Effects of insomnia and restless legs syndrome on sleep arterial blood pressure: A systematic review and meta-analysis.

Hypertension and blunted blood pressure (BP) dipping during nighttime sleep are associated with increased cardiovascular risk. Chronic insomnia and restless legs syndrome (RLS) may affect the 24-h BP profile. We systematically reviewed the association of insomnia and RLS with BP values during nighttime sleep and the relative BP dipping pattern. We searched relevant articles in any language with selection criteria including enrolment of subjects with insomnia or RLS and with obstructive sleep apnea comorbidity assessment. Of the 872 studies originally retrieved, seven were selected. Four studies enrolled subjects with insomnia. One study relied on sleep diaries to classify nighttime sleep BP, whereas three relied only on clock time. At meta-analysis, subjects with insomnia displayed an attenuated dipping of systolic BP (-2.00%; 95% confidence interval (CI): -3.61 - -0.39%) and diastolic BP (-1.58%; 95% CI: -2.66 ̶ -0.49%) during nighttime sleep compared to controls. Three studies enrolled subjects with RLS. One study relied on polysomnography to classify nighttime sleep BP, whereas two relied only on clock time. Subjects with RLS showed increases in nighttime sleep systolic BP (5.61 mm Hg, 95% CI 0.13̶-11.09 mm Hg) compared to controls. In conclusion, the limited available data suggest that insomnia and RLS are both associated with altered BP control during nighttime sleep. There is need for more clinical studies to confirm these findings, specifically focusing on measurements of BP during objectively defined sleep, on causal roles of leg movements during sleep and alterations in sleep architecture, and on implications for cardiovascular risk. PROSPERO ACKNOWLEDGEMENT OF NUMBER: CRD42020217947.

Salt, Aldosterone, and Parathyroid Hormone: What Is the Relevance for Organ Damage?

Structured interventions on lifestyle have been suggested as a cost-effective strategy for prevention of cardiovascular disease. Epidemiologic studies demonstrate that dietary salt restriction effectively decreases blood pressure, but its influence on cardiovascular morbidity and mortality is still under debate. Evidence gathered from studies conducted in patients with primary aldosteronism, essential hypertension, or heart failure demonstrates that long-term exposure to elevated aldosterone results in cardiac structural and functional changes that are independent of blood pressure. Animal experiments and initial clinical studies indicate that aldosterone damages the heart only in the context of an inappropriately elevated salt status. Recent evidence suggests that aldosterone might functionally interact with the parathyroid hormone and thereby affect calcium homeostasis with important sequelae for bone mineral density and strength. The interaction between aldosterone and parathyroid hormone might have implications also for the heart. Elevated dietary salt is associated on the one hand with increased urinary calcium excretion and, on the other hand, could facilitate the interaction between aldosterone and parathyroid hormone at the cellular level. This review summarizes the evidence supporting the contribution of salt and aldosterone to cardiovascular disease and the possible cardiac and skeletal consequences of the mutual interplay between aldosterone, parathyroid hormone, and salt.

Novel role for SGK3 in glucose homeostasis revealed in SGK3/Akt2 double-null mice.

The phosphatidylinositol-3-kinase-dependent kinase, Akt2, plays a central role in mediating insulin effects in glucose-metabolizing tissues. Akt2 knockout mice display insulin resistance with a reactive increase in pancreatic islet mass and hyperinsulinemia. The related phosphatidylinositol-3-kinase-dependent kinase, serum- and glucocorticoid-regulated kinase 3 (SGK3), is essential for normal postnatal hair follicle development but plays no apparent role in glucose homeostasis. We report here an unexpected role of SGK3 in islet ß-cell function, which is revealed in Akt2/SGK3 double-knockout (DKO) mice. DKO mice have markedly worse glucose homeostasis than Akt2 single-null animals, including greater baseline glucose, and greater rise in blood glucose after glucose challenge. However, surprisingly, our data strongly support the idea that this exacerbation of the glucose-handling defect is due to impaired ß-cell function, rather than increased insulin resistance in peripheral tissues. DKO mice had lower plasma insulin and C-peptide levels, lower ß-cell mass, reduced glucose-stimulated insulin secretion, and greater sensitivity to exogenous insulin than Akt2 single nulls. We further demonstrated that SGK3 is strongly expressed in normal mouse islets and, interestingly, that ß-catenin expression is dramatically lower in the islets of DKO mice than in those of Akt2(-/-)/SGK3(+/+) or Akt2(-/-)/SGK3(+/-) mice. Taken together, these data strongly suggest that SGK3 plays a previously unappreciated role in glucose homeostasis, likely through direct effects within ß-cells, to stimulate proliferation and insulin release, at least in part by controlling the expression and activity of ß-catenin.

Involvement of endothelium-dependent and -independent mechanisms in midazolam-induced vasodilation.

