Nongenomic Effects of Aldosterone on Intracellular pH in Vascular Smooth Muscle Cells

Wehling, Martin; Bauer, Matthias M.; Ulsenheimer, Axel; Schneider, Manfred; Neylon, Craig B.; Christ, Michael

doi:10.1006/bbrc.1996.0866

Cited by 72 publications

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“…On the other hand, several recent studies have demonstrated the rapid nongenomic effects of Aldo in cardiovascular tissues. In cultured VSMC, physiologic concentrations (subnanomolar) of Aldo induces a prompt (Ͻ1 min) increase in intracellular Ca 2ϩ concentration, which was not inhibited by a MR antagonist spironolactone (19). Moreover, in humans, intravenous application of Aldo significantly increases systemic vascular resistance within a few minutes (34,35), suggesting a nongenomic vasoconstrictor action because of the short time frame.…”

Section: Discussionmentioning

confidence: 99%

“…We next examined a possible involvement of phospholipase C (PLC), which mediates nongenomic actions of Aldo in cultured vascular smooth muscle cells (VSMCs) (18,19), in the Aldo-induced vasoconstriction. After the equilibration period, Af-or Ef-Arts were treated with neomycin (300 M; Sigma), a specific inhibitor of PLC, for 60 min.…”

Section: Effect Of Neomycin On Aldo-induced Constrictionmentioning

confidence: 99%

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Nongenomic Vascular Action of Aldosterone in the Glomerular Microcirculation

Arima¹,

Kohagura²,

Xu³

et al. 2003

Journal of the American Society of Nephrology

178

147

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Abstract. Aldosterone (Aldo) accelerates hypertension, proteinuria, and glomerulosclerosis in animal models of malignant hypertension or chronic renal failure. Aldo may exert these deleterious renal effects by elevating renal vascular resistance and glomerular capillary pressure. To test this possibility, directly examined were the action of Aldo on the afferent (Af) and efferent (Ef) arterioles (Arts). Examined were the effect of Aldo added to both the bath and lumen on the intraluminal diameter (measured at the most responsive point) of rabbits. Aldo caused dose-dependent constriction in both arterioles with a higher sensitivity in Ef-Arts. Vasoconstrictor action of Aldo was not affected by a mineralocorticoid receptor antagonist spironolactone and was reproduced by membrane-impermeable albumin-conjugated Aldo, suggesting that the vasoconstrictor actions are nongenomic. Pretreatment with neomycin (a specific inhibitor of phospholipase C) abolished the vasoconstrictor action of Aldo in both arterioles. In addition, the vasoconstrictor action of Aldo on Af-Arts was inhibited by both nifedipine and efonidipine, whereas that on Ef-Arts was inhibited by efonidipine but not nifedipine. The results demonstrate that Aldo causes nongenomic vasoconstriction by activating phospholipase C with a subsequent calcium mobilization thorough L-or T-type voltage-dependent calcium channels in Af-or Ef-Arts, respectively. These vasoconstrictor actions on the glomerular microcirculation may play an important role in the pathophysiology and progression of renal diseases by elevating renal vascular resistance and glomerular capillary pressure.There is increasing evidence that renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathogenesis and progression of renal diseases (1-5). Although angiotensin II (AngII) has been identified as the primary mediator of the system, recent studies have raised the possibility that aldosterone (Aldo), independent of renin-angiotensin, also participates in mediating renal injury (5-10). Greene et al. (7) have evaluated the ability of Aldo to reverse the renal protective effects of RAAS blockade in the 5/6 nephrectomy model of hypertension and glomerulosclerosis. They found that pharmacologic blockade of RAAS with angiotensin-converting enzyme inhibitor and AngII receptor blocker reduces plasma Aldo levels, systolic BP, proteinuria and renal lesions, all of which were reversed when Aldo was infused concurrently. Rocha et al. (8) also demonstrated that renal-protective effects of captopril, an angiotensin-converting enzyme inhibitor, were reversed by an Aldo infusion in stroke-prone spontaneously hypertensive rat (SHRSP), an animal model of malignant hypertension. They found that captopril treatment prevented the development of proteinuria and glomerular-renal vascular lesions with reducing endogenous Aldo levels, whereas subsequent Aldo infusion reversed these protective effects of captopril. Although the underlying mechanisms for these actions are not well defined, Aldo may e...

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Section: Discussionmentioning

confidence: 99%

Section: Effect Of Neomycin On Aldo-induced Constrictionmentioning

confidence: 99%

Nongenomic Vascular Action of Aldosterone in the Glomerular Microcirculation

Arima¹,

Kohagura²,

Xu³

et al. 2003

Journal of the American Society of Nephrology

178

147

View full text Add to dashboard Cite

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“…• Upregulates VEGF in cultured cortical collecting duct epithelial cells flux, 21 change in intracellular pH, 22 and protein kinase C activity. 23 However, the pathophysiological role of these non-genomic actions on progressive renal injury is not fully understood.…”

