Nitric Oxide – ABC CARDIOL

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Original Article

Short-term Oral Nitrite Administration Decreases Arterial Stiffness in Both Trained and Sedentary Wistar Rats

Thiago Pereira Souza et al. Lidieli Pazin Tardelli Rafael Antunes Nicoletti André Mourão Jacomini … Gabriel Francisco de Mello Martins Lucas Cézar Pinheiro José Eduardo Tanus-Santos Sandra Lia do Amaral Anderson Saranz Zago

Abstract

Background

Nitric Oxide (NO) plays an important role in blood pressure (BP) regulation, acting directly on peripheral vascular resistance through vasodilation. Physical training (via eNOS/NO) and intake of nitrite have been considered major stimuli to increase NO.

Objective

We examined the effects of oral nitrite administration and aerobic exercise training on BP and arterial stiffness in Wistar rats.

Methods

Thirty-nine (39) young male Wistar rats were divided into the following groups (n = 9 or 10 per group): Sedentary-Control (SC), Sedentary-Nitrite (SN), Trained-Control (TC), and Trained-Nitrite (TN). They were submitted to aerobic physical training on treadmills for 8 weeks (50-60% of physical capacity, 1h/day, 5 days/week) or kept sedentary. In the last 6 days of training, oral nitrite was administered (15 mg/Kg by gavage). BP, arterial stiffness, and plasma and tissue nitrite concentrations were assessed after the training and oral nitrite administration period. The significant level was defined as p < 0.05.

Results

Oral administration of nitrite was effective in reducing arterial stiffness values (TN, -23%; and SN, -15%). Both groups that had only one type of intervention showed lower systolic BP compared with control (TC vs. SC, -14.23; and SN vs. SC, – 12.46).

Conclusion

We conclude that short-term oral administration for 6 days and an aerobic physical training program promote several hemodynamic benefits in male Wistar rats, such as improvements in arterial stiffness and BP. These responses suggest that physical training and sodium nitrite supplementation can be alternatives for the prevention and treatment of hypertension.

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Original Article

Acute Effects of Dietary Nitrate on Central Pressure and Endothelial Function in Hypertensive Patients: A Randomized, Placebo-Controlled Crossover Study

Samanta Mattos et al. Michelle Rabello Cunha Bianca Cristina Marques Jenifer d´El-Rei … Diego dos Santos Baião Vania M. F. Paschoalin Wille Oigman Mario Fritsch Neves Fernanda Medeiros

Abstract

Background

The diet’s inorganic nitrate (NO₃^–) may provide a physiological substrate for reducing nitrate (NO₂^–) to NO independent of the endothelium. Studies suggest that inorganic NO₃^– has beneficial effects on cardiovascular health.

Objective

This study evaluated the acute effects of 500 mL nitrate-rich beetroot juice (BRJ; containing 11.5mmol NO₃^–) on blood pressure and endothelial function in treated hypertensive patients.

Methods

A randomized, placebo-controlled, crossover study was conducted in treated hypertensive patients (n=37; women=62%) who underwent clinical and nutritional evaluation and assessment of central hemodynamic parameters and microvascular reactivity. The significance level was p<0.05.

Results

The mean age was 59±7 years, and mean systolic and diastolic blood pressures were 142±10/83±9mmHg. There was a significant increase in the subendocardial viability ratio (SEVR; 149±25 vs. 165±30%, p<0.001) and reduction in ejection duration (ED; 37±4 vs. 34±4%, p<0.001) in the beetroot phase but no significant SEVR difference in the control phase. The % increase in perfusion (155 vs. 159 %, p=0.042) was significantly increased in the beetroot phase, which was not observed in the control phase. In the beetroot phase, the change in SEVR showed a significant correlation with the change in the area under the curve of post-occlusive reactive hyperemia (AUC-PORH) (r=0.45, p=0.012). The change in ED showed a significant correlation with the post-intervention perfusion peak (r=-0.37, p=0.031) and AUC-PORH (r=-0.36, p=0.046).

Conclusions

The acute ingestion of BRJ by hypertensive patients resulted in an improvement of endothelial function, which was associated with higher subendocardial viability and performance in myocardial contraction.

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Editorial

We need to talk about why we don’t talk about exercise!

Fabrício Braga da Silva

We usually avoid subjects that make us feel uncomfortable. As in general these subjects are those we cannot deal with, the consequences of such omission can be really bad. Problems with our children are classical examples of topics we avoid. Published in 2003, “We Need to Talk About Kevin” is a novel written by Lionel Shriver, adapted to the big screen in 2011. The film addresses the vicious cycle of problems caused by the mother who neglects her child with overt psychopathy, culminating in a catastrophe. In this fiction, avoiding the subject cost the lives of many people.

This introductory metaphor was the preamble to the following question: based on available evidence, why do we not have proper conversation about exercise with our patients? Why is physical exercise little addressed in medical visits? Why are healthcare providers not concerned about individual and collective consequences of physical inactivity?

