The stress hormone cortisol acts onthe brain, supporting adaptation andtime-adjusted coping processes.Whereas previous research has focused on slow emerging, genomic effects of cortisol, we addressed the rapid, nongenomic cortisol effects on in vivo neuronal activity in humans. Three independent placebo-controlled studies in healthy men were conducted. We observed changes in CNS activity within 15 min after intravenous administration of a physiological dose of 4 mg of cortisol (hydrocortisone). Two of the studies demonstrated a rapid bilateral thalamic perfusion decrement using continuous arterial spin labeling. The third study revealed rapid, cortisol-induced changes in global signal strength and map dissimilarity of the electroencephalogram. Our data demonstrate that a physiological concentration of cortisol profoundly affects the functioning and perfusion of the human brain in vivo via a rapid, nongenomic mechanism. The changes in neuronal functioning suggest that cortisol acts on the thalamic relay of background as well as on task-specific sensory information, allowing focus and facilitation of adaptation to challenges.
The physiological origins of the observed changes in CBF can be twofold. One, GCs may hypothetically act on the vascular resistance on the levels of arterioles, which would influence the postarteriole blood flow (Gros et al., 2007). Another explanation lies in the effect on the metabolism of cells: a GC-mediated decrease in neuronal activity would decrease metabolic needs and cause reduced CBF. The specific endocrine pathways by which GCs can rapidly and nongenomically influence such changes in neuronal activity are still unknown (for a general overview of possible pathways in animal models, see Groeneweg et al., 2011).
Women showed greater improvement than did men on the physical scale at 6 months (P = .01).
The effect of estrogen (E) on the hypothalamic-pituitary-adrenal axis was investigated in female Sprague-Dawley rats. Animals were bilaterally ovariectomized (OVX), and a Silastic capsule (0.5 cm) containing 17 beta-estradiol was sc implanted. Control animals received a blank capsule. Animals were killed 21 days later. In E-treated rats, we found significantly higher corticosterone (CORT) peak levels 20 min after a 5-sec footshock (1.0 mamp) or exposure to ether vapors (P less than 0.05) compared to those in OVX controls. In addition, the recovery of the ACTH and CORT responses to footshock stress was significantly prolonged (P less than 0.05) in the presence of E. Furthermore, the ACTH and CORT secretory responses to ether stress could be suppressed by exogenous RU 28362 (a specific glucocorticoid receptor agonist; 40 micrograms/100 g BW for 4 days) in OVX controls (P less than 0.05), but not in E-treated animals. These data suggest that E can impair glucocorticoid receptor-mediated delayed or slow negative feedback. Consequently, we examined the influence of E on mineralocorticoid and glucocorticoid receptor concentrations using in vitro binding assays. E did not alter mineralocorticoid or glucocorticoid receptor concentrations in any of the brain regions examined. The administration of RU 28362 (40 micrograms/100 g BW for 4 days) to OVX control or E-treated rats significantly down-regulated hippocampal glucocorticoid receptor (P less than 0.02) in control rats only. In contrast, aldosterone administration (40 micrograms/100 g BW for 4 days) significantly down-regulated hippocampal glucocorticoid receptor (P less than 0.0008) in both control and E-treated animals. Thus, E treatment results in a loss of the glucocorticoid receptor's ability to autoregulate; this suggests that E may cause a functional impairment of the glucocorticoid receptor even though receptor binding appears normal. These findings suggest that hyperactivation of the hypothalamic-pituitary-adrenal axis after stress in E-treated rats is due in part to impaired glucocorticoid receptor-mediated slow negative feedback.
