Spironolactone inhibits the activity of the Na+/H+exchanger in the aorta of mineralocorticoid-induced hypertensive rats
Juan CarrenoFernando VerdugoFelipe ContrerasFelipe A. MontellanoSebastian N. VelosoKurt A. SchalperMauricio SandovalSandra VillanuevaElisa T. MarusicCarlos E. Irarrázabal
6
Citation
34
Reference
10
Related Paper
Citation Trend
Abstract:
Introduction: Aldosterone can induce changes in the expression or activity of Na + /H + exchanger isoform 1 (NHE–1) in vascular smooth muscle cells. We aimed to clarify whether chronic mineralocorticoid receptor activation exerts an effect on the activity of NHE–1 in the aorta of mineralocorticoid-induced hypertensive rats. Methods: Uninephrectomized male Sprague-Dawley rats received subcutaneously 10 mg/week of desoxycorticosterone (DOCA) with or without 20 mg/kg of spironolactone, or vehicle alone ( n = 20). After four weeks of treatment, the animals were sacrificed; the aorta was excised for subsequent studies, including histological analysis, RT-PCR, Western blot, measurement of NHE-1 activity and vascular contractility in the presence or absence of the selective NHE-1 inhibitor ethyl-isopropyl amiloride (EIPA). Results: Chronic DOCA treatment increased the NHE-1 activity, systolic and diastolic blood pressure, and aortic wall thickness. All these effects were prevented by co-treatment with Spironolactone ( p < 0.05). Phenylephrine-induced vascular contractility was significantly reduced in the DOCA group when EIPA was added in the media ( p < 0.05). No significant differences in NHE-1 mRNA or protein levels were detected between groups. Conclusions: Chronic DOCA administration induced functional and morphological alterations in the rat aorta that are partially explained by enhanced NHE-1 activity and prevented by spironolactone. However, we did not observe changes in the NHE-1 transcript or protein levels, suggesting that the effect may be due to post-transcriptional modifications induced by mineralocorticoid receptor activation.Keywords:
Contractility
Mineralocorticoid
Amiloride
Phenylephrine
The antihypertensive action of spironolactone has been ascribed to both a nonspecific diuretic and a specific antimineralocorticoid effect. To better evaluate the relative importance of these effects, we compared its effects with the mineralocorticoid-independent drug amiloride. Spironolactone (400 mg/day) and amiloride (40 mg/day) were given to 10 patients with essential hypertension (EH) and to 10 patients with hypertension and supranormal aldosterone secretion (SNA). After 6 wk, blood pressure responded better to spironolactone (−20.5%) than to amiloride (− 10.4%) in patients with SNA, but the response was similar in patients with EH (−7.4% and −6.5%). The decrease in body weight—as a measure of volume depletion—was greater after spironolactone (−4.6%) than after amiloride both in patients with SNA (−4.6% and −0.8%) and in patients with EH (−3.7% and −0.6%). After both drugs, plasma sodium decreased (−3.4% and −2.6%) and plasma potassium increased (+37.2% and +32.6%) to the same extent in patients with SNA, reflecting a similar degree of antimineralocorticoid-like activity. After spironolactone patients with SNA showed a greater rise in PRA than after amiloride (412% and 82%). Despite the greater rise in PRA, the rise in aldosterone excretion was in the same range after both drugs (113% and 195%), pointing to inappropriately low aldosterone excretion after treatment with spironolactone. We conclude that differences in volume depletion or antimineralocorticoid-like activity cannot explain the better response in blood pressure of patients with SNA after spironolactone than after amiloride. Our data provide evidence for a specific antialdosterone effect of spironolactone in lowering the blood pressure, especially in patients with aldosterone excess. Clinical Pharmacology and Therapeutics (1980) 27, 317–323; doi:10.1038/clpt.1980.42
Amiloride
Mineralocorticoid
Cite
Citations (24)
Mineralocorticoid
Steroid hormone
Cite
Citations (58)
Plasma renin activity
Loop diuretic
Cite
Citations (322)
Triamterene
Amiloride
Cite
Citations (0)
Mineralocorticoid receptor (MR) antagonism has proven to effectively attenuate the pathophysiological effects of aldosterone in clinical and experimental settings of hypertension and heart failure. MR activates transcription of target genes upon aldosterone binding, and eplerenone selectively binds to MR and blocks aldosterone- mediated activation. In this review, we summarize the preclinical and clinical evidence supporting the beneficial effects of eplerenone (INSPRATM), a selective aldosterone blocker, in the treatment of hypertension and heart failure. We also review the current status in understanding the molecular mechanisms of action of the MR and its ligand. In addition, we compare the effects of eplerenone and spironolactone, a nonselective aldosterone blocker, on the transcriptional activity of MR and provide a molecular explanation for the improved side-effect profile of eplerenone compared with spironolactone.
Eplerenone
Mineralocorticoid
Cite
Citations (36)
Cite
Citations (22)
Eplerenone
Mineralocorticoid
Cite
Citations (0)
Hydroxysteroid Dehydrogenases
Mineralocorticoid
Hydroxysteroid Dehydrogenases
Cite
Citations (33)
Spironolactone (Aldactone-A), 1 triamterene (Dytac) 2 3 and amiloride (Midamor) 2 are all potassium-sparing diuretics which we have reviewed separately. Spironolactone is a steroid which competitively antagonises aldosterone in the distal renal tubule; triamterene and amiloride directly affect electrolyte transport in the distal tubule without antagonising aldo-sterone. However, the ultimate effects of these drugs are quite similar, and it is not clear whether they should be regarded as interchangeable or whether their uses should differ.
Triamterene
Amiloride
Cite
Citations (6)