Ouabain-inhibiting activity of aldosterone antagonists

Semplicini, Andrea; Serena, Luca; Valle, Roberto; Ceolotto, Giulio; Felice, Marcella; Fontebasso, Alessandra; Pessina, Achille C.

doi:10.1016/0039-128x(94)00005-w

Cited by 22 publications

(11 citation statements)

References 37 publications

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“…A reasonable explanation for the enhanced response of spontaneously hypertensive rats to ouabain could be an active mechanism of production of ouabain-like substances in this strain. 13 However, high levels of ouabain have also been observed in DOCA-salt hypertensive rats, 14 and we did not observe an excitatory effect of ouabain on BNA in this model at either the prehypertensive (20 days) or hypertensive (40 days) stage. This could not be attributed to DOCA alone because ouabain, when injected into DOCA-water rats, increased BNA to the same levels observed in normotensive rats.…”

Section: Discussioncontrasting

confidence: 46%

l- Arginine Restores the Effect of Ouabain on Baroreceptor Activity and Prevents Hypertension

et al. 1999

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Abstract-In spontaneously hypertensive rats, ouabain exerts an excitatory effect on baroreceptor nerve activity (BNA).The aim of this study was to determine the effects of ouabain on BNA in other experimental models of hypertension and its interaction with nitric oxide. Rats were made hypertensive using the procedures for N -nitro-L-arginine methyl ester (L-NAME), deoxycorticosterone acetate (DOCA) salt, and 2-kidney, 1 clip (2K1C) hypertension models. In these groups, systolic arterial pressure was 195Ϯ7, 149Ϯ6, and 148Ϯ4 mm Hg, respectively, compared with 110Ϯ4 mm Hg in normotensive rats. Acute ouabain administration had an excitatory effect on BNA in normotensive rats (37Ϯ4%), an inhibitory effect in L-NAME hypertensive rats (Ϫ60Ϯ7%), and no effect in DOCA-salt and 2K1C hypertensive rats. The effects of ouabain were not related to arterial pressure levels, and no excitatory effect on BNA was observed in prehypertensive DOCA-salt rats. Long-term administration of L-arginine (3 g ⅐ kg Ϫ1 ⅐ day Ϫ1 ) prevented DOCA-salt (121Ϯ8 mm Hg) and 2K1C (104Ϯ4 mm Hg) hypertension, markedly attenuated L-NAME (130Ϯ9 mm Hg) hypertension, and restored the excitatory effect of ouabain on BNA in these groups to levels similar to the normotensive rats and their respective control groups. We conclude that ouabain has a diverse effect on BNA in experimental models of hypertension, and it can be normalized by L-arginine. The data also indicate that nitric oxide may play a pivotal role in mediating the excitatory effect of ouabain on BNA, and we speculate that a therapeutic combination of ouabain and L-arginine may be beneficial in secondary hypertension. Key Words: arginine Ⅲ ouabain Ⅲ L-NAME Ⅲ baroreceptors Ⅲ hypertension T he baroreflex acts to impede short-term fluctuations in arterial pressure (AP), 1 but it is impaired in pathological states such as long-term hypertension. 2 Although mechanical deformation of the nerve endings is considered the primary mechanism of baroreceptor activation, baroreceptor sensitivity is modulated by endothelial factors, such as nitric oxide (NO), which is known to inhibit baroreceptor nerve activity (BNA). 3 However, ionic mechanisms, including the inhibition of Na ϩ -K ϩ -ATPase pump activity, increase BNA. 4,5 Ouabain, which is known as an inhibitor of Na ϩ -K ϩ -ATPase pump activity, reportedly has an excitatory effect on BNA. 6,7 Recently, we reported that the excitatory effect of ouabain on BNA is increased in spontaneously hypertensive rats. 7 The purpose of the present study was to determine whether ouabain has an excitatory effect on BNA in deoxycorticosterone acetate (DOCA) salt and 2-kidney, 1 clip (2K1C) hypertensive rats. Because we did not observe such an effect in these models and because the high plasma volume could elicit greater vascular shear stress, which is a stimulus for NO, 8 we tried to restore the excitatory effect of ouabain on BNA in these models of hypertension by treating the animals with L-arginine long term. Additionally, we evaluated the effects of ouabain on BNA in N...

