Effect of Vitamin D supplementation on blood pressure in hypertensive individuals with hypovitaminosis D: a systematic review and meta-analysis.

In the present study, we aimed to conduct a literature review and meta-analysis to assess the effect of Vitamin D supplementation on SBP and DBP levels in individuals with hypertension and hypovitaminosis D. PubMed, Scopus, Web of Science, and SciELO were systematically searched for relevant publications until January 2023. The review has been registered at PROSPERO (CRD42023400035). To compare the effects of vitamin D with placebo, the mean differences with 95% confidence intervals (95% CIs) were pooled based on the random-effects model. Subgroup analyses were performed to identify the source of heterogeneity, and assessment of study quality was conducted using the GRADE approach. Publication bias was evaluated using funnel plots and Egger's tests. In total, 14 randomized controlled trials (RCTs) were included in this systematic review, and 11 trials were selected for meta-analysis. The data showed that Vitamin D significantly decreased SBP levels; however, it did not affect DBP levels. In subgroup analysis, Vitamin D supplementation significantly decreased in SBP in studies involving individuals over 60 years of age, with a dose greater than 400 000 IU, duration greater than 8 weeks, frequency of weekly supplementation in studies conducted in Asia. In addition, subgroup analysis revealed a significant reduction in DBP in the weekly frequency subgroups and in the studies carried out in Asia. This meta-analysis indicated that Vitamin D significantly reduced the SBP in individuals with hypertension and hypovitaminosis D. Further, well designed trials are necessary to validate these results.

G-protein-coupled receptor MAS deletion produces a preeclampsia-like phenotype in FVB/N mice.

BACKGROUND: An unbalance in the renin-angiotensin (Ang) system (RAS) between the Ang II/AT1 and Ang-(1-7)/Mas axis appears to be involved in preeclampsia (PE), in which a reduction in Ang-(1-7) was observed. Here, we tested whether the reduction in the activity of the Ang-(1-7)/Mas axis could be a contributing factor for the development of PE, using Mas-deficient (Mas-/-) mice. METHODS AND RESULTS: Cardiovascular parameters were evaluated by telemetry before, during pregnancy and 4 days postpartum in 20-week-old Mas-/- and wild-type (WT) female mice. Mas-/- mice presented reduced arterial blood pressure (BP) at baseline (91.3 ± 0.8 in Mas-/- vs. 94.0 ± 0.9 mmHg in WT, Diastolic, P<0.05). However, after the 13th day of gestation, BP in Mas-/- mice started to increase, time-dependently, and at day 19 of pregnancy, these animals presented a higher BP in comparison with WT group (90.5 ± 0.7 in Mas-/- vs. 80.3 ± 3.5 mmHg in WT, Diastolic D19, P<0.0001). Moreover, pregnant Mas-/- mice presented fetal growth restriction, increase in urinary protein excretion as compared with nonpregnant Mas-/-, oliguria, increase in cytokines, endothelial dysfunction and reduced ACE, AT1R, ACE2, ET-1A, and eNOS placental mRNA, similar to some of the clinical manifestations found in the development of PE. CONCLUSIONS: These results show that Mas-deletion produces a PE-like state in FVB/N mice.

Novas angiotensinas e suas implicações fisiológicas / Novel angiotensin peptides and their physiological implications