[…]

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Research Letter

Reduced Systemic Nitric Oxide Bioavailability Parallels Microvascular Endothelial Dysfunction during Cardiopulmonary Bypass

Viviana Ugenti et al. Ana Catarina Romano Andrea De Lorenzo Eduardo Tibirica

Introduction

Cardiopulmonary bypass (CPB) is currently performed in infants and newborns for surgical correction of congenital heart diseases (CHDs). CPB exposes the body to extreme, nonphysiologic conditions that initiate a systemic inflammatory response accompanied by vasomotor dysfunction, and can lead to multiple organ dysfunction. Additionally, CPB has been linked to activation and injury of endothelial cells, which is associated with global inflammatory response, triggering of the coagulation system and subsequent organ dysfunction, not only in adult patients, but particularly in infants and newborns.

Systemic microvascular dysfunction during CPB results in inadequate blood flow, organ perfusion and oxygen delivery to the tissues.⁴ We have shown, using laser Doppler perfusion monitoring (LDPM) (a non-invasive method coupled with local heating of the skin), that the microcirculatory bed of the skin of the forehead is an appropriate model for the study of microvascular reactivity and tissue perfusion in cardiovascular surgery with CPB in adults. Actually, local thermal hyperemia (LTH) is a useful method in the evaluation of systemic microvascular endothelial function.^, In addition, using LDPM, we demonstrated that microvascular dysfunction and hypoperfusion occur during CPB in surgical correction of congenital heart disease in infants and children, despite adequate macrohemodynamic parameters. The mismatch between macro- and microcirculation in severely ill patients with septic or cardiogenic shock, which can be misleading to an adequate clinical management of these patients, has also stimulated the search for new methods to monitor microcirculatory perfusion in the intensive care units.

[…]

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Original Article

Exercise Training Improves Functions of Endothelial Progenitor Cells in Patients with Metabolic Syndrome

Qiang Tan et al. Yang Li Yao Guo

Abstract

Background

Endothelial progenitor cells (EPCs) play an important role in maintaining endothelial function. Metabolic syndrome (MetS) is associated with EPC dysfunction. Although physical exercise has a beneficial impact on EPC activity, its mechanism is not completely clear yet.

Objective

The purpose of this study is to investigate the effects of physical exercise on the functions of EPCs and the underlying mechanisms in patients with MetS.

Methods

Volunteers with MetS were divided into exercise group (n=15) and control group (n=15). Before and after 8 weeks exercise training, EPCs were isolated from peripheral blood. Colony forming unit (CFU) assay, tube-formation assay, the protein expression of endothelial nitric oxide synthase (eNOS), phosphatidylinositol-3-kinase (PI3-K) and protein kinase B (AKT) were determined. A probability value <0.05 was considered to indicate statistical significance.

Results

After 8 weeks, the number of CFUs was significantly increased in the exercise group compared to the control group (p<0.05). In addition, we observed a significant decrease of homeostasis model assessment for insulin resistance (HOMA-IR), endothelin-1, high-sensitive C-reactive protein, and homocysteine levels in the exercise group. Exercise intervention could also enhance tube-formation capacity of EPCs and increase phosphorylation level of eNOS, PI3-K and AKT.

Conclusion

Physical exercise enhanced the functions of EPCs. The mechanism may be related to exercise, activating the PI3-K/AKT/eNOS pathway.

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Editorial

Endothelial Progenitor Cells and Exercise: Working Together to Target Endothelial Dysfunction in Metabolic Syndrome

Christina Grüne de Souza e Silva

Our understanding of the crucial role played by the endothelium in cardiovascular biology has evolved over the past couple of decades, with the recognition that it is a dynamically-regulated organ, essential in maintaining vascular homeostasis. A healthy endothelium is able to adequately respond to physical and chemical signals and, through the release of a wide range of mediators, regulate, among others, vascular tone and growth, cellular adhesion, thrombogenicity, and inflammation.

Furthermore, it has been acknowledged that when the endothelium loses its physiological properties due to an imbalance between its injury and its appropriate recovery, a tendency towards vasoconstriction, pro-thrombotic, and pro-inflammatory states are shown. This condition, termed endothelial dysfunction, has been shown to precede the development of pro-atherosclerotic changes, leading to atherosclerotic plaque formation and its later clinical complications.

[…]

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Review Article

Effect of Physical Training on Nitric Oxide Levels in Patients with Arterial Hypertension: An Integrative Review

Tábata de Paula Facioli et al. Mariana Colombini Buranello Eloisa Maria Gatti Regueiro Renata Pedrolongo Basso-Vanelli Marina de Toledo Durand

Abstract

The regular practice of physical exercise as a non-pharmacological treatment of arterial hypertension (AH) has been encouraged due to causing a series of physiological responses in the cardiovascular system, such as the production of vasoactive substances, including nitric oxide (NO). NO is a relaxation factor released by the endothelium, and the decrease in its bioavailability is related to coronary and arterial diseases, such as AH. This study aimed to perform an integrative literature review to elucidate the effect of physical training on NO levels in patients with AH and to establish a relationship between these levels and blood pressure (BP) control. A literature review was was performed by searching PubMed / MEDLINE, Lilacs, Scielo, Cinahl and Embase databases. The search string used was (“arterial hypertension” OR hypertension) AND (exercise OR “physical exercise” OR “aerobic exercise” OR “exercise training” or “physical activity”) AND (“nitric oxide”). We included fully available controlled and uncontrolled clinical trials published in English and Portuguese languages in the last 10 years. The review consisted of 16 articles, of which 13 reported an increase in NO production after the physical training intervention, and three studies found no change. In addition, 15 studies observed a reduction in BP after the intervention. In conclusion, regular practice of physical exercises, advocating moderate intensity, can improve NO bioavailability in pre-hypertensive and hypertensive individuals, which seems to be one of the mechanisms responsible for BP reduction.