Aldosterone exerts actions in the vascular endothelium through acute, non-genomic and chronic, genomic effects that modulate vascular resistance and blood flow. Aldosterone-induced vasculopathy is characterized by a reduction of endothelial NO synthesis and bioavailability and by increased generation of superoxide radicals that degrade endogenous NO. The present article describes how endothelial function is altered by acutely administered aldosterone and in addition compares it with the effect of chronic exposure to aldosterone in humans, experimental animals and isolated endothelial cells. We will discuss the mechanisms of its unwanted actions and the interactions between aldosterone and ET-1, Ca2+ flux through T-type Ca2+ channels and sodium, with reference to the bioavailability of endothelial NO. Therapeutic efficacies of MR inhibitors, ETA receptor antagonists, and T-type Ca2+ channel blockers through beneficial actions of NO on blood flow against inappropriately elevated plasma aldosterone concentrations or aldosteronism and resistant hypertension are also summarized.
Aldosterone has detrimental effects on various peripheral vascular beds. In the cerebral vasculature, it reduced blood flow and therefore promoted cerebral ischaemia (Rigsby et al., 2005). When cerebral ischaemia was induced experimentally, the volume of the resultant infarct was greater in SHRSP than in Wistar Kyoto rats. The infarct size was reduced by spironolactone treatment to an extent similar to that seen in Wistar Kyoto rats (Dorrance et al., 2001). The lumen diameter of middle cerebral arteries was greater in the spironolactone-treated (6 weeks) aldosterone SHRSP than in the control SHRSP. Spironolactone had no effect on systolic blood pressure (Rigsby and Dorrance, 2004). Chronic aldosterone appears to participate in impairment of cerebral blood perfusion. There was a cerebrovascular protective effect of spironolactone in the absence of lowered blood pressure in saline-drinking SHRSP (Rocha et al., 1998). High plasma aldosterone concentration is a risk factor of cognitive impairment in hypertensive patients (Yagi et al., 2011), and cerebral hypoperfusion is associated with later cognitive decline (Kitagawa et al., 2009). Vascular endothelial dysfunction via high aldosteronaemia may participate in cerebral hypoperfusion that is associated with cognitive decline. Reduced cerebral blood flow associated with impairment of endothelial function and NO bioavailability leads to the generation and development of Alzheimer's disease (Toda and Okamura, 2012).
In contrast to these detrimental effects, aldosterone or MR activation in the brain may be required for neuronal survival by inhibiting cell death via the expression of anti-apoptotic genes (Macleod et al., 2003; Rigsby et al., 2005). Aldosterone facilitates neuronal damage through deleterious actions on vasculature. Conversely, MR activation in the brain may inhibit cell death.
Taken together, aldosterone non-genomically impairs or enhances endothelial function in humans, whereas it increases endothelial function in most instances of experimental animals in situ and in isolated preparations (Table 1). This discrepancy may not be explained by different doses of aldosterone used in humans and animals, use of different animal species in the experiments and use of in vivo or in vitro preparations. Differences in ambient redox or sodium status during experiments and in involvement of NO-independent (PLC, ET, PKC and sodium–proton exchanger) or MR-independent mechanisms may participate in the different actions of aldosterone. Chronic exposure to high aldosterone milieu is harmful to endothelial functions. Aldosterone-induced endothelial dysfunction and hypoperfusion in the brain seem to participate in the genesis of cognitive decline. An imbalance between NO synthesis and actions and superoxide anion generation plays an important role in endothelial dysfunction elicited either by acute or chronic exposures to aldosterone.
Primary venous insufficiency
A dysfunctional venous system is caused for the main part by functional failure of venous valves.
The molecular mechanisms uncovered recently that enter into functional valve failure are mentioned
above. Other factors are traditionally cited as contributing to venous valve failure; these
include female sex, pregnancy, obesity, a standing occupation in women,7 and heredity.8,9 An increase
in vein diameter is one cause of valve dysfunction and reflux. Progesterone inhibits smooth
muscle contraction. This is useful in preventing uterine contraction and spontaneous abortion
in pregnancy. However, preventing vein wall smooth muscle contraction allows passive dilation
of veins and when a critical diameter is reached, a functioning venous valve becomes dysfunctional
or incompetent. As half of a women’s adult lifetime is under the influence of progesterone,
and this is exacerbated markedly during pregnancy, it is no wonder that primary venous insufficiency
is twice as common in women than in men.7
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