.

The effect of a six-week course of spironolactone 300 mg/day was examined in 25 unselected patients with essential hypertension. In the blood spironolactone produced a significant rise in urea and potassium concentrations and a fall in sodium and bicarbonate concentrations. In six patients blood pressure was normal at the end of the course, while in five patients there was almost no change. Studies of the effects of spironolactone on various indices usually affected by mineralocorticoids-namely, blood electrolytes, total body potassium, and rectal electrical properties-showed no differences between responding and non-responding patients. Mineralocorticoid excess therefore seems to be rarely responsible for essential hypertension and the influence of spironolactone cannot at present be fully explained.     

Suppression of renin secretion by propranolol in salt-depleted dogs

d, 1-propranolol was infused into salt-depleted, conscious dogs at two dosages: 1 mg/kg followed by 0.60 ? 0.67 mg/kg/hr, and 5 mg/kg followed by 1.57 ? 1.76 mg/kg/hr. At both dosages, propranolol decreased plasma renin activity (PRA), plasma aldosterone concentration, and heart rate significantly. Renin substrate concentration remained unchanged. PRA was suppressed with the higher dosage but not with the lower dosage, to values found with dietary salt loading. Mean arterial blood pressure (MABP) remained unchanged with the low-dose infusions, but decreased significantly with the high-dose infusions. The data suggest that the mechanism(s) for the increase in PRA with low-salt diets is sensitive to propranolol and that the effect of propranolol on MABP is dependent on the salt intake and on the dose administered.     

Renin-dependency of glycyrrhizin-induced pseudoaldosteronism

A prospective study was carried out on 12 patients with chronic hepatitis who were taking 546 mg/day of glycyrrhizin for 4 weeks in order to identify the factors responsible for the development of hypertension and hypokalemia. In 5 patients, blood pressure increased and serum potassium decreased after the treatment (responders). In the remaining 7 patients, these values were unchanged (nonresponders). There were no significant differences in age, plasma aldosterone, the catecholamine concentrations or serum transaminases. The basal plasma renin activity (PRA) in the responders was more than 1.5 ng/m/h (2.5 +/- 0.3 ng/m/h), while that in the non-responders was less than 1.5 ng/m/h (0.7 +/- 0.1 ng/ml/h). Furthermore, a positive correlation between the basal RPA and the changes in blood pressure, and a negative correlation between the basal PRA and the changes in potassium were found. These results suggest that patients with higher PRA levels are more likely to develop hypertension and hypokalemia when treated with glycrrhizin.     

High dose propranolol in the treatment of angina pectoris: relationship of dose to blood levels and hemodynamic consequences

Propranolol blood levels and the effect of these levels on hemodynamic parameters were evaluated in 25 patients with coronary artery disease undergoing cardiac catheterization and coronary angiography. Fifteen patients were receiving high doses of propranolol (320--1920 mg/day) while ten patients were receiving conventional doses (80--240 mg/day). The high dose propranolol group had significantly higher plasma propranolol levels than the conventional dose group (788 +/- 134 SD vs. 43 +/- 7.2 ng/ml SD), and there was a direct linear relationship between propranolol dose and plasma drug levels (r = 0.85, P < 0.001). There were no significant differences between high and conventional dose propranolol groups in terms of all hemodynamic parameters measured, namely ejection fraction, ventricular volume, cardiac index, or peripheral vascular resistance. Despite high drug dosage and blood levels, only mild side effects were seen.     

Antihypertensive efficacy of propranolol given twice daily.

The therapeutic efficacy of propranolol in four and two daily doses was compared in 63 treated hypertensive patients in a multicentre trial. After 3 months of a stable diastolic blood pressure while receiving propranolol four times a day the patients were switched to a twice-a-day regimen, the drug being given at 8 am and 8 pm, with the same total daily dose, for 3 more months. Blood pressures and heart rates were measured at 8 am, 12 noon, 4 pm and 8 pm at 4-week intervals. There were no significant changes in mean blood pressure after the change to the twice-a-day regimen, although some patients reported new side effects. Compliance appeared to be unaffected.     