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Original Article

Effect of Diterpene Manool on the Arterial Blood Pressure and Vascular Reactivity in Normotensive and Hypertensive Rats

Ariadne Santana e Neves Monteiro et al. Debora Ribeiro Campos Agnes Afrodite Sumarelli Albuquerque Paulo Roberto Barbosa Evora … Luciana Garros Ferreira Andrea Carla Celotto

Abstract

Background:

Many studies have shown that the diterpenoid classes exert a significant effect on the cardiovascular system. Diterpenes, in particular, are among the main compound links to cardiovascular properties such as vasorelaxant, inotropic, diuretic and hypotensive activity. While the manool vasorelaxation mechanism is visible, its effect on blood pressure (BP) is still unknown.

Objective:

To evaluate the in vivo hypotensive effect of manool and check the ex vivo vasorelaxation effect in rat aortic rings.

Methods:

The animals were divided randomly into two groups: normotensive and hypertensive. The normotensive group was sham-operated, and the 2K1C model was adopted for the hypertensive group. Invasive BP monitoring was performed for manool tests at different doses (10, 20 and 40 mg/kg). Concentration-response curves for manool were obtained in the aorta rings, with endothelium, pre-contracted with phenylephrine (Phe) after incubation with Nω-nitro-L-arginine methyl ester(L-NAME) or oxadiazole [4,3-a]quinoxalin-1-one (ODQ). Nitric oxide (NOx) plasma levels were measured by chemiluminescence assay.

Results:

After manool administration, BP was reduced in normotensive and hypertensive groups, and this effect was inhibited by L-NAME in hypertensive animals only in 10 mg/kg dose. Ex vivo manool promoted vasorelaxation, which was inhibited by L-NAME and ODQ incubation or endothelium removal. NOx plasma levels increased in the hypertensive group after manool administration. Manool elicits endothelium-dependent vascular relaxation in rat aorta mediated by the NO/cGMP signaling pathway and BP reduction, also by NOx plasma increase. These combined effects could be involved in modulating peripheral resistance, contributing to the antihypertensive effect of diterpene.

Conclusion:

These effects together could be involved in modulating peripheral resistance, contributing to the antihypertensive effect of diterpene.

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Original Article

Inter-Individual Responses to Citrulline Malate Oral Supplementation on Post-Exercise Hypotension in Hypertensives: A 24-Hour Analysis

Juliano Casonatto et al. Daniel Massaharu Enokida Kamila Grandolfi

Abstract

Background:

Studies have persuasively demonstrated that citrulline has a key role in the arginine-nitric oxide system, increasing nitric oxide bioavailability, an important mediator of peripheral vasodilation.

Objective:

To analyze the inter-individual post-exercise hypotension responsiveness following acute citrulline supplementation in hypertensives.

Methods:

Forty hypertensives were randomly assigned to one of the four experimental groups (control-placebo, control-citrulline, exercise-placebo, and exercise-citrulline). They ingested placebo or citrulline malate [CM] (6 grams). During the exercise session, individuals performed 40 minutes of walking/running on a treadmill at 60-70% of HR reserve. For the control session, the individuals remained seated at rest for 40 minutes. Office blood pressure (BP) was taken every 10 minutes until completing 60 minutes after the experimental session. The ambulatory BP device was programmed to take the readings every 20 minutes (awake time) and every 30 minutes (sleep time) over the course of 24 hours of monitoring. Statistical significance was defined as p < 0.05.

Results:

Unlike the other experimental groups, there were no “non-responders” in the exercise/citrulline (EC) for “awake” (systolic and diastolic BP) and “24 hours” (diastolic BP). The effect sizes were more consistent in the EC for systolic and diastolic ambulatorial BP response. The effects were “large” (> 0.8) for “awake”, “asleep”, and “24 hours” only in the EC for diastolic BP.

Conclusion:

CM supplementation can increase the post-exercise hypotensive effects in hypertensives. In addition, the prevalence of non-responders is lower when associated with aerobic exercise and CM supplementation.

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Editorial

Endothelial Function and Physical Exercise

Luana Urbano Pagan et al. Mariana Janini Gomes Marina Politi Okoshi

The endothelium is considered an active and dynamic tissue with important properties such as maintenance of blood circulation, regulation of vascular tone, microvascular permeability, signaling, and vascular angiogenesis and inflammatory response. The endothelium allows the connection among components of the circulation and body systems. Endothelial cells produce and, depending on the stimulus received, release factors that lead to vascular smooth muscle cells contraction or relaxation. Vascular tone control by the endothelium is modulated by the production and release of mediators such as nitric oxide, prostacyclins, prostaglandins, thromboxane, angiotensin II, endothelin-1 and reactive oxygen species. Under physiological conditions, these factors are balanced. Imbalance in the production of substances by the endothelium leads to triggering and progression of several conditions and diseases such as ischemia, thrombosis, atherosclerosis, arterial hypertension, inflammation and tumor growth.^, Therefore, vascular endothelial dysfunction is an important pathophysiological factor in human diseases.

