The expanding class of mineralocorticoid receptor modulators: New ligands for kidney, cardiac, vascular, systemic and behavioral selective actions.

This paper reviews the class of mineralocorticoid receptor (MR) modulators, especially new nonsteroidal antagonists. MR is a nuclear receptor expressed in many tissues and cell types. Aldosterone, the most important mineralocorticoid hormone and MR agonist, has many unfavorable effects, especially on the heart, blood vessels, and kidneys, by promoting fibrosis and tissue remodelling. Classical synthetic MR antagonists (spironolactone, eplerenone) have proven useful in clinical practice through their antihypertensive effects in resistant forms, and through benefits on morbidity and mortality in heart failure with reduced ejection fraction. These benefits are associated with important side effects, hyperkalemia being the main limitation. In the latest years, a new generation of MR modulators with a nonsteroidal structure has emerged. These compounds are more selective than classical MR antagonists, with much higher affinity for the MR than for the glucocorticoid, androgen, or progesterone receptors. Recent clinical and experimental observations suggest that nonsteroidal MR antagonists, especially finerenone, have proven superior renoprotective properties, antiproteinuric efficacy, inhibition of inflammation and heart fibrosis in animal models, without sharing the side effects of steroidal MR antagonists. Nonsteroidal MR modulators represent an interesting new therapeutic approach for the prevention and progression of chronic kidney disease and for patients with heart failure and renal disease. Despite these promising data, there are still many issues to be clarified and it is necessary to accumulate solid evidence from studies on larger numbers of patients and from head-to-head clinical trials.

Arterial hypertension in patients with atrial fibrillation in Europe: A report from the EURObservational Research Programme pilot survey on atrial fibrillation.

BACKGROUND: Hypertension (HTN) is the most prevalent co-morbidity among atrial fibrillation (AF) patients; the relationship between the two is bidirectional, with an incremental effect on adverse outcomes. PURPOSE: To study clinical features, treatment patterns and 1year outcomes amongst AF patients with HTN in the EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot Registry, a prospective multi-national survey conducted by the European Society of Cardiology in 9 European countries. METHODS: Of 3119 enrolled AF patients, 2194 were diagnosed with HTN (AF-HTN) and 909 were normotensive (AF-NT) (16 patients had unknown HTN status). We compared baseline clinical features, management strategy and 1-year outcomes in terms of all-cause death, cardiovascular (CV) death, and any thrombosis-related event (TE: stroke, transient ischemic attack, acute coronary syndrome, coronary intervention, cardiac arrest, peripheral/pulmonary embolism) in AF-HTN vs AF-NT patients. RESULTS: The AF-HTN patients had more prevalent CV risk factors and comorbidities (median CHA2DS2-VASc score (IQR) 4 (3, 5) in AF-HTN, versus 2 (1, 3) in AF-NT; p<0.01). Crude rate of all-cause death and any TE event was higher in AF-HTN (194 (11.2%) versus 60 (8.2%), p=0.02). Kaplan-Meier analysis curves for death by hypertensive status showed no significant differences between the subgroups (log rank test, p=0.22). On logistic regression analysis, HTN did not emerge as an independent risk factor for outcomes (OR 1.08, 95% CI 0.76-1.54). CONCLUSION: AF-HTN patients have a higher prevalence of comorbidities and this conferred a higher risk for a composite endpoint of all-cause death and thromboembolic events. In this cohort HTN did not independently predict all-cause mortality at 1-year.

Circulating microparticles and endothelial progenitor cells in atherosclerosis: pharmacological effects of irbesartan.

