Papers by DANIELLA BONAVENTURA
Frontiers in Physiology, Feb 10, 2021
Perivascular adipose tissue (PVAT) has recently entered in the realm of cardiovascular diseases a... more Perivascular adipose tissue (PVAT) has recently entered in the realm of cardiovascular diseases as a putative target for intervention. Notwithstanding its relevance, there is still a long way before the role of PVAT in physiology and pathology is fully understood. The general idea that PVAT anti-contractile effect is beneficial and its pro-contractile effect is harmful is being questioned by several reports. The role of some PVAT important products or systems such as nitric oxide (NO), reactive oxygen species (ROS), and RAS may vary depending on the context, disease, place of production, etc., which adds doubts on how mediators of PVAT anti-and pro-contractile effects are called to action and their final result. This short review will address some points regarding NO, ROS, and RAS in the beneficial and harmful roles of PVAT.
Frontiers in Physiology, 2021
Perivascular adipose tissue (PVAT) has recently entered in the realm of cardiovascular diseases a... more Perivascular adipose tissue (PVAT) has recently entered in the realm of cardiovascular diseases as a putative target for intervention. Notwithstanding its relevance, there is still a long way before the role of PVAT in physiology and pathology is fully understood. The general idea that PVAT anti-contractile effect is beneficial and its pro-contractile effect is harmful is being questioned by several reports. The role of some PVAT important products or systems such as nitric oxide (NO), reactive oxygen species (ROS), and RAS may vary depending on the context, disease, place of production, etc., which adds doubts on how mediators of PVAT anti- and pro-contractile effects are called to action and their final result. This short review will address some points regarding NO, ROS, and RAS in the beneficial and harmful roles of PVAT.
Nitric Oxide, 2019
The perivascular adipose tissue (PVAT) is located around the adventitia, composed primarily by ad... more The perivascular adipose tissue (PVAT) is located around the adventitia, composed primarily by adipocytes, stromal cells, leukocytes, fibroblasts and capillaries. It is well described that PVAT is an important modulator of the vascular tone being considered a biologically active tissue, releasing both vasoconstrictor and vasodilators factors. The literature shows that the anticontractile effect induced by PVAT may be due to activation of the reninangiotensin system (RAS). Aim: Investigate whether the renin-angiotensin system participates in the effect exerted by perivascular adipose tissue on the vascular tone. Methods and Results: For this study we used thoracic aorta from Balb/c mice and performed vascular reactivity, nitric oxide and hydrogen peroxide quantification using selective probes and fluorescence microscopy, immunofluorescence to locate receptors and enzymes involved in this response. Our results demonstrated that perivascular adipose tissue induces an anti-contractile effect in endothelium-independent manner and involves Mas and AT 2 receptors participation with subsequent PI3K/Akt pathway activation. This pathway culminated with nitric oxide and hydrogen peroxide production by neuronal nitric oxide synthase, being hydrogen peroxide most relevant for the anti-contractile effect of perivascular adipose tissue. Conclusion: For the first time in the literature, our results show the presence of Mas and AT 2 receptors, as well as, nitric oxide synthase on perivascular adipose tissue. Furthermore, our results show the involvement of Mas and AT 2 receptors and consequently nitric oxide synthase activation in the anti-contractile effect exerted by perivascular adipose tissue.
Journal of the Brazilian Chemical Society, 2017
Xanthenones were synthesized via one-pot tricomponent reaction, under solvent-free conditions, us... more Xanthenones were synthesized via one-pot tricomponent reaction, under solvent-free conditions, using aldehydes, phenolic and cyclic 1,3-dicarbonyl compounds. Natural organic acids (NOAs), compounds present in many living metabolisms, were used as potential green catalysts. NOA are considered to be more eco-friendly and user-friendly alternative to traditional methodologies. Optimization studies showed that oxalic acid was the best NOA catalyst for such reaction furnishing the xanthenones with up to 93% of yield. Theoretical calculations were performed to evaluate this reaction mechanism and regioselectivity. The results showed that the regiospecificity of this three-component reaction is kinetically and thermodynamically controlled by the addition of b-naphthol C2, instead of C10, to the aldehyde. Our results also disclosed two xanthenones as novel calcium channels blockers. Eco-friendly reaction conditions, easy workup procedure, short reaction times and good yields are some of the advantages of our methodology.