Endothelial dysfunction is mainly characterized by changes in endothelial actions involving the reduction of vasodilation and the induction of a pro-inflammatory or prothrombotic state. Due to its clinical importance, endothelial dysfunction is considered an independent predictor of cardiovascular risk. In addition, it can also be observed in non-cardiovascular diseases, such as rheumatic and autoimmune diseases.

[…]

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Original Article

Endothelial Dysfunction and Inflammation Precedes Elevations in Blood Pressure Induced by a High-Fat Diet

Jorge Camargo Oishi et al. Cynthia Aparecida Castro Karina Ana Silva Victor Fabricio … Evelin Capelari Cárnio Shane A. Phillips Ana Claudia Garcia de Oliveira Duarte Gerson Jhonatan Rodrigues

Abstract

Background:

Obesity leads to a chronic inflammatory state, endothelial dysfunction and hypertension.

Objective:

To establish the time-course of events regarding inflammatory markers, endothelial dysfunction, systolic blood pressure (SBP) in obesity in only one experimental model.

Methods:

We fed male Wistar rats (eight-week age) with a standard diet (Control – CT, n = 35), or palatable high-fat diet (HFD, n = 35) for 24 weeks. Every six weeks, 7 animals from each group were randomly selected for euthanasia. SBP and serum levels of interleukin-6, tumor necrosis factor-α, C-reactive protein, adiponectin and nitric oxide were determined. Endothelial and vascular smooth muscle functions were determined in dissected aorta and lipid peroxidation was measured. Statistical significance was set at p < 0.05.

Results:

Levels of pro-inflammatory cytokines began to increase after six weeks of a high-fat diet, while those of the anti-inflammatory cytokine adiponectin decreased. Interestingly, the endothelial function and serum nitric oxide began to decrease after six weeks in HFD group. The SBP and lipid peroxidation began to increase at 12 weeks in HFD group. In addition, we showed that total visceral fat mass was negatively correlated with endothelial function and positively correlated with SBP.

Conclusion:

Our results show the time-course of deleterious effects and their correlation with obesity.

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Editorial

G-Proteins Agonists and NO/cGMP Blockers: Unexplored Frontiers in the Pharmaceutical Industry

Paulo Roberto B. Evora

G-proteins: potential therapeutic role

The release of nitric oxide (NO) can occur by different pathways involving G-proteins. The Gi-protein is responsible for the mediation of inhibitory effects of receptors in the adenylate cyclase and guanylate cyclase pathways. An early stage of the majority of the responses mediated by receptors is the activation of G-proteins in the cell membrane, which is the target of the modulation of a variety of intracellular events. The role of G-proteins in the pathophysiology of vasospasm after global ischemia and reperfusion is still a matter of investigations. Their participation was documented in a comparative study of vascular relaxation induced by sodium fluoride, which produces biphasic responses in human, bovine, and porcine coronary arteries, causing an endothelium-dependent relaxation and an endothelium-independent contraction. G-protein dysfunction in the endothelium has also been postulated as responsible for the endothelial dysfunction in conditions of endothelial cell regeneration after injury, atherosclerosis, and coronary vasospasm. Myocardial ischemia and reperfusion selectively impair receptor-mediated NO release. However, the ability of the endothelial cell to produce NO or generate endothelium-dependent relaxation to nonnitric oxide-dependent agonists remains intact.^,

In summary: 1. Endothelial cells maintain their capacity to release NO based on their ability in receiving the transduction signal through the membrane; 2. G-proteins have a fundamental role in the signal transduction; 3. This paradigm is extended to all vasotonic cardiovascular diseases that coexist with platelet dysfunction. These data would be highly relevant in the research of G-protein-targeting drugs.

[…]

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Original Article

Ruthenium Complex Improves the Endothelial Function in Aortic Rings From Hypertensive Rats

Izabela Pereira Vatanabe et al. Carla Nascimento dos Santos Rodrigues Tereza Cristina Buzinari Thiago Francisco de Moraes … Roberto Santana da Silva Gerson Jhonatan Rodrigues

Abstract

Background:

The endothelium is a monolayer of cells that extends on the vascular inner surface, responsible for the modulation of vascular tone. By means of the release of nitric oxide (NO), the endothelium has an important protective function against cardiovascular diseases.

Objective:

Verify if cis- [Ru(bpy)₂(NO₂)(NO)](PF₆)₂ (BPY) improves endothelial function and the sensibility of conductance (aorta) and resistance (coronary) to vascular relaxation induced by BPY.

Methods:

Normotensive (2K) and hypertensive (2K-1C) Wistar rats were used. For vascular reactivity study, thoracic aortas were isolated, rings with intact endothelium were incubated with: BPY(0.01 to10 µM) and concentration effect curves to acetylcholine were performed. In addition, cumulative concentration curves were performed to BPY (1.0 nM to 0.1 µM) in aortic and coronary rings, with intact and denuded endothelium.

