Aldosterone and the autocrine modulation of potassium currents and oxidative stress in the diabetic rat heart

Abstract

Background and purpose: Aldosterone plays a major role in cardiac pathology. This study was designed to investigate the role of cardiac aldosterone in modulating K þ currents and oxidative stress in the streptozotocin-induced diabetic rat heart. Experimental approach: Transient and sustained K þ currents were measured in ventricular myocytes by voltage clamp. Plasma and cellular aldosterone were measured by ELISA. Fluorescent dihydroethidium (DHE) was used to assess superoxide ions as markers of oxidative stress. Key results: The mineralocorticoid antagonist spironolactone (1 mM, 5-9 h) significantly augmented both K þ currents in diabetic males, with a concomitant shortening of the action potential but had no effect in myocytes from control males or from diabetic females. Effects of spironolactone were restored in ovariectomized diabetic females and abolished in orchidectomized diabetic males. The aldosterone synthase inhibitor FAD286 (1 mM, 5-9 h) significantly augmented K þ currents in cells from diabetic males, but not females. Spironolactone and FAD286 significantly reduced oxidative stress in cells from diabetic males. Plasma aldosterone content was elevated in diabetic males (relative to control), but not in females. Cellular aldosterone was also elevated, but not significantly. The elevation in aldosterone was only partly dependent on a concomitant increase in cellular angiotensin II. Conclusions and implications: A gender-related, sex-hormone-dependent elevation in plasma and cardiac cell aldosterone contributed to oxidative stress and to attenuation of K þ currents in diabetic male rats. Aldosterone may thus contribute to diabetes-associated cardiac arrhythmias. Aldosterone elevation was partly related to levels of angiotensin II, but residual, angiotensin II-independent, aldosterone maintains functional relevance.

Effects of aldosterone and mineralocorticoid receptor antagonism on cardiac ion channels in the view of upstream therapy of atrial fibrillation

“…A physiological increase in serum aldosterone concentration in response to restriction in sodium intake does not affect I Ca,L , I to and action potential duration in the rat left ventricle in vivo. Shimoni et al 2008 In streptozotocin-induced diabetic rat heart, spironolactone augments I to in diabetic males (with a concomitant shortening of action potential duration) but has no effect in diabetic female animals.…”

“…Even more complicated seems to be a genderrelation and sex-hormone dependence of I to alteration by aldosterone or MR antagonism: in streptozotocin-induced diabetic rat heart, spironolactone augmented I to in diabetic males (with a concomitant shortening of action potential duration) but had no effect in diabetic female animals. Effects of spironolactone were restored in ovariectomized diabetic females and abolished in orchidectomized diabetic males (Shimoni et al 2008). Boixel et al (2006) showed that incubation of isolated adult mouse ventricular myocytes with aldosterone resulted in a significant increase of cardiac sodium current I Na (without alterations of the biophysical properties) which was prevented by co-incubation with spironolactone.…”

“…By reacting with macromolecules like lipids, nucleic acids and proteins including ion channels, free radicals provoke fibrosis and inflammation (Korantzopoulos et al 2007). Aldosterone seems to promote inflammation and oxidative stress (Pitt et al 2003b;Chai et al 2006;Cachofeiro et al 2008) where as in turn, MR antagonism seems to reduce oxidative stress (Korantzopoulos et al 2004;Shimoni et al 2008;Lendeckel et al 2010). Both of these pathophysiological states can affect ion channels, therefore anti-inflammatory effects of MR antagonism or, respectively, its impact on oxidative stress might also alter atrial electrophysiology: reduction of oxidative stress is attended by a reduced activity /expression of NAD(P)H oxidase (Cai et al 2003) resulting in diminished atrial superoxide concentrations (Takemoto et al 2001).…”

Sex and Gender Differences in Endocrinology

“…44 There may be sex differences in the mediation of glucose regulation by stress response, and glucocorticoid stress might also play a more relevant role in development of DM in male rodents. 45 …”

Susceptibility of Diabetic Heart to Catecholamine-induced Arrhythmias is Independent of Contractile Dysfunction

“…Both bradycardia and malignant ventricular arrhythmias occur in diabetic subjects (5,6). Prolongation of the action potential duration leading to myocardial electrical instability predisposes the heart to rhythm disturbances and is considered to be a main feature of cardiac dysfunction of diabetic subjects (7)(8)(9)(10). In addition, the diabetic heart is characterized by an early asymptomatic left ventricular diastolic dysfunction followed by late systolic dysfunction (11,12).…”