Life sciences, Jan 21, 2017
To determine the role of reactive oxygen species (ROS) on sodium nitroprusside (SNP)-induced tole... more To determine the role of reactive oxygen species (ROS) on sodium nitroprusside (SNP)-induced tolerance. Additionally, we evaluated the role of ROS on NF-κB activation and pro-inflammatory cytokines production during SNP-induced tolerance. To induce in vitro tolerance, endothelium-intact or -denuded aortic rings isolated from male Balb-c mice were incubated for 15, 30, 45 or 60min with SNP (10nmol/L). Tolerance to SNP was observed after incubation of endothelium-denuded, but not endothelium-intact aortas for 60min with this inorganic nitrate. Pre-incubation of denuded rings with tiron (superoxide anion (O2(-)) scavenger), and the NADPH oxidase inhibitors apocynin and atorvastatin reversed SNP-induced tolerance. l-NAME (non-selective NOS inhibitor) and l-arginine (NOS substrate) also prevented SNP-induced tolerance. Similarly, ibuprofen (non-selective cyclooxygenase (COX) inhibitor), nimesulide (selective COX-2 inhibitor), AH6809 (prostaglandin PGF2α receptor antagonist) or SQ29584 [P...
The Open Inorganic Chemistry Journal, 2008
Several attempts have been made toward the production of oxide (NO)-releasing agents based on met... more Several attempts have been made toward the production of oxide (NO)-releasing agents based on metallic complexes. However, many of these agents have been shown to undergo hydroxide electrophilic attack, thus generating the corresponding nitro species. Entrapped nitrosyl ruthenium species can be stabilized in an oil-in-water (o/w) emulsion and be further used for local NO delivery. This study describes the transdermal permeation of cis and trans-[RuCl(bpy) 2 NO](PF 6 ) 2 complexes as NO-donor agents from a topically applied emulsion, with NO release rates of 0.042 ± 0.002 and 0.035 ± 0.003 mol/cm 2 .h, respectively. In vitro skin permeation studies performed with the cis and trans-[RuCl(bpy) 2 (NO)](PF 6 ) 2 complexes in o/w emulsion showed that they tend to accumulate in the stratum corneum (SC) and viable skin, with spontaneous NO release occurring in the viable skin only. NO release was detected by using an NOsensor when the complexes were in contact with the sonicated skin. The vascular responses to the NO released from the cis and trans-[RuCl(bpy) 2 (NO)](PF 6 ) 2 complexes in o/w emulsion were also evaluated by vasodilation experiments.
Fundamental & clinical pharmacology, Jan 25, 2015
This study aimed to investigate the modulation of nitric oxide/reactive oxygen species in sodium ... more This study aimed to investigate the modulation of nitric oxide/reactive oxygen species in sodium nitroprusside relaxation in mice aorta. Sodium nitroprusside induced relaxation in endothelium-intact (e+) and denuded (e-) aortas with greater potency in e+ than in e-. The nitric oxide synthase inhibitor did not alter the sodium nitroprusside relaxation in both e+ and e- aortas. However, the superoxide anion scavenger abolished the difference in sodium nitroprusside potency between e+ and e-. Sodium nitroprusside reduced dihydroethidium-derived fluorescent products in both groups, however, the difference between intact and denuded mice aorta remains. The glutathione levels and basal antioxidant activity of superoxide dismutase were reduced in e- aorta when compared with e+, and these values were not altered by sodium nitroprusside. Confirming these results, the levels of lipid peroxidation in e+ were significantly lower when compared to e-, and these values were not altered by sodium n...
Vascular Pharmacology, 2007
We studied the mechanisms involved in the relaxation induced by nitric oxide (NO) donors, rutheni... more We studied the mechanisms involved in the relaxation induced by nitric oxide (NO) donors, ruthenium complex ([Ru(terpy)(bdq)NO(+)](3+)-TERPY) and sodium nitroprusside (SNP) in denuded rat aorta. Both NO donors induced vascular relaxation independent of the agonist used in the pre-contraction. [Ru(terpy)(bdq)NO(+)](3+) and SNP activated guanylyl cyclase (GC) and K(+) channels. The production of cGMP induced by [Ru(terpy)(bdq)NO(+)](3+) - was higher than that obtained with SNP. The combination of GC inhibitor with K(+)channels blocker almost abolished the relaxation induced by the NO donors. The extracellular NO scavenger oxyhemoglobin reduced the potency without changing the maximum effect (Emax) of both NO donors. By using specific NO species scavengers, hydroxocobalamin and l-cysteine, we have identified the contribution of free radical NO (NO()) and nytroxil anion (NO(-)), respectively, to the rat aorta relaxation induced by both NO donors. The selective scavengers for NO() and NO(-) reduced the potency but not the Emax of [Ru(terpy)(bdq)NO(+)](3+). However, the NO(-) scavenger had no effect on the relaxation induced by SNP and NO() scavenger reduced only the potency to SNP. The inhibition of sarcoplasmic reticulum Ca(2+)-ATPase reduced only the potency of SNP without effect on the relaxation induced by [Ru(terpy)(bdq)NO(+)](3+). Our results demonstrate that both NO donors induce relaxation by activating the GC and K(+) channels. The NO() is the unique NO specie involved in the SNP-relaxation. On the other hand, the relaxant effect of [Ru(terpy)(bdq)NO(+)](3+) involves both NO() and NO(-), that produce higher concentration of cGMP. The inhibition of sarcoplasmic reticulum Ca(2+)-ATPase reduces the relaxation induced by SNP but it did not alter the relaxation induced by [Ru(terpy)(bdq)NO(+)](3+).