Results:

In aorta from 2K-1C animals, the treatment with BPY 0.1µM increased the potency of acetylcholine-induced relaxation and it was able to revert the endothelial dysfunction. The presence of the endothelium did not modify the effect of BPY in inducing the relaxation in aortas from 2K and 2K-1C rats. In coronary, the endothelium potentiated the vasodilator effect of BPY in vessels from 2K and 2K-1C rats.

Conclusion:

Our results suggest that 0.1 µM of BPY is able to normalize the relaxation endothelium dependent in hypertensive rats, and the compound BPY induces relaxation in aortic from normotensive and hypertensive rats with the same potency. The endothelium potentiate the relaxation effect induced by BPY in coronary from normotensive and hypertensive rats, with lower effect on coronary from hypertensive rats.

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Original Article

Effects of a Single Bout of Resistance Exercise in Different Volumes on Endothelium Adaptations in Healthy Animals

Marcelo Mendonça Mota et al. Tharciano Luiz Teixeira Braga da Silva Fabricio Nunes Macedo Thássio Ricardo Ribeiro Mesquita … Lucindo José Quintans Júnior Valter Joviniano de Santana-Filho Sandra Lauton-Santos Márcio Roberto Viana Santos

Abstract

Background:

Resistance exercise (RE) has been recommended for patients with cardiovascular diseases. Recently, a few studies have demonstrated that the intensity of a single bout of RE has an effect on endothelial adaptations to exercise. However, there is no data about the effects of different volumes of RE on endothelium function.

Objective:

The aim of the study was to evaluate the effects of different volumes of RE in a single bout on endothelium-dependent vasodilatation and nitric oxide (NO) synthesis in the mesenteric artery of healthy animals.

Methods:

Male Wistar rats were divided into three groups: Control (Ct); low-volume RE (LV, 5 sets x 10 repetitions) and high-volume RE (HV, 15 sets x 10 repetitions). The established intensity was 70% of the maximal repetition test. After the exercise protocol, rings of mesenteric artery were used for assessment of vascular reactivity, and other mesenteric arteries were prepared for detection of measure NO production by DAF-FM fluorescence. Insulin responsiveness on NO synthesis was evaluated by stimulating the vascular rings with insulin (10 nM).

Results:

The maximal relaxation response to insulin increased in the HV group only as compared with the Ct group. Moreover, the inhibition of nitric oxide synthesis (L-NAME) completely abolished the insulin-induced vasorelaxation in exercised rats. NO production showed a volume-dependent increase in the endothelial and smooth muscle layer. In endothelial layer, only Ct and LV groups showed a significant increase in NO synthesis when compared to their respective group under basal condition. On the other hand, in smooth muscle layer, NO fluorescence increased in all groups when compared to their respective group under basal condition.

Conclusions:

Our results suggest that a single bout of RE promotes vascular endothelium changes in a volume-dependent manner. The 15 sets x 10 repetitions exercise plan induced the greatest levels of NO synthesis.

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Original Article

A Single Resistance Exercise Session Improves Aortic Endothelial Function in Hypertensive Rats

Thaís de Oliveira Faria et al. Jhuli Keli Angeli Luiz Guilherme Marchesi Mello Gustavo Costa Pinto … Ivanita Stefanon Dalton Valentim Vassallo Juliana Hott de Fúcio Lizardo

Abstract

Background:

Physical exercise is an important tool for the improvement of endothelial function.

Objective:

To assess the effects of acute dynamic resistance exercise on the endothelial function of spontaneously hypertensive rats (SHR).

Methods:

Ten minutes after exercise, the aorta was removed to evaluate the expression of endothelial nitric oxide synthase (eNOS), phosphorylated endothelial nitric oxide synthase (p-eNOS1177) and inducible nitric oxide synthase (iNOS) and to generate concentration-response curves to acetylcholine (ACh) and to phenylephrine (PHE). The PHE protocol was also performed with damaged endothelium and before and after N^G-nitro-L-arginine methyl ester (L-NAME) and indomethacin administration. The maximal response (E_max) and the sensitivity (EC₅₀) to these drugs were evaluated.

Results:

ACh-induced relaxation increased in the aortic rings of exercised (Ex) rats (E_max= -80 ± 4.6%, p < 0.05) when compared to those of controls (Ct) (E_max = -50 ± 6.8%). The E_max to PHE was decreased following exercise conditions (95 ± 7.9%, p < 0.05) when compared to control conditions (120 ± 4.2%). This response was abolished after L-NAME administration or endothelial damage. In the presence of indomethacin, the aortic rings' reactivity to PHE was decreased in both groups (EC₅₀= Ex -5.9 ± 0.14 vs. Ct -6.6 ± 0.33 log µM, p < 0.05 / E_max = Ex 9.5 ± 2.9 vs. Ct 17 ± 6.2%, p < 0.05). Exercise did not alter the expression of eNOS and iNOS, but increased the level of p-eNOS.