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confidence: 99%

Mineralocorticoid Receptor Antagonist for Renal Protection

King-Wing

Szeto

2012

Renal Failure

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The renin-angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular and renal diseases. In chronic kidney disease (CKD), blockade of RAS by angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) has been shown to reduce proteinuria and retard the progression of renal function deterioration. However, aldosterone, another key hormone of the RAS, is not directly targeted by ACEI or ARB. Hyperaldosteronism, apart from promoting sodium and fluid retention, causes inflammation and fibrosis in the heart and kidney. Studies have shown that although plasma aldosterone level shows an initial decrease following ACEI or ARB treatment, it returns to pretreatment level or even increases paradoxically after prolonged treatment. This "aldosterone breakthrough" forms the basis of adding mineralocorticoid receptor (MR) antagonist on top of ACEI or ARB for renal protection. New insights into the pathophysiological role of aldosterone in CKD further expands its potential indications, and there was a growing body of evidence in the past 10 years, which showed a substantial antiproteinuric effect and possibly a considerable renoprotective effect of MR antagonist. Since aldosterone does not act on the efferent glomerular arteriole and has no effect on intraglomerular hemodynamics, the very fact that MR antagonist ameliorates proteinuria sheds light on the physiology of glomerular permeability barrier. This review summarizes the data regarding the theoretical benefit as well as clinical use of MR antagonist in renal diseases.

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“…Based on these characteristics, nongenomic effects of aldosterone have been reported from a number of laboratories in renal epithelial cells, 13 vascular smooth muscle cells, 14,15 skeletal muscle cells, 16 and colonic. The molecular basis of these nongenomic effects of aldosterone actions have been ascribed to changes in intracellular pH (pHi), [17][18][19] 20 -25 Although it has been observed that aldosterone does have rapid effects on protein kinase C activity in cultured cardiac cells, 26 and that aldosterone has rapid effects on cardiac sodiumhydrogen exchange, 27 the molecular mechanism of the rapid inotropic effect of aldosterone is still unclear.The spironolactone issue is less well defined and perhaps of greater interest because of the favorable results of the RALES trial. 1 We previously observed that substantial inotropy could be observed with levels of spironolactone that were comparable to those achieved with this agent in standard clinical practice.…”

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confidence: 99%

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Mechanisms for Aldosterone and Spironolactone-Induced Positive Inotropic Actions in the Rat Heart

et al. 2004

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Abstract-Previously, we reported that aldosterone and spironolactone have inotropic effects in the isolated perfused heart.To address the mechanisms underlying these inotropic effects, we examined the effects of aldosterone and spironolactone on isolated cardiac myocyte shortening, intracellular calcium ( ). Collectively, these data strongly suggest that the inotropic actions of aldosterone and spironolactone are caused by different mechanisms of action. Aldosterone appeared to increase inotropy primarily through increased cytosolic pH, whereas spironolactone increased myosin ATPase calcium sensitivity and diastolic calcium concentration. Key Words: mineralocorticoid Ⅲ cardiac function Ⅲ heart failure Ⅲ calcium T he Randomized ALdactone Evaluation Study (RALES) demonstrated significant reductions in morbidity and mortality when spironolactone, the aldosterone mineralocorticoid receptor antagonist, was included in the treatment of heart failure. 1 This study, along with many translational reports, strongly developed the concept that aldosterone may play an important, deleterious effect in human congestive heart failure. [2][3][4][5] In addition, we have previously observed that aldosterone has rapid, inotropic effects in the isolated perfused rat heart; 6 however, rapid, inotropic effects were observed as early as the 1960s. 7,8 This rapid, inotropic effect of aldosterone almost certainly occurs through nongenomic mechanism(s).Nongenomic actions of aldosterone were first identified by Wehling et al in smooth muscle cells. 9 -12 These actions were classified as nongenomic because of their speed, lack of inhibition by spironolactone, and independence from new protein synthesis. Based on these characteristics, nongenomic effects of aldosterone have been reported from a number of laboratories in renal epithelial cells, 13 vascular smooth muscle cells, 14,15 skeletal muscle cells, 16 and colonic. The molecular basis of these nongenomic effects of aldosterone actions have been ascribed to changes in intracellular pH (pHi), [17][18][19] 20 -25 Although it has been observed that aldosterone does have rapid effects on protein kinase C activity in cultured cardiac cells, 26 and that aldosterone has rapid effects on cardiac sodiumhydrogen exchange, 27 the molecular mechanism of the rapid inotropic effect of aldosterone is still unclear.The spironolactone issue is less well defined and perhaps of greater interest because of the favorable results of the RALES trial. 1 We previously observed that substantial inotropy could be observed with levels of spironolactone that were comparable to those achieved with this agent in standard clinical practice. Moreover, the inotropic effect of spironolactone was found to be additive to that of aldosterone when both agents were administered together. These studies strongly suggest that although aldosterone and spironolactone are similar in structure, they have independent mechanism(s) of actions. Therefore, the objective of the present study was

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Nongenomic Effects of Aldosterone on Intracellular pH in Vascular Smooth Muscle Cells

Cited by 72 publications

References 0 publications

Nongenomic Vascular Action of Aldosterone in the Glomerular Microcirculation

Nongenomic Vascular Action of Aldosterone in the Glomerular Microcirculation

Mineralocorticoid Receptor Antagonist for Renal Protection

Mechanisms for Aldosterone and Spironolactone-Induced Positive Inotropic Actions in the Rat Heart

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