Introdução: O sistema renina-angiotensina (SRA) é a maior rede regulatória da pressão arterial, do balanço hidroeletrolítico e da homeostase do organismo. Desde que o papel do SRA na regulação da função cardiovascular foi descrito, os componentes do eixo endócrino do sistema, em especial a angiotensina II - na regulação e fisiologia cardiovascular e renal, têm sido foco de pesquisa. Os achados das últimas décadas, no entanto, mostraram que o sistema é muito mais complexo e intricado do que se imaginava. Objetivo: Apresentar, através de uma revisão da literatura, alguns dos novos elementos que compõem o SRA e suas implicações fisiológicas, atualizando o leitor sobre o estado da arte. Material de Métodos:Revisão bibliográfica abordando as principais publicações, indexadas pelo PubMed, relacionadas aos novos peptídeos do SRA. Resultados: Dentre os novos componentes do SRA, encontram-se a angiotensina­(1-9), um nonapeptídeo que promove vasodilatação, ação anti-hipertrófica em cardiomiócitos e ação anti-hipertensiva. A Angiotensina-(1-7), por sua vez, apesar de se diferenciar da Ang II apenas pela ausência de um único aminoácido, é responsável por efeitos fisiológicos opostos aos observados com a Ang II. A Angiotensina A, outro peptídeo biologicamente ativo, é formado a partir da descarboxilação do aspartato, desempenhando efeitos semelhantes à Ang II. A Alamandina, também derivada de uma descarboxilação, é um heptapeptídeo vasodilatador, anti-hipertensivo e cardioprotetor. Conclusão: Os achados envolvendo as novas angiotensinas permitem o entendimento do sistema como uma extensa rede composta de vias e eixos alternativos, muitos dos quais, ainda sem esclarecimento científico. O enfoque em novas vias de formação de produtos com funções biológicas poderá ser útil para o desenvolvimento de novas estratégias terapêuticas e, descobertas no campo da fisiologia e fisiopatologia de uma série de condições.

Introdution: The renin-angiotensin system (RAS) is the major regulatory system of arterial blood pressure, hydroelectrolytic balance, and body homeostasis. Since the role of the RAS in the cardiovascular function has been described, much of the research in this area has focused on the role of its endocrine axis components, mainly angiotensin II (Ang II), in the cardiovascular and renal physiology. Over the last decades, the findings have shown that the system is much more intricate than thought. Objective:To present, upon a literature review, some of the new elements about the RAS and its physiological implications, updating the reader about the state of the art. Methods Material: Bibliographic review addressing the main PubMed publications related of the novels angiotensin-peptides. Results: Among the novel RAS components, angiotensin­(1-9) is a nonapeptide that exerts antihypertrophy effects in cardiomyocytes, and vasodilatory and anti-hypertensive actions. Angiotensin-(1-7), which differs from Ang II due to the absence of only one aminoacid, is responsible for physiological effects opposite to those of Ang II. Angiotensin A, another biologically active peptide, is synthesized through aspartate decarboxylation, and exerts effects similar to those of Ang II. Alamandine, also formed through decarboxylation, is a heptapeptide showing vasodilatory, antihypertensive, and cardioprotective effects. Conclusion: The discovery of novel angiotensins sheds more light on the view that the RAS is an extensive regulatory system with pathways and alternative axis, much of which without scientific knowledge. Scientific efforts envisioning novel formation pathways of biologically active products may be useful for development of innovative therapeutic strategies and discoveries in the field of several physiological and pathological conditions.

Discovery and characterization of alamandine: a novel component of the renin-angiotensin system.

RATIONALE: The renin-angiotensin system (RAS) is a key regulator of the cardiovascular system, electrolyte, and water balance. Here, we report identification and characterization of alamandine, a new heptapeptide generated by catalytic action of angiotensin-converting enzyme-2 angiotensin A or directly from angiotensin-(1-7). OBJECTIVE: To characterize a novel component of the RAS, alamandine. METHODS AND RESULTS: Using mass spectrometry we observed that alamandine circulates in human blood and can be formed from angiotensin-(1-7) in the heart. Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. Binding of alamandine to Mas-related G-protein-coupled receptor, member D is blocked by D-Pro(7)-angiotensin-(1-7), the Mas-related G-protein-coupled receptor, member D ligand ß-alanine and PD123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/ß-hydroxypropyl cyclodextrin produced a long-term antihypertensive effect in spontaneously hypertensive rats and antifibrotic effects in isoproterenol-treated rats. Alamandine had no noticeable proliferative or antiproliferative effect in human tumoral cell lines. CONCLUSIONS: The identification of these 2 novel components of the RAS, alamandine and its receptor, provides new insights for the understanding of the physiological and pathophysiological role of the RAS and may help to develop new therapeutic strategies for treating human cardiovascular diseases and other related disorders.