Conclusion:

A single resistance exercise session improves endothelial function in hypertensive rats. This response seems to be mediated by increased NO production through eNOS activation.

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Viewpoint

Detailing Peripheral Arterial Tonometry in Heart Failure. An Endothelial Function Evaluation

Aline Cristina Tavares et al. Edimar Alcides Bocchi Guilherme Veiga Guimarães

Introduction

Endothelium regulates cardiac function and vasomotor tone, adjusts vascular permeability, preserves blood fluidity, playing an important role in cardiovascular homeostasis.^, In adults with heart failure (HF), endothelial dysfunction severity is related to diastolic dysfunction,^, increase in cardiovascular risk,^– heart failure,^, exercise incapacity, severity of cardiovascular symptoms,^,^,^,^, cardiovascular events, cardiac transplant and death.^,

Although endothelium is at the interface between circulating cardiovascular factors and underlying organ tissues, cardiovascular and endothelial peripheral dysfunctions are not totally linked so far.^– Evaluation of endothelial function appears as a tempting adjunct for cardiovascular risk stratification, and understanding this matter may help having a faster approach and better screening in the cardiomyopathy field in everyday clinical practice, which brings the importance of this paper.

[…]

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Original Article

Is Local Nitric Oxide Availability Responsible for Myocardial Salvage after Remote Preconditioning?

Esbeidira Aranet Arroyo-Martínez et al. Alejandra Meaney Gabriela Gutiérrez-Salmeán Juan Miguel Rivera-Capello … Vidal González-Coronado Alejandro Alcocer-Chauvet Genaro Castillo Nayelli Nájera Guillermo Ceballos Eduardo Meaney

Abstract

Background:

Remote ischemic preconditioning (RIPC) represents an attractive therapy for myocardial protection, particularly when ischemic events can be anticipated. Although several hypothetic mechanisms have been proposed, no definite molecular pathways have been elucidated.

Objective:

We evaluated the effect of brachial circulation cuff occlusion on myocardial ischemic tolerance, necrosis, and nitric oxide (NO) in patients with ischemic heart disease undergoing elective percutaneous coronary interventions (PCI).

Methods:

46 patients were randomly allocated into two groups: control and RIPC before PCI procedures. Electrocardiographic analysis, serum concentrations of troponin I (cTn-I) were measured at baseline and 24 hours after PCI. A blood sample from the atherosclerotic plaque was drawn to determine nitrate and nitrites.

Results:

RIPC increased the availability of NO in the stented coronary artery. Control patients presented a small but significant increase in cTn-I, whilst it remained unchanged in preconditioned group. The preconditioning maneuver not only preserved but also enhanced the sum of R waves.

Conclusions:

RIPC induced an intracoronary increase of NO levels associated with a decrease in myocardial damage (measured as no increase in cTn-I) with electrocardiographic increases in the sum of R waves, suggesting an improved myocardium after elective PCI.

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Original Article

The Effect of Sleep Deprivation on Cardiac Function and Tolerance to Ischemia-Reperfusion Injury in Male Rats

Sajad Jeddi et al. Amir Nezami Asl Alireza Asgari Asghar Ghasemi

Abstract

Background:

Sleep deprivation (SD) is strongly associated with elevated risk for cardiovascular disease.

Objective:

To determine the effect of SD on basal hemodynamic functions and tolerance to myocardial ischemia-reperfusion (IR) injury in male rats.

Method:

SD was induced by using the flowerpot method for 4 days. Isolated hearts were perfused with Langendorff setup, and the following parameters were measured at baseline and after IR: left ventricular developed pressure (LVDP); heart rate (HR); and the maximum rate of increase and decrease of left ventricular pressure (±dp/dt). Heart NOx level, infarct size and coronary flow CK-MB and LDH were measured after IR. Systolic blood pressure (SBP) was measured at start and end of study.

Results:

In the SD group, the baseline levels of LVDP (19%), +dp/dt (18%), and -dp/dt (21%) were significantly (p < 0.05) lower, and HR (32%) was significantly higher compared to the controls. After ischemia, hearts from SD group displayed a significant increase in HR together with a low hemodynamic function recovery compared to the controls. In the SD group, NOx level in heart, coronary flow CK-MB and LDH and infarct size significantly increased after IR; also SD rats had higher SBP after 4 days.

Conclusion:

Hearts from SD rats had lower basal cardiac function and less tolerance to IR injury, which may be linked to an increase in NO production following IR.

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Original Article

Role of microRNAs 221/222 on Statin Induced Nitric Oxide Release in Human Endothelial Cells

Alvaro Cerda et al. Cristina Moreno Fajardo Rodrigo Gouveia Basso Mario Hiroyuki Hirata Rosario Dominguez Crespo Hirata

Background:

Nitric oxide (NO) has been largely associated with cardiovascular protection through improvement of endothelial function. Recently, new evidence about modulation of NO release by microRNAs (miRs) has been reported, which could be involved with statin-dependent pleiotropic effects, including anti-inflammatory properties related to vascular endothelium function.

Objective:

To evaluate the effects of cholesterol-lowering drugs including the inhibitors of cholesterol synthesis, atorvastatin and simvastatin, and the inhibitor of cholesterol absorption ezetimibe on NO release, NOS3 mRNA expression and miRs potentially involved in NO bioavailability.