Comparison of Surgery and Prolonged Spironolactone Therapy in Patients with Hypertension,Aldosterone Excess,and Low Plasma Renin

The effect of prolonged preoperative treatment with spironolactone has been studied in a series of 67 patients with hypertension, aldosterone excess, and low plasma renin. In the series as a whole a highly significant reduction in both systolic and diastolic pressures was achieved, with no evidence of escape from control during therapy lasting several years in some cases. The drug was equally effective in controlling blood pressure in patients with and without adrenocortical adenomata. Occasional unresponsive patients were encountered in both groups; pretreatment blood urea levels in these were significantly higher than in the responsive patients. The hypotensive effect of spironolactone usually predicted the subsequent response to adrenal surgery.Spironolactone in all cases corrected plasma electrolyte abnormalities; significant increases in total exchangeable (or total body) potassium and significant reductions in total exchangeable sodium, total body water, extracellular fluid, and plasma volumes were seen. Plasma urea rose during treatment and there was a slight fall in mean body weight. Significant increases in peripheral venous plasma renin and angiotensin II concentrations occurred during treatment.In two patients no increase in aldosterone secretion rate was found during treatment, although plasma aldosterone rose in three of four subjects studied.Severe side effects were rare; in only two of the 67 patients did the drug have to be stopped.In addition to its routine preoperative use, spironolactone can now be advised as long-term therapy in selected patients.     

Role of renin-angiotensin-aldosterone system in salt-sensitive hypertension induced by sensory denervation

To define the role of the renin-angiotensin-aldosterone system in a novel salt-sensitive model, neonatal Wistar rats were given capsaicin (50 mg/kg sc) on the first and second days of life. After weaning, male rats were divided into the following six groups and treated for 3 wk with: control + normal sodium diet (CON-NS), CON + high-sodium diet (CON-HS), CON + HS + spironolactone (50 mg x kg(-1) x day(-1), CON-HS-SP), capsaicin pretreatment + NS (CAP-NS), CAP-HS, and CAP-HS-SP. Radioimmunoassay shows that plasma renin activity (PRA) and plasma aldosterone level (PAL) were suppressed by HS, but they were higher in CAP-HS than in CON-HS and CON-HS-SP (P < 0.05). Both tail-cuff systolic blood pressure and mean arterial pressure were higher in CAP-HS than in all other groups (P < 0.05). Urine water and sodium excretion were increased with HS intake, but they were lower in CAP-HS than in CON-HS (P < 0.05). Western blot did not detect differences in adrenal AT1 receptor content. Therefore, insufficiently suppressed PRA and PAL in response to HS intake by sensory denervation may contribute to increased salt sensitivity and account for effectiveness of spironolactone in lowering blood pressure in this model.     

Potential beneficial as well as detrimental effects of chronic treatment with lisinopril and (or) spironolactone on isolated hearts following low-flow ischemia in normal and infarcted rats

This study was designed to demonstrate potential beneficial as well as detrimental effects of lisinopril and spironolactone given in combination. In patients with congestive heart failure or myocardial infarction, the use of angiotensin-converting enzyme (ACE) inhibitors may inhibit aldosterone production. Spironolactone, a specific aldosterone receptor antagonist may exert other independent and additive effects to those of ACE inhibitors. Given the consequences of aldosterone on ischemic hearts, we evaluated the protective effects of spironolactone or lisinopril and combined spironolactone-lisinopril therapy during low-flow ischemia and reperfusion in isolated rat hearts. Normal and infarcted (left coronary artery ligature) male Wistar rats were submitted to chronic action of drugs (0.8 mg.kg-1.day-1 for lisinopril and 8 or 50 mg.kg-1.day-1 for spironolactone) for 1 month. Hearts were rapidly excised and perfused (constant pressure) for a 40-min period of stabilization followed by a 25-min period of global low-flow ischemia and a 30-min reperfusion. In normal rats, spironolactone decreased ischemic and reperfusion contracture, reduced ventricular tachycardia, suppressed action-potential duration dispersion, and increased reactive hyperemia leading to an improvement of contractile recovery. Lisinopril also decreased ventricular tachycardia and action-potential duration dispersion concomitantly with increased reactive hyperemia and better contractile recovery. These beneficial effects of the drugs were lost when the two treatments were combined (lisinopril and 50 mg.kg-1.day-1 spironolactone), despite a synergistic effect on plasmatic K+ and Mg2+. However, an interaction between the ACE inhibitor and spironolactone potentiating the effects of either drug alone was observed with a lower dose of spironolactone (lisinopril and 8 mg.kg-1.day-1 spironolactone). Similar beneficial effects have been noted in infarcted rat hearts on reactive hyperemia, ventricular tachycardia, and contractile recovery with the combined treatment and for both spironolactone concentrations (8 or 50 mg). Chronic spironolactone treatment produces similar beneficial effects to ACE inhibitor treatment on normal rat hearts during an ischemia-reperfusion protocol. Synergistic effects have been observed with the combined therapy when a lower dose of spironolactone was utilized in normal and infarcted rats. However, in the case of a high dose of spironolactone, the two effective drugs seem to cancel each other but only in normal rats.     