Vascular Pharmacology, 2011
Nitric oxide has been pointed out as the main agent involved in the vasodilatation, which is the ... more Nitric oxide has been pointed out as the main agent involved in the vasodilatation, which is the major symptom of septic shock. However, there must be another mediator contributing to the circulatory failure observed in sepsis. This study aimed to investigate the endothelium-dependent relaxation induced by acetylcholine and the factors involved in this relaxation, using aortic rings isolated from rats submitted to cecal ligation and perforation (CLP), 2 h after induction of sepsis, which characterizes the hyperdynamic phase of sepsis. Under inhibition of constitutive NO-synthases (cNOS), the relaxation induced by acetylcholine was greater in the aortic rings of rats submitted to CLP compared with sham-operated rat aortic rings. The cyclooxygenase inhibitor indomethacin normalized this response, and the concentration of the stable metabolite of prostacyclin in the aorta of CLP rats increased in basal conditions and after stimulation with acetylcholine. Acetylcholine-induced NO production was lower in the endothelial cells from the aorta of CLP rats compared with sham rat aorta, but the protein expression of the cNOS was not altered. Moreover, iNOS protein expression could not be detected. Therefore, prostacyclin, and not only nitric oxide, is a mediator of the vasorelaxation induced by acetylcholine in aortas from rats submitted to CLP.
Pharmacology, 2009
The carotid artery has a pivotal role in the body since it supplies the head and neck with oxygen... more The carotid artery has a pivotal role in the body since it supplies the head and neck with oxygenated blood. Alterations in the functional and structural integrity of these vessels can decrease blood flow to the brain. For this reason, it is important to understand how the carotid artery responds to various stimuli. The organ bath is a traditional experimental set-up that has been used extensively to investigate the (patho)physiology and pharmacology of in vitro tissue preparations including the rat carotid artery. Molecular biology developed from related fields such as biochemistry, genetics and biophysics is now considered an important tool for understanding physiological pathways in a variety of tissues. Several local and systemic factors regulate carotid reactivity, including vaso-active peptides, such as endothelin 1 (ET-1), angiotensin II (Ang II) and bradykinin (BK). These vaso-active peptides play a fundamental role in controlling the functional and structural integrity of t...
Nitric Oxide, 2012
Nitric oxide (NO) has been pointed out as being the main mediator involved in the hypotension and... more Nitric oxide (NO) has been pointed out as being the main mediator involved in the hypotension and tissue injury taking place during sepsis. This study aimed to investigate the cellular mechanisms implicated in the acetylcholine (ACh)-induced relaxation detected in aortic rings isolated from rats submitted to cecal ligation and perforation (CLP group), 6h post-CLP. The mean arterial pressure was recorded, and the concentration-effect curves for ACh were constructed for endothelium-intact aortic rings in the absence (control) or after incubation with one of the following NO synthase inhibitors: L-NAME (non-selective), L-NNA (more selective for eNOS), 7-nitroindazole (more selective for nNOS), or 1400W (selective for iNOS). The NO concentration was determined by using confocal microscopy. The protein expression of the NOS isoforms was quantified by Western blot analysis. The prostacyclin concentration was indirectly analyzed on the basis of 6-keto-prostaglandin F(1α) (6-keto-PGF(1α)) levels measured by enzyme immunoassay. There were no differences between Sham- and CLP-operated rats in terms of the relaxation induced by acetylcholine. However, the NOS inhibitors reduced this relaxation in both groups, but this effect remained more pronounced in the CLP group as compared to the Sham group. The acetylcholine-induced NO production was higher in the rat aortic endothelial cells of the CLP group than in those of the Sham group. eNOS protein expression was larger in the CLP group, but the iNOS protein was not verified in any of the groups. The basal 6-keto-PGF(1α) levels were higher in the CLP group, but the acetylcholine-stimulated levels did not increase in CLP as much as they did in the Sham group. Taken together, our results show that the augmented NO production in sepsis syndrome elicited by cecal ligation and perforation is due to eNOS up-regulation and not to iNOS.