Methods:

Human umbilical vein endothelial cells (HUVEC) were exposed to atorvastatin, simvastatin or ezetimibe (0 to 5.0 μM). Cells were submitted to total RNA extraction and relative quantification of NOS3 mRNA and miRs -221, -222 and -1303 by qPCR. NO release was measured in supernatants by ozone-chemiluminescence.

Results:

Both statins increased NO levels and NOS3 mRNA expression but no influence was observed for ezetimibe treatment. Atorvastatin, simvastatin and ezetimibe down-regulated the expression of miR-221, whereas miR-222 was reduced only after the atorvastatin treatment. The magnitude of the reduction of miR-221 and miR-222 after treatment with statins correlated with the increment in NOS3 mRNA levels. No influence was observed on the miR-1303 expression after treatments.

Conclusion:

NO release in endothelial cells is increased by statins but not by the inhibitor of cholesterol absorption, ezetimibe. Our results provide new evidence about the participation of regulatory miRs 221/222 on NO release induction mediated by statins. Although ezetimibe did not modulate NO levels, the down-regulation of miR-221 could involve potential effects on endothelial function.

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Original Article

Vascular Response of Ruthenium Tetraamines in Aortic Ring from Normotensive Rats

Ana Gabriela Conceição-Vertamatti et al. Luiz Alberto Ferreira Ramos Ivy Calandreli Aline Nunes Chiba … Douglas Wagner Franco Elia Tfouni Dora Maria Grassi-Kassisse

Background:

Ruthenium (Ru) tetraamines are being increasingly used as nitric oxide (NO) carriers. In this context, pharmacological studies have become highly relevant to better understand the mechanism of action involved.

Objective:

To evaluate the vascular response of the tetraamines trans-[Ru^II(NH₃)₄(Py)(NO)]³⁺, trans-[Ru^II(Cl)(NO) (cyclan)](PF₆)₂, and trans-[Ru^II(NH₃)₄(4-acPy)(NO)]³⁺.

Methods:

Aortic rings were contracted with noradrenaline (10⁻⁶ M). After voltage stabilization, a single concentration (10⁻⁶ M) of the compounds was added to the assay medium. The responses were recorded during 120 min. Vascular integrity was assessed functionally using acetylcholine at 10⁻⁶ M and sodium nitroprusside at 10⁻⁶ M as well as by histological examination.

Results:

Histological analysis confirmed the presence or absence of endothelial cells in those tissues. All tetraamine complexes altered the contractile response induced by norepinephrine, resulting in increased tone followed by relaxation. In rings with endothelium, the inhibition of endothelial NO caused a reduction of the contractile effect caused by pyridine NO. No significant responses were observed in rings with endothelium after treatment with cyclan NO. In contrast, in rings without endothelium, the inhibition of guanylate cyclase significantly reduced the contractile response caused by the pyridine NO and cyclan NO complexes, and both complexes caused a relaxing effect.

Conclusion:

The results indicate that the vascular effect of the evaluated complexes involved a decrease in the vascular tone induced by norepinephrine (10⁻⁶ M) at the end of the incubation period in aortic rings with and without endothelium, indicating the slow release of NO from these complexes and suggesting that the ligands promoted chemical stability to the molecule. Moreover, we demonstrated that the association of Ru with NO is more stable when the ligands pyridine and cyclan are used in the formulation of the compound.

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Original Article

Effects of Ischemic Postconditioning on the Hemodynamic Parameters and Heart Nitric Oxide Levels of Hypothyroid Rats

Sajad Jeddi et al. Jalal Zaman Asghar Ghasemi

Background:

Ischemic postconditioning (IPost) is a method of protecting the heart against ischemia-reperfusion (IR) injury. However, the effectiveness of IPost in cases of ischemic heart disease accompanied by co-morbidities such as hypothyroidism remains unclear.

Objective:

The aim of this study was to determine the effect of IPost on myocardial IR injury in hypothyroid male rats.

Methods:

Propylthiouracil in drinking water (500 mg/L) was administered to male rats for 21 days to induce hypothyroidism. The hearts from control and hypothyroid rats were perfused in a Langendorff apparatus and exposed to 30 min of global ischemia, followed by 120 min of reperfusion. IPost was induced immediately following ischemia.

Results:

Hypothyroidism and IPost significantly improved the left ventricular developed pressure (LVDP) and peak rates of positive and negative changes in left ventricular pressure (±dp/dt) during reperfusion in control rats (p < 0.05). However, IPost had no add-on effect on the recovery of LVDP and ±dp/dt in hypothyroid rats. Furthermore, hypothyroidism significantly decreased the basal NO metabolite (NO_x) levels of the serum (72.5 ± 4.2 vs. 102.8 ± 3.7 μmol/L; p < 0.05) and heart (7.9 ± 1.6 vs. 18.8 ± 3.2 μmol/L; p < 0.05). Heart NO_x concentration in the hypothyroid groups did not change after IR and IPost, whereas these were significantly (p < 0.05) higher and lower after IR and IPost, respectively, in the control groups.