Myocardial changes after spironolactone in spontaneous hypertensive rats. A laser scanning confocal microscopy study

The present study aims to objectivate by laser scanning confocal microscopy, the cardiac structure of the spontaneously hypertensive rats (SHR) treated with different doses of spironolactone, either alone or in combination with an angiotensin converting enzyme inhibitor or with a calcium channel blocker. Thirty SHRs were divided into six groups and treated during 13 weeks as follows: control, spironolactone (5, 10 and 30 mg/kg/day), spironolactone + enalapril and spironolactone + verapamil. Spironolactone action on the SHR blood pressure (BP) was dose-dependent. The cardiac hypertrophy was affected by the treatment with spironolactone (high dose) or a combination of spironolactone and Enalapril. The myocardial structure was less affected by the spironolactone monotherapy (at all doses) showing hypertrophied cardiac myocytes, focal areas of the reactive fibrosis, inflammatory infiltrate. The treatment with spironolactone in combination with enalapril or verapamil prevented these alterations. In conclusion, the monotherapy with spironolactone had only a limited effect in the preservation of the myocardial structure and in the attenuation of the interstitial fibrosis in SHRs, even after high dose. This action on the myocardium is more efficient when the spironolactone (even in medium dose) was associated with enalapril or verapamil.     

Double-blind comparison of tolamolol,propranolol, practolol,and placebo in the treatment of angina pectoris.

Forty-two patients with angina pectoris have completed a randomized, double-blind trial comparing tolamolol 100 mg and 200 mg with propranolol 80 mg, practolol 100 mg, and placebo, all given three times a day. Tolamolol 200 mg thrice daily was found to be equivalent to propranolol 80 mg thrice daily in anti-anginal efficacy. Anginal attack rates and trinitrin consumption were significantly reduced by all active treatments as compared with the placebo but tolamolol and propranolol were the most effective. Tolamolol 200 mg thrice daily was most effective in reducing blood pressure, while propranolol was most effective in reducing the resting heart rate. All treatments except the placebo significantly increased the amount of exercise which could be performed before angina appeared (exercise work), while tolamolol 200 mg thrice daily significantly reduced Robinson''s index when compared with all other active agents. The degree of S-T segment depression induced by exercise was significantly lessened by both tolamolol and propranolol but not by practolol or placebo. There was no difference in patient preference between tolamolol and propranolol but tolamolol at both dose levels was preferred to practolol. Both tolamolol and propranolol are potent adrenergic beta-receptor antagonists and equal in anti-anginal efficacy but tolamolol has the advantage of being cardioselective. It is superior to practolol.     

Comparison of natriuretic,uricosuric, and antihypertensive properties of tienilic acid,bendrofluazide, and spironolactone.

The antihypertensive properties of the new diuretic tienilic acid were investigated. Thirteen previously untreated hypertensive patients took part in a double-blind crossover study in which 30 days'' treatment with tienilic acid 250 mg, bendrofluazide 5 mg, and spironolactone 100 mg were compared. Bendrofluazide caused the greatest natriuresis on the first treatment day and the most rapid fall in blood pressure. The ultimate antihypertensive effect of all three drugs was similar. Tienilic acid caused a noticeable reduction in serum urate concentrations and a rise in urate clearance, in contrast to the other two agents, which caused slight urate retention. Tienilic acid and bendrofluazide caused falls and spironolactone a rise in plasma potassium concentrations. No untoward effects were seen from any of the drugs. It is concluded that tienilic acid is a moderately potent diuretic that lowers plasma urate concentrations. It may be the drug of first choice for hypertensive patients who already have gout or are likely to develop it when taking thiazide diuretics.