AIMS: This study aimed to (i) employ our newly designed model, the hypertensive-hypercholesterolemic hamster (HH), in order to find out whether a correlation exists between circulating microparticles (MPs), endothelial progenitor cells (EPCs) and their contribution to vascular dysfunction and (ii) to assess the effect of irbesartan treatment on HH animals (HHI). METHODS AND RESULTS: The results showed that compared with the control (C) group, HH displayed: (i) a significant increase in plasma cholesterol and triglyceride concentration, and an augmentation of systolic and diastolic arterial blood pressure, and of heart rate; (ii) a marked elevation of MPs and a significant decrease in EPCs; (iii) structural modifications of the arterial wall correlated with altered protein expression of MMP2, MMP9, MMP12, TIMP1, TIMP2 and collagen type I and III; (iv) a considerably altered reactivity of the arterial wall closely correlated with MPs and EPC adherence; and (v) an inflammatory process characterized by augmented expression of P-Selectin, E-Selectin, von Willebrand factor, tissue factor, IL-6, MCP-1 and RANTES. Additionally, the experiments showed the potential of irbesartan to correct all altered parameters in HH and to mobilize EPCs by NO, chemokines and adhesion molecule-dependent mechanisms. CONCLUSIONS: Hypertension associated with hypercholesterolemia is accompanied by structural modifications and expression of pro-inflammatory molecules by the vessel wall, the alteration of vascular tone, enhanced release of MPs and reduced EPCs; the ratio between the latter two may be considered as a marker of vascular dysfunction. Irbesartan, which exhibits a pharmacological control on the levels of MPs and EPCs, has the potential to restore homeostasis of the arterial wall.

Prevalence, Awareness, Treatment, and Control of Hypertension in Romania: Results of the SEPHAR Study.

East European countries have reported high prevalence of Arterial Hypertension (AHT). In order to investigate the data for Romania, we firstly performed a national survey-the Study for the Evaluation of Prevalence of Hypertension and Cardiovascular Risk in Adult Population in Romania (SEPHAR). A representative population was selected using stratified proportional sampling, including 2017 adult subjects, ≥18 years old. The general prevalence of AHT was 44,92%, higher in men (50,17%) than in women (41,11%) (P < .0001) and predominant in rural areas (49,47%) in comparison to the urban ones (41,58%) (P < .02). AHT awareness attended 44,26%, rising with age, significantly lower in men (34,58%) than in women (52,8%) (P < .0006). We have found a 38,85% proportion of treated hypertensive persons, worse for men (30,11%) then for women (46,56%) (P < .003). The rate of AHT control was 19,88%, with no significant differences between gender. In conclusion, we estimated for Romania a high prevalence of AHT, a level of awareness and treatment lower than in many European countries and a rate of treatment control at the inferior limit of the European average. Males, characterized by a higher prevalence of AHT, were also less aware and less treated than women.

Nebivolol induces a hyperpolarizing effect on smooth muscle cells in the mouse renal artery by activation of beta-2-adrenoceptors.

Nebivolol is a highly selective beta(1)-adrenoceptor antagonist with vasodilator properties involving the vascular endothelium, but its effect on the smooth muscle cells (SMC) is still unclear. In this paper, we tested the effect of nebivolol on renal artery smooth muscle cells and investigated the cellular mechanism involved. To this purpose, the denuded renal arteries isolated from mice were studied in vitro using the myograph and the nitric oxide (NO) sensor techniques, while the SMC in culture were analyzed by the patch-clamp technique. The myograph technique was used to assay the vasodilator effect of nebivolol on the arterial muscular layer, and to establish the optimal dose of the drug to be tested on single SMC by the patch-clamp technique. Using both the myograph and the patch-clamp techniques, we examined the potential contribution of beta(2)-adrenoceptors and Ca(2+)-activated K(+) channels to the nebivolol-induced effects, by exposing the denuded arteries and SMC cultures to specific inhibitors such as butoxamine (100 micromol/l), tetraethylammonium (TEA, 1 mmol/l), and iberiotoxin (100 nmol/l). The direct measurement of NO using the NO sensor enabled us to evaluate if nebivolol induces/or not the release of NO in denuded renal arteries. The results of this study show that nebivolol exerts vasodilator effects on the SMC in the denuded renal arteries and the maximal response is achieved at a concentration of 50 micromol/l. Nebivolol effects involve binding to the beta(2)-adrenoceptors and the subsequent activation of Ca(2+)-activated K(+) channels in SMC, with no contribution of NO. Taken together, the study brings new insights into the mechanism underlying the nebivolol-induced arterial vasodilation.