Glutamine synthetase regulation by dexamethasone,RU486, and compound A in astrocytes derived from aged mouse cerebral hemispheres is mediated via glucocorticoid receptor

Molecular and Cellular Biochemistry - Glucocorticoids (GCs) regulate astrocyte function, while glutamine synthetase (GS), an enzyme highly expressed in astrocytes, is one of the most remarkable...     

Nongenomic effects of mineralocorticoid receptor activation in the cardiovascular system

Fifteen years ago Wehling and colleagues showed unequivocal rapid effects of aldosterone, neither mimicked by cortisol nor blocked by spironolactone, and postulated that these nongenomic effects are mediated via a membrane receptor distinct from the classical mineralocorticoid receptor (MR). Several recent studies have challenged this view. Alzamora et al. showed 11beta-hydroxysteroid denydrogenase 1 and 2 (11betaHSD1, 11betaHSD2) expression in human vascular smooth muscle cells, and that aldosterone rapidly raises intracellular pH via sodium-hydrogen exchange; cortisol is without effect and spironolactone does not block the aldosterone response. When, however, 11betaHSD activity is blocked by carbenoxolone, cortisol shows agonist effects indistinguishable from aldosterone; in addition, the effect of both aldosterone and cortisol is blocked by the open E-ring, water soluble MR antagonist RU28318. In rabbit cardiomyocytes, aldosterone increases intracellular [Na+] by activating Na+/K+/2Cl- cotransport, with secondary effects on Na+/K+ pump activity. Pump current rises approximately 10-fold within 15', is unaffected by actinomycin D or the MR antagonist canrenone, and not elevated by cortisol. Pump current is, however, completely blocked by the open E-ring, water soluble MR antagonist K+ canrenoate and stoichometrically by cortisol. PKCepsilon agonist peptides (but not PKCalpha, PKCdelta or scrambled PKCepsilon peptides) mimic the effect of aldosterone, and PKCepsilon antagonist peptides block the effect. Very recently, cortisol has been shown to mimic the effect of aldosterone when cardiomyocyte redox state is altered by the installation of oxidized glutathione (GSSG) via the pipet, paralleling the effect of carbenoxolone on vascular smooth cells and suggesting possible pathophysiologic roles for an always glucocorticoid occupied MR.     

Angiotensin regulates the selectivity of the Na+-K+ pump for intracellular Na+

Treatment of rabbits with angiotensin-converting enzyme (ACE)inhibitors increases the apparent affinity of theNa⁺-K⁺pump for Na⁺. To explore themechanism, we voltage clamped myocytes from control rabbits and rabbitstreated with captopril with patch pipettes containing 10 mMNa⁺. When pipette solutions wereK⁺ free, pump current(I_p) formyocytes from captopril-treated rabbits was nearly identical to thatfor myocytes from controls. However, treatment caused a significantincrease in I_pmeasured with pipettes containingK⁺. A similar difference wasobserved when myocytes from rabbits treated with the ANG II receptorantagonist losartan and myocytes from controls were compared.Treatment-induced differences in I_p wereeliminated by in vitro exposure to ANG II or phorbol 12-myristate 13-acetate or inclusion of the protein kinase C fragment composed ofamino acids 530-558 in pipette solutions. Treatmentwith captopril had no effect on the voltage dependence ofI_p. We concludethat ANG II regulates the pump's selectivity for intracellularNa⁺ at sites near the cytoplasmicsurface. Protein kinase C is implicated in the messenger cascade.

     

The effect of exercise on circulating immunoreactive calcitonin in men

Moderate-duration exercise increases serum catecholamine and serum calcium levels and might as a result be also expected to increase the levels of circulating serum immunoreactive human calcitonin (HCT). To explore this possibility, HCT was studied during and after moderate duration symptom-limited dynamic exercise in 13 healthy males, mean age 28 +/- 6.9 (SD) years. The mean duration of exercise using the Bruce treadmill protocol was 14.1 +/- 2.2 (SD) minutes. The mean heart rate (HR) peaked at 185 +/- 6 (SD) bpm which was 96.1% of the predicted maximal HR for age. Values for HCT, uncorrected for changes in plasma volume, showed a minimal decrease in the recovery phase, whilst HCT corrected for changes in plasma volume did not alter during exercise or recovery. The serum parathyroid hormone (PTH) also did not change. At peak exercise, uncorrected but not corrected values for plasma noradrenaline, adrenaline and dopamine had increased significantly. Corrected plasma total calcium increased during recovery. In summary, dynamic weight-bearing moderate-duration exercise did not elevate HCT in healthy males.     

Nongenomic actions of aldosterone: physiological or pathophysiological role?

The actions of aldosterone are usually divided into persistent genomic mediated by the classical mineralocorticoid receptor versus acute nongenomic actions. Rapid, nongenomic effects of aldosterone have been shown in a variety of tissues, although the physiological relevance of these nongenomic actions remains to be established. There is now growing evidence that both the nongenomic and genomic actions of aldosterone, are mediated via the same classical mineralocorticoid receptor, and there is cross talk between the nongenomic and classical actions of steroid hormones. Activation of tissue-specific, second messenger pathways may contribute to integration of nongenomic and classical actions of aldosterone. Further studies are required to determine the physiological or pathophysiological role of these nongenomic actions of aldosterone and whether they might amplify pathophysiological effects of aldosterone.     

Na+ influx and Na+-K+ pump activation during short-term exposure of cardiac myocytes to aldosterone

To examine the effect of aldosterone on sarcolemmalNa⁺ transport, we measuredouabain-sensitive electrogenicNa⁺-K⁺pump current(I_p) involtage-clamped ventricular myocytes and intracellularNa⁺ activity(aⁱ_Na) in right ventricularpapillary muscles. Aldosterone (10 nM) induced an increase in bothI_p and the rateof rise of aⁱ_Na duringNa⁺-K⁺pump blockade with the fast-acting cardiac steroid dihydroouabain. Thealdosterone-induced increase inI_p and rate ofrise of aⁱ_Na was eliminated bybumetanide, suggesting that aldosterone activates Na⁺ influx through theNa⁺-K⁺-2Clcotransporter. To obtain independent support for this, theNa⁺,K⁺, andCl concentrations in thesuperfusate and solution of pipettes used to voltage clamp myocyteswere set at levels designed to abolish the inward electrochemicaldriving force for theNa⁺-K⁺-2Clcotransporter. This eliminated the aldosterone-induced increase inI_p. We concludethat in vitro exposure of cardiac myocytes to aldosterone activates theNa⁺-K⁺-2Clcotransporter to enhance Na⁺influx and stimulate theNa⁺-K⁺pump.