Regulation of placental growth by aldosterone and cortisol

During pregnancy, trophoblasts grow to adapt the feto-maternal unit to fetal requirements. Aldosterone and cortisol levels increase, the latter being inactivated by a healthy placenta. By contrast, preeclamptic placental growth is reduced while aldosterone levels are low and placental cortisol tissue levels are high due to improper deactivation. Aldosterone acts as a growth factor in many tissues, whereas cortisol inhibits growth. We hypothesized that in preeclampsia low aldosterone and enhanced cortisol availability might mutually affect placental growth and function. Proliferation of cultured human trophoblasts was time- and dose-dependently increased with aldosterone (P < 0.04 to P < 0.0001) and inhibited by spironolactone and glucocorticoids (P < 0.01). Mineralo- and glucocorticoid receptor expression and activation upon agonist stimulation was verified by visualization of nuclear translocation of the receptors. Functional aldosterone deficiency simulated in pregnant mice by spironolactone treatment (15 μg/g body weight/day) led to a reduced fetal umbilical blood flow (P < 0.05). In rat (P < 0.05; R(2) = 0.2055) and human (X(2) = 3.85; P = 0.0249) pregnancy, placental size was positively related to plasma aldosterone. Autocrine production of these steroid hormones was excluded functionally and via the absence of specific enzymatic transcripts for CYP11B2 and CYP11B1. In conclusion, activation of mineralocorticoid receptors by maternal aldosterone appears to be required for trophoblast growth and a normal feto-placental function. Thus, low aldosterone levels and enhanced cortisol availability may be one explanation for the reduced placental size in preeclampsia and related disorders.

Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series

OBJECTIVE: To evaluate the effect of IL-6 blockade using tocilizumab in inducing remission of arterial large vessel vasculitides (LVV). METHODS: Five consecutive patients with giant-cell arteritis (GCA) and two with Takayasu’s arteritis (TA) were treated by tocilizumab infusions (8 mg/kg). Tocilizumab was given every other week for the first month and once monthly thereafter. Clinical symptoms of disease activity, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level and glucocorticoid (GC) dosage necessary to maintain remission were prospectively assessed. MR angiography was performed to monitor local inflammation. RESULTS: Of the seven patients three were newly diagnosed and four showed GC resistance, i.e. GC could not be lowered to less than 7.5 mg/day. The mean follow-up time was 4.3 months (range 3–7 months). All patients achieved a rapid and complete clinical response and normalisation of the acute phase proteins. Remarkably, prednisone dosage could be reduced within 12 weeks to a mean of 2.5 mg/day (range 0–10 mg/day). No relapse and no drug-related side effects were noted. CONCLUSION: Collectively the data suggest that IL-6 blockade using tocilizumab qualifies as a therapeutic option to induce rapid remission in large vessel vasculitides.

Perioperative nerve blockade: clues from the bench

Peripheral and neuraxial nerve blockades are widely used in the perioperative period. Their values to diminish acute postoperative pain are established but other important outcomes such as chronic postoperative pain, or newly, cancer recurrence, or infections could also be influenced. The long-term effects of perioperative nerve blockade are still controversial. We will review current knowledge of the effects of blocking peripheral electrical activity in different animal models of pain. We will first go over the mechanisms of pain development and evaluate which types of fibers are activated after an injury. In the light of experimental results, we will propose some hypotheses explaining the mitigated results obtained in clinical studies on chronic postoperative pain. Finally, we will discuss three major disadvantages of the current blockade: the absence of blockade of myelinated fibers, the inappropriate duration of blockade, and the existence of activity-independent mechanisms.

Does Aldosterone participate in placental angiogenesis via PLGF?