Nitric Oxide, 2004
The vasorelaxation induced by a nitrosyl macrocyclic ruthenium complex, proposed as a new nitric ... more The vasorelaxation induced by a nitrosyl macrocyclic ruthenium complex, proposed as a new nitric oxide (NO) carrier, was studied in rat isolated aorta. The compound trans-[RuCl([15]aneN4)NO]2+ was characterized by elemental analysis, UV-visible spectrum, and infrared spectrum. Based on the electrochemical process, the reduction of the compound was followed by NO release, which was also observed using norepinephrine as a reducing agent and NO released was analyzed by a sensor. Vasorelaxation induced by this NO donor was studied and compared to those obtained with sodium nitroprusside (SNP). The relaxation induced by the compound was concentration-dependent in denuded rat aortas and occurred only in pre-contracted arteries with norepinephrine. The macrocyclic compound induced relaxation with a similar efficacy as SNP, although the potency of SNP was slightly greater. The time to reach maximum relaxation (595 s) was longer than that of SNP (195 s). Relaxation was completely abolished by oxyhemoglobin, a known NO scavenger.
Nitric Oxide, 2008
• To investigate the contribution of the endothelium on SNP vasorelaxation, NO release and Ca2+ m... more • To investigate the contribution of the endothelium on SNP vasorelaxation, NO release and Ca2+ mobilization.
Nitric Oxide, 2006
Nitric oxide (NO) plays an important role in the control of vascular tone. NO donors have therape... more Nitric oxide (NO) plays an important role in the control of vascular tone. NO donors have therapeutic use and the most used NO donors, nitroglycerin and sodium nitroprusside have problems in their use. Thus, new NO donors have been synthesized to minimize these undesirable effects. Nytrosil ruthenium complexes have been studied as a new class of NO donors. trans-[RuCl([15]aneN(4))NO](2+), induces vasorelaxation only in presence of reducing agent. In this study, we characterized the mechanisms of vasorelaxation of trans-[RuCl([15]aneN(4))NO](2+) in denuded rat aorta and identified which NO forms are involved in this relaxation. We also evaluated the effect of this NO donor in decreasing the cytosolic Ca(2+) concentration ([Ca(2+)]c) of the vascular smooth muscle cells. Vasorelaxation to trans-[RuCl([15]aneN(4))NO](2+) (E(max): 101.8 +/- 2.3%, pEC(50): 5.03 +/- 0.15) was almost abolished in the presence of the NO* scavenger hydroxocobalamin (E(max): 4.0 +/- 0.4%; P < 0.001) and it was partially inhibited by the NO(-) scavenger L-cysteine (E(max): 79.9 +/- 6.9%, pEC(50): 4.41 +/- 0.06; P < 0.05). The guanylyl cyclase inhibitor ODQ reduced the E(max) (57.7 +/- 4.0%, P < 0.001) and pEC(50) (4.21 +/- 0.42, P < 0.01) and the combination of ODQ and TEA abolished the response to trans-[RuCl([15]aneN(4))NO](2+). The blockade of voltage-dependent (K(v)), ATP-sensitive (K(ATP)), and Ca(2+)-activated (K(Ca) K(+) channels reduced the vasorelaxation induced by trans-[RuCl([15]aneN(4))NO](2+). This compound significantly reduced [Ca(2+)]c (from 100% to 85.9 +/- 3.5%, n = 4). In conclusion, our data demonstrate that this NO donor induces vascular…
Journal of Pharmacy and Pharmacology, 2008
The present investigation was designed to investigate the effect of the diterpene ent-pimara-8(14... more The present investigation was designed to investigate the effect of the diterpene ent-pimara-8(14),15-dien-19-oic acid (pimaradienoic acid, PA) on smooth muscle extracellular Ca2+ influx. To this end, the effect of PA on phenylephrine- and KCl-induced increases in cytosolic calcium concentration ([Ca2+]c), measured by the variation in the ratio of fluorescence intensities (R340/380 nm) of Fura-2, was analysed. Whether bolus injection of PA could induce hypotensive responses in conscious normotensive rats was also evaluated. PA inhibited the contraction induced by phenylephrine (0.03 or 10 μmol L−1) and KCl (30 or 90 μmol L−1) in endothelium-denuded rat aortic rings in a concentration dependent manner. Pre-treatment with PA (10, 100, 200 μmol L−1) attenuated the contraction induced by CaCl2 (0.5 nmol L−1 or 2.5 μmol L−1) in denuded rat aorta exposed to Ca2+-free medium containing phenylephrine (0.1 μmol L−1) or KCl (30 μmol L−1). Interestingly, the inhibitory effect displayed by PA o...
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Papers by DANIELLA BONAVENTURA