BPP-5a produces a potent and long-lasting NO-dependent antihypertensive effect.

BACKGROUND: The bradykinin potentiating peptides (BPPs) are oligopeptides found in different animal venoms. BPPs isolated from Bothrops jararaca venom were the first natural inhibitors described for somatic angiotensin I-converting enzyme (ACE). They were used in the structural modeling for captopril development, a classical ACE inhibitor widely used to treat human hypertension. METHODS: We evaluated the effect of BPP-5a on cardiovascular parameters of conscious Wistar (WTs) and spontaneously hypertensive rats (SHRs). RESULTS: In SHR, BPP-5a showed potent cardiovascular effects, at doses ranging from 0.47 to 710 nmol/kg. The maximal changes in mean arterial pressure (MAP) and heart rate (HR) were found at the dose of 2.37 nmol/kg (Δ MAP: -38 ± 4 mmHg, p < 0.01; Δ HR: -71 ± 17 bpm, p < 0.05). Reductions in MAP and HR occurred throughout 6 hours of post-injection period. In contrast to active site-directed ACE inhibitors, no ACE inhibition, evaluated by the Ang I pressor effect, or bradykinin potentiation was observed during the antihypertensive effect of the pentapeptide. In vitro assays showed no effects of BPP-5a upon argininosuccinate synthetase and B(1), B(2), AT(1), AT(2) or Mas receptors. Ex vivo assays showed that BPP-5a induced endothelium-dependent vasorelaxation in isolated aortic rings of SHRs and WTs. CONCLUSIONS: Although the BPP-5a is considered an ACE inhibitor, our results indicate that its antihypertensive effect is exerted via a unique target, a nitric-oxide-dependent mechanism.

Vascular relaxation, antihypertensive effect, and cardioprotection of a novel peptide agonist of the MAS receptor.

Mas stimulation with angiotensin (Ang)-(1-7) produces cardioprotective effects and vasorelaxation. Using a computational discovery platform for predicting novel naturally occurring peptides that may activate G protein-coupled receptors, we discovered a novel Mas agonist peptide, CGEN-856S. An endothelium- and NO-dependent vasodilating effect was observed for CGEN-856S in thoracic aorta rings of rats (maximal value for the relaxant effect: 39.99+/-5.034%), which was similar to that produced by Ang-(1-7) (10(-10) to 10(-6) mol/L). In addition, the vasodilator activity of this peptide depended on a functional Mas receptor, because it was abolished in aorta rings of Mas-knockout mice. CGEN-856S appears to bind the Mas receptor at the same binding domain as Ang-(1-7), as suggested by the blocking of its vasorelaxant effect with the Ang-(1-7) analogue d-Ala(7)-Ang-(1-7), and by its competitive inhibition of Ang-(1-7) binding to Mas-transfected cells. The effect of CGEN-856S on reperfusion arrhythmias and cardiac function was studied on ischemia reperfusion of isolated rat hearts. We found that picomolar concentration of CGEN-856S (0.04 nmol/L) had an antiarrhythmogenic effect, as demonstrated by a reduction in the incidence and duration of reperfusion arrhythmias. Furthermore, acute infusion of CGEN-856S produced a shallow dose-dependent decrease in mean arterial pressure of conscious spontaneously hypertensive rats. The maximum change during infusion was observed at the highest dose. Strikingly, blood pressure continued to drop in the postinfusion period. The results presented here indicate that the novel Mas agonist, CGEN-856S, might have a therapeutic value, because it induces vasorelaxing, antihypertensive, and cardioprotective effects.