Introduction Angiogenic signals are a vital signal of placental integrity. Aldosterone has recently been shown to enhance placental growth factor (PlGF) expression in the peripheral vasculature [1] and to promote trophoblast growth [2]. The plgf gene possesses a functional mineralocorticoid receptor responsive element in the promoter region. Objectives Thus, we hypothesized that aldosterone adapts placental angiogenesis to trophoblast growth by secreting PlGF. Methods The human choriocarcinoma cell line BeWo and first and third trimester human primary trophoblasts cells were subjected to several syncytialization signals. Upon visual confirmation, the cultured cells were subjected to either control conditions, the known stimulator forskolin, and increasing amounts of aldosterone (10−9 to 10−6 M) with and without the competitive aldosterone receptor blocker spironolactone. After 6 and 24 h of incubation, RNA and protein were extracted. PlGF transcripts were quantified by Taqman PCR normalized to several housekeeping genes. Protein expression was quantified by ELISA. Results PlGF mRNA expression increased 3-fold with forskolin in BeWo cells. In this cell line, aldosterone could slightly stimulate PlGF production. In non-syncytialized primary human first trimester trophoblasts, aldosterone did not exert a specific effect. In contrast, the term primary human trophoblasts did respond with a 2.5-fold increase after incubation with aldosterone (10−7 M) in the presence of forskolin to allow forming a syncytial layer. PlGF protein was already slightly upregulated following 6 h of incubation with aldosterone. Conclusion We concluded that aldosterone does regulate PlGF expression in specified conditions during pregnancy. Inappropriately low aldosterone levels such as in preeclampsia might such not only compromise plasma volume and trophoblast growth but also placental vascularization and systemic PlGF availability. These observations merit further investigation.

Blockade of the renin-angiotensin system and renal tissue oxygenation as measured with BOLD-MRI in patients with type 2 diabetes

To assess whether blockade of the renin-angiotensin system (RAS), a recognized strategy to prevent the progression of diabetic nephropathy, affects renal tissue oxygenation in type 2 diabetes mellitus (T2DM) patients.

Vascular endothelial growth factor-A and aldosterone: relevance to normal pregnancy and preeclampsia

Aldosterone levels are markedly elevated during normal pregnancy but fall even though volume contracts when preeclampsia occurs. The level of aldosterone in either condition cannot be explained solely by the activity of the renin-angiotensin II system. In normal gestation, vascular endothelial growth factor (VEGF) is thought to maintain vascular health, but its role in adrenal hormone production is unknown. We hypothesized that the role of VEGF in the adrenal gland is to maintain vascular health and regulate aldosterone production. Here, we demonstrate that supernatant of endothelial cells grown in the presence of VEGF enhanced aldosterone synthase activity in human adrenocortical cells. VEGF either alone or combined with angiotensin II increased aldosterone production in adrenal cells. These data suggest that endothelial cell-dependent and independent activation of aldosterone is regulated by VEGF. In contrast to angiotensin II, VEGF did not upregulate the steroidogenic acute regulatory protein. Consistent with this observation, angiotensin II stimulated both aldosterone and cortisol synthesis from progesterone, whereas VEGF stimulated selectively aldosterone production. In rats, overexpression of soluble fms-like tyrosine kinase-1, an endogenous VEGF inhibitor, led to adrenocortical capillary rarefaction and fall in aldosterone concentrations that correlated inversely with soluble fms-like tyrosine kinase-1 levels. These findings may explain why aldosterone increases so markedly during normal gestation and why preeclampsia, a condition characterized by high soluble fms-like tyrosine kinase-1, is associated with inappropriately low aldosterone levels in spite of relatively lower plasma volumes.