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Section: Discussioncontrasting

confidence: 46%

l- Arginine Restores the Effect of Ouabain on Baroreceptor Activity and Prevents Hypertension

et al. 1999

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“…Previous studies indicated that mineralocorticoid antagonists are capable of binding to the receptor site on the Na/K-ATPase and acting as antagonists of digitalis glycosides and of endogenous CTS including MBG [6,7,20]. Accordingly, canrenone was reported to reduce blood pressure in rat hypertensive models in which plasma levels of CTS were elevated [5,15].…”

Section: Discussionmentioning

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%

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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“…Therefore, it should be possible to lower the elevated BP in salt-dependent hypertension by blocking the effect of EO. Indeed, canrenone, a product of spironolactone metabolism with ouabain antagonist activity (27) has been used clinically as an antihypertensive agent (71,104).…”

Section: Ouabain Antagonism As a Therapy For Hypertensionmentioning

confidence: 99%

How does salt retention raise blood pressure?

Blaustein¹,

Zhang²,

Ling³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

129

121

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A critical question in hypertension research is: How is long-term blood pressure controlled? Excessive NaCl ingestion or NaCl retention by the kidneys and the consequent tendency toward plasma volume expansion lead to hypertension. Nevertheless, the precise mechanisms linking salt to high blood pressure are unresolved. The discovery of endogenous ouabain, an adrenocortical hormone, provided an important clue. Ouabain, a selective Na ϩ pump inhibitor, has cardiotonic and vasotonic effects. Plasma endogenous ouabain levels are significantly elevated in Ϸ40% of patients with essential hypertension and in animals with several forms of salt-dependent hypertension. Also, prolonged ouabain administration induces hypertension in rodents. Mice with mutant Na ϩ pumps or Na/Ca exchangers (NCX) and studies with a ouabain antagonist and an NCX blocker are revealing the missing molecular mechanisms. These data demonstrate that ␣ 2 Na ϩ pumps and NCX1 participate in long-term regulation of vascular tone and blood pressure. Pharmacological agents or mutations in the ␣ 2 Na ϩ pump that interfere with the action of ouabain on the pump, and reduced NCX1 expression or agents that block NCX all impede the development of salt-dependent or ouabain-induced hypertension. Conversely, nanomolar ouabain, reduced ␣ 2 Na ϩ pump expression, and smooth muscle-specific overexpression of NCX1 all induce hypertension. Furthermore, ouabain and reduced ␣ 2 Na ϩ pump expression increase myogenic tone in isolated mesenteric small arteries in vitro, thereby tying these effects directly to the elevation of blood pressure. Thus, endogenous ouabain, and vascular ␣ 2 Na ϩ pumps and NCX1, are critical links between salt and hypertension. New pharmacological agents that act on these molecular links have potential in the clinical management of hypertension.ouabain; Na ϩ pump; Na/Ca exchanger; Ca 2ϩ ; myogenic tone HYPERTENSION, DEFINED AS A diastolic blood pressure (BP) Ն 90 mmHg and/or systolic BP Ն 140 mmHg, is endemic in Westernized societies. This is a very important public health issue because hypertension is a major risk factor for premature death and disability from heart attack, heart failure, stroke, and many other afflictions (16,59). In the United States, alone, Ϸ20% of the population (i.e., Ϸ50 million individuals) are hypertensive; moreover, more than half of all individuals over the age of 60 years have hypertension. In a small fraction of cases, the hypertension is due to specific causes, such as renal vascular disease or excessive secretion of aldosterone (primary aldosteronism) or catecholamines (pheochromocytoma). The vast majority (Ϸ90%) of patients, however, have elevated BP of unknown cause; hence the terms, primary or essential hypertension. The immediate cause for the elevated BP in nearly all chronic hypertensive persons is excessive narrowing of the small (resistance) arteries. Nevertheless, a key question in any discussion of hypertension is: What specific mechanisms actually lead to the abnormal arterial constriction and elevation ...

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Ouabain-inhibiting activity of aldosterone antagonists

Cited by 22 publications

References 37 publications

l- Arginine Restores the Effect of Ouabain on Baroreceptor Activity and Prevents Hypertension

l- Arginine Restores the Effect of Ouabain on Baroreceptor Activity and Prevents Hypertension

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

How does salt retention raise blood pressure?

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