Conclusion:

Hypothyroidism protects the heart from IR injury, which may be due to a decrease in basal nitric oxide (NO) levels in the serum and heart and a decrease in NO after IR. IPost did not decrease the NO level and did not provide further cardioprotection in the hypothyroid group.

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Artigo Original

Genetic polymorphism G894T and the prognosis of heart failure outpatients

Oziel Marcio Araujo Tardin et al. Sabrina Bernardez Pereira Monica Wanderley Monçores Velloso Henrique Miller Balieiro … Bruno Costa Thiago Oliveira e Alves Camila Giro Leandro Pontes Pessoa Georgina Severo Ribeiro Evandro Tinoco Mesquita

BACKGROUND: Previous studies have analyzed the role of the genetic polymorphism of endothelial nitric oxide synthase on heart failure prognosis. However, there are no studies relating the G894T and heart failure in Brazil. OBJECTIVE: To evaluate the association between G894T GP and the prognosis of a sample of Brazilian outpatients with heart failure. METHODS: Cohort study included 145 patients with systolic heart failure, followed for up to 40 months (mean = 22), at two university hospitals, in the State of Rio de Janeiro. We evaluated the relationship between G894T and the following outcomes: reverse remodeling, improvement in functional class (NYHA), and mortality and hospitalization rates. The diameters of the left atrium and ventricle, as well as the ejection fraction of the left ventricle, were evaluated at baseline and at 6 months to assess reverse remodeling. The improvement in functional class was evaluated after 6 months, and mortality rate and hospitalization were evaluated during follow-up. Race was self-declared. G894T polymorphism was analyzed by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: The genotypic frequencies were GG (40%), GT (48.3%) and TT (11.7%). The allele frequency was guanine (64.1%) and thiamine (35.8%). There were no differences between the genotype or allelic frequencies according to self-declared race, either as baseline characteristics. There was no relationship between genotype or allele frequency and the outcome measures. CONCLUSION: No association was observed between the G894T polymorphism (Glu298Asp) and prognosis in this sample of Brazilian outpatients with systolic heart failure.

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Original Article

Effects of atorvastatin and T-786C polymorphism of eNOS gene on plasma metabolic lipid parameters

Vanessa Helena de Souza Zago et al. José Eduardo Tanus dos Santos Mirian Regina Gardin Danelon Roger Marcelo Mesquita da Silva … Natália Baratella Panzoldo Eliane Soler Parra Fernanda Alexandre Vítor Wilson de Moura Virgínio Eder Carlos Rocha Quintão Eliana Cotta de Faria

BACKGROUND: Endothelial nitric oxide synthase (eNOS) activity may be modulated by high-density lipoprotein cholesterol (HDL-C), statins or polymorphisms, such as the T-786C of eNOS. OBJECTIVE: This study aimed at evaluating if the T-786C polymorphism is associated with changes of atorvastatin effects on the lipid profile, on the concentrations of metabolites of nitric oxide (NO) and of high sensitivity C-reactive protein (hsCRP). METHODS: Thirty male volunteers, asymptomatic, aged between 18 and 56 years were genotyped and classified according to absence (TT, n = 15) or presence (CC, n = 15) of the polymorphism. They were randomly selected for the use of placebo or atorvastatin (10 mg/day/14 days). After each treatment lipids, lipoproteins, HDL2 and HDL3 composition, cholesteryl ester transfer protein (CETP) activity, metabolites of NO and hsCRP were evaluated. RESULTS: The comparisons between genotypes after placebo showed an increase in CETP activity in a polymorphism-dependent way (TT, 12±7; CC, 22±12; p < 0.05). The interaction analyses between treatments indicated that atorvastatin has an effect on cholesterol, LDL, nitrite and lipid-protein ratios (HDL2 and HDL3) (p < 0.001) in both genotypes. Interestingly, we observed genotype/drug interactions on CETP (p < 0.07) and lipoprotein (a) (Lp(a)) (p < 0.056), leading to a borderline decrease in CETP, but with no effect on Lp(a). HsCRP showed no alteration. CONCLUSION: These results suggest that statin treatment may be relevant for primary prevention of atherosclerosis in patients with the T-786C polymorphism of eNOS, considering the effects on lipid metabolism.

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Artigo Original

Vascular alterations in high-fat diet-obese rats: role of Endothelial L-arginine/NO Pathway

Thiago Bruder Nascimento et al. Rafaela de Fátima Ferreira Baptista Priscila Cristina Pereira Dijon Henrique Salomé Campos … André Soares Leopoldo Ana Paula Lima Leopoldo Silvio A. Oliveira Júnior Carlos Roberto Padovani Antônio Carlos Cicogna Sandra Cordellini

BACKGROUND: Mechanisms underlying vascular abnormalities in obesity remain to be completely clarified. OBJECTIVE: L-arginine/nitric oxide pathway was evaluated on vascular response of high-fat diet-obese rats, focusing on endothelial and smooth muscle cells. METHODS: 30-day-old rats were divided in two groups: control (C) and obese (OB, high-fat diet for 30 weeks). After 30 weeks, body weight, adiposity index, blood pressure