Benzodiazepine (BDZ) infusion has been shown to reduce blood pressure in both humans and animals. Although the inhibitory effects of BDZ on the central nervous system have been well documented, less is known about the direct effects of BDZ on the vascular bed. The aims of this study were to assess the effects of the BDZ midazolam on the vascular system in C57/BL6 mouse aortic rings and to investigate the mechanisms of its direct vascular action. We found that midazolam induced reversible, dose-dependent vasodilation in potassium- and phenylephrine-precontracted rings. In rings that were precontracted with potassium or phenylephrine, treatment with 10 µmol l(-1) midazolam increased vasodilation by 15 and 60%, respectively, compared with baseline. Vasodilation increased by 80 and 87%, respectively, after treatment with 50 µmol l(-1) midazolam. Only the low concentration of midazolam (10 µmol l(-1)) induced endothelium-dependent vasodilation in phenylephrine-precontracted rings. Vasodilation increased by 60% in rings with endothelium and by 20% in rings without endothelium. Conversely, only the high concentration of midazolam (50 µmol l(-1)) reduced the CaCl(2)-induced vasoconstriction of aortic rings with EC(50) (the concentration giving 50% of the maximal effect) values of 1 and 6 mmol l(-1) for vehicle- and midazolam-treated rings, respectively. Furthermore, the incubation of phenylephrine-precontracted rings with an inhibitor of the nitric oxide synthase (NOS) NG-nitro-L-arginine methyl ester or the inhibitors of central or peripheral type BDZ receptors (flumazenil or PK 11195, respectively) produced no change in midazolam-induced vasodilation. Thus, low concentrations of midazolam induce vasodilation via an endothelium-dependent mechanism that does not involve NO production. In contrast, high concentrations of midazolam induce vasodilation via an endothelium-independent mechanism that implies reduced sensitivity of aortic rings to calcium ions. Additionally, neither the central γ-amino-butyric acid receptor type A nor the peripheral type BDZ receptors seem to be involved in the mechanism of midazolam-induced vasodilation.

Renal cysts and hypokalemia in primary aldosteronism: results of long-term follow-up after treatment.

BACKGROUND: Cross-sectional studies have reported an elevated prevalence of renal cysts in patients with primary aldosteronism. The nature of this association could be related to hypokalemia and/or hypertension and has never been evaluated in prospective studies. METHODS: A consecutive sample of 54 patients with tumoral or idiopathic primary aldosteronism was followed after adrenalectomy or treatment with aldosterone antagonists. At baseline, renal cysts were evaluated by renal ultrasound and patients with primary aldosteronism were compared with 323 essential hypertension patients with the same severity and duration of disease, and 113 age- and sex-matched normotensive subjects. RESULTS: The adjusted prevalence and average number of renal cysts were significantly greater in patients with primary aldosteronism than in patients with essential hypertension and normotensive subjects. Multivariate analysis revealed that age and plasma potassium levels were independently associated with the presence of renal cysts in patients with primary aldosteronism. Treatment of primary aldosteronism decreased blood pressure (BP) and restored normal potassium concentrations. After a median follow-up of 6.2 years, no significant change from baseline of cyst number and cyst total volume was observed in patients with both tumoral and idiopathic aldosteronism and in a subset of 100 patients with essential hypertension. In patients with primary aldosteronism, stepwise logistic analysis showed that the presence of renal cysts was associated with worse BP outcome after treatment. CONCLUSION: Renal cystic disease is highly frequent in patients with primary aldosteronism and either surgical or medical treatment halt its progression, supporting the contention that hypokalemia and its severity are the main contributors to cyst formation in these patients.

Long-term renal outcomes in patients with primary aldosteronism.

CONTEXT: Experimental animal studies indicate that exposure to increased aldosterone levels might result in renal damage, but the clinical evidence supporting this role of aldosterone is preliminary. OBJECTIVE: To determine the long-term outcome of renal function in patients with primary aldosteronism after surgical or medical treatment. DESIGN, SETTING, AND PARTICIPANTS: Prospective study conducted at an Italian university medical center among a consecutive sample of 50 patients who were diagnosed as having primary aldosteronism between January 1994 and December 2001 and who were followed up for a mean of 6.4 years after treatment with adrenalectomy or spironolactone. Patients with primary aldosteronism were compared with 100 patients with essential hypertension, matched for severity and duration of hypertension. All patients were treated with antihypertensive drugs to reach a target blood pressure of less than 140/90 mm Hg. MAIN OUTCOME MEASURES: Primary outcome measures were rates of change of glomerular filtration rate and albuminuria during follow-up. Detection of new-onset microalbuminuria and restoration of normal albumin excretion during follow-up were considered as secondary outcomes. RESULTS: At baseline, glomerular filtration rate and albuminuria were higher in patients with primary aldosteronism than those with essential hypertension. The mean blood pressure during the study was 136/81 mm Hg in the primary aldosteronism group and 137/81 mm Hg in the essential hypertension group. Glomerular filtration rate and albuminuria declined during the initial 6-month period in both groups, with a change that was significantly greater (P<.001 for both variables) in patients with primary aldosteronism. Subsequent rate of decline of glomerular filtration was comparable in the 2 groups, whereas albuminuria did not progress in the remainder of the follow-up. Restoration of normal albumin excretion from microalbuminuria was significantly more frequent in primary aldosteronism than in essential hypertension (P = .02). CONCLUSION: In the majority of patients in this study, primary aldosteronism was characterized by partially reversible renal dysfunction in which elevated albuminuria is a marker of a dynamic rather than structural renal defect.

Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3Kgamma.

Hypertension affects nearly 20% of the population in Western countries and strongly increases the risk for cardiovascular diseases. In the pathogenesis of hypertension, the vasoactive peptide of the renin-angiotensin system, angiotensin II and its G protein-coupled receptors (GPCRs), play a crucial role by eliciting reactive oxygen species (ROS) and mediating vessel contractility. Here we show that mice lacking the GPCR-activated phosphoinositide 3-kinase (PI3K)gamma are protected from hypertension that is induced by administration of angiotensin II in vivo. PI3Kgamma was found to play a role in angiotensin II-evoked smooth muscle contraction in two crucial, distinct signaling pathways. In response to angiotensin II, PI3Kgamma was required for the activation of Rac and the subsequent triggering of ROS production. Conversely, PI3Kgamma was necessary to activate protein kinase B/Akt, which, in turn, enhanced L-type Ca(2+) channel-mediated extracellular Ca(2+) entry. These data indicate that PI3Kgamma is a key transducer of the intracellular signals that are evoked by angiotensin II and suggest that blocking PI3Kgamma function might be exploited to improve therapeutic intervention on hypertension.