Aldosterone deficiency adversely affects pregnancy outcome in mice

Circulating aldosterone levels are increased in human pregnancy. Inadequately low aldosterone levels as present in preeclampsia, a life-threatening disease for both mother and child, are discussed to be involved in its pathogenesis or severity. Moreover, inactivating polymorphisms in the aldosterone synthase gene have been detected in preeclamptic women. Here, we used aldosterone synthase-deficient (AS(-/-)) mice to test whether the absence of aldosterone is sufficient to impair pregnancy or even to cause preeclampsia. AS(-/-) and AS(+/+) females were mated with AS(+/+) and AS(-/-) males, respectively, always generating AS(+/-) offspring. With maternal aldosterone deficiency in AS(-/-) mice, systolic blood pressure was low before and further reduced during pregnancy with no increase in proteinuria. Yet, AS(-/-) had smaller litters due to loss of fetuses as indicated by a high number of necrotic placentas with massive lymphocyte infiltrations at gestational day 18. Surviving fetuses and their placentas from AS(-/-) females were smaller. High-salt diet before and during pregnancy increased systolic blood pressure only before pregnancy in both genotypes and abolished the difference in blood pressure during late pregnancy. Litter size from AS(-/-) was slightly improved and the differences in placental and fetal weights between AS(+/+) and AS(-/-) mothers disappeared. Overall, an increased placental efficiency was observed in both groups paralleled by a normalization of elevated HIF1α levels in the AS(-/-) placentas. Our results demonstrate that aldosterone deficiency has profound adverse effects on placental function. High dietary salt intake improved placental function. In this animal model, aldosterone deficiency did not cause preeclampsia.

Are beta-blockers needed in patients receiving spironolactone for severe chronic heart failure? An analysis of the COPERNICUS study

BACKGROUND: The beneficial effects of beta-blockers and aldosterone receptor antagonists are now well established in patients with severe systolic chronic heart failure (CHF). However, it is unclear whether beta-blockers are able to provide additional benefit in patients already receiving aldosterone antagonists. We therefore examined this question in the COPERNICUS study of 2289 patients with severe CHF receiving the beta1-beta2/alpha1 blocker carvedilol compared with placebo. METHODS: Patients were divided post hoc into subgroups according to whether they were receiving spironolactone (n = 445) or not (n = 1844) at baseline. Consistency of the effect of carvedilol versus placebo was examined for these subgroups with respect to the predefined end points of all-cause mortality, death or CHF-related hospitalizations, death or cardiovascular hospitalizations, and death or all-cause hospitalizations. RESULTS: The beneficial effect of carvedilol was similar among patients who were or were not receiving spironolactone for each of the 4 efficacy measures. For all-cause mortality, the Cox model hazard ratio for carvedilol compared with placebo was 0.65 (95% CI 0.36-1.15) in patients receiving spironolactone and 0.65 (0.51-0.83) in patients not receiving spironolactone. Hazard ratios for death or all-cause hospitalization were 0.76 (0.55-1.05) versus 0.76 (0.66-0.88); for death or cardiovascular hospitalization, 0.61 (0.42-0.89) versus 0.75 (0.64-0.88); and for death or CHF hospitalization, 0.63 (0.43-0.94) versus 0.70 (0.59-0.84), in patients receiving and not receiving spironolactone, respectively. The safety and tolerability of treatment with carvedilol were also similar, regardless of background spironolactone. CONCLUSION: Carvedilol remained clinically efficacious in the COPERNICUS study of patients with severe CHF when added to background spironolactone in patients who were practically all receiving angiotensin-converting enzyme inhibitor (or angiotensin II antagonist) therapy. Therefore, the use of spironolactone in patients with severe CHF does not obviate the necessity of additional treatment that interferes with the adverse effects of sympathetic activation, specifically beta-blockade.

Role of aldosterone availability in preeclampsia

Preeclampsia is a hypertensive disorder unique to pregnancy and remains the leading cause of maternal and fetal morbidity and mortality. Despite active research, the etiology of this disease remains still an enigma. There is increasing evidence that a combination of several factors is responsible for the development of preeclampsia. In this review, we discuss the role of aldosterone in the regulation of body fluid in pregnancy and preeclampsia. Aldosterone is produced by the enzyme aldosterone synthase and competes with cortisol and progesterone for the mineralocorticoid receptor, thus affecting sodium reabsorption and maternal volume expansion. Aldosterone seems to play a pivotal role in controlling blood pressure during pregnancy and to contribute to the well-being of the mother-to-be. Novel findings in understanding the underlying causes of preeclampsia provide a rationale for future novel prophylactic and therapeutic interventions in the treatment of this pregnancy-associated disease.