Antihypertensive Effect of Canrenone in a Model Where Endogenous Ouabain-Like Factors are Present

Mendonca, M. De; Grichois, Marie‐Laure; Pernollet, Marie-Gabrielle; Wauquier, I; Trouillet-Thormann, B; Meyer, Philippe; Devynck, Marie‐Aude; Garay, Ricardo P.

doi:10.1097/00005344-198801000-00012

Cited by 27 publications

(20 citation statements)

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“…Accordingly, canrenone was reported to reduce blood pressure in rat hypertensive models in which plasma levels of CTS were elevated [5,15]. Subsequently, in hypertensive human subjects canrenone was shown to prevent ouabain-induced vasoconstriction [21], and to block inhibition of erythrocyte Na/K-ATPase induced by intravenous saline loading [22].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Mineralocorticoid antagonists exert anti-fibrotic effects [3,4], and, in addition to blocking the effects of aldosterone, are capable to oppose effects of endogenous digitalis-like cardiotonic steroids (CTS) [5–7]. Thus, canrenone, an active metabolite of spironolactone, has reported to reduce arterial pressure in those forms of hypertension in which CTS are elevated [5,6]. CTS, including marinobufagenin (MBG) (Figure 1a), act as physiological ligands of the sodium pump and are implicated in pathogenesis of several diseases including salt-sensitive hypertension, chronic kidney disease and preeclampsia by inducing vasoconstriction [8,9] and causing cardiovascular and renal fibrosis [10,11], all effects antagonized by canrenone in rats with hypertension induced by renal failure [7].…”

Section: Introductionmentioning

confidence: 99%

“…Subsequently spironolactone and its active metabolite, canrenone (Figure 1b), were reported to reverse digitalis toxicity [14], and to lower blood pressure in rat hypertension models, in which levels of CTS are elevated [5,15,16]. Most recently spironolactone was reported to suppress cardiac fibrosis in rats chronically treated by MBG [7].…”

Section: Introductionmentioning

confidence: 99%

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Marinobufagenin-induced vascular fibrosis is a likely target for mineralocorticoid antagonists

Федорова

Емельянов

Bagrov

et al. 2015

Journal of Hypertension

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Objective Endogenous cardiotonic steroids (CTS), including marinobufagenin (MBG), stimulate vascular synthesis of collagen. Because mineralocorticoid antagonists competitively antagonize effect of CTS on the Na/K-ATPase, we hypothesized that spironolactone would reverse the pro-fibrotic effects of MBG. Methods Experiment 1. Explants of thoracic aortae and aortic vascular smooth muscle cells (VSMC) from Wistar rats were cultured for 24 hours in the presence of vehicle or MBG (100 nmol/L) with or without canrenone (10 µmol/L), an active metabolite of spironolactone. Experiment 2. In 16 patients (56 ± 2 yrs) with resistant hypertension (RH) on a combined (Lisinopril / amlodipine / hydrochlorothiazide) therapy, we determined arterial pressure, pulse wave velocity (PWV), plasma MBG, and erythrocyte Na/K-ATPase before and six months after addition of placebo (n=8) or spironolactone (50 mg/day; n=8) to the therapy. Results In rat aortic explants and in VSMC, pretreatment with MBG resulted in a two-fold rise in collagen-1, and a marked reduction in the sensitivity of the aortic rings to the vasorelaxant effect of sodium nitroprusside following endothelin-1-induced constriction (EC50=480±67 nmol/L vs. 23±3 nmol/L in vehicle-treated rings; P<0.01). Canrenone blocked effects of MBG on collagen synthesis and restored sensitivity of vascular rings to sodium nitroprusside (EC50 = 17±1 nmol/L). RH patients exhibited elevated plasma MBG (0.42 ± 0.07 vs. 0.24 ± 0.03 nmol/L; P=0.01) and reduced Na/K-ATPase activity (1.9 ± 0.15 vs 2.8 ± 0.2 µmol Pi/ml/hr, P<0.01) vs. 7 healthy subjects. Six-month administration of spironolactone, unlike placebo treatment, was associated with a decrease in PWV and arterial pressure, and with restoration of Na/K-ATPase activity in the presence of unchanged MBG levels. Conclusion MBG-induced vascular fibrosis is a likely target for spironolactone.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Marinobufagenin-induced vascular fibrosis is a likely target for mineralocorticoid antagonists

Федорова

Емельянов

Bagrov

et al. 2015

Journal of Hypertension

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show abstract

“…In some rat models of hypertension, canrenone exerted a rapid hypotensive effect, possibly by displacing an endogenous ouabain-like pressor. 13,14 If this action is important in resistant essential hypertension, aldosterone antagonists that lack an effect on ATPase will not be as effective as spironolactone. The only other aldosterone antagonist approved in the United States is eplerenone, a sibling of spironolactone synthesized at the same pharmaceutical company.…”

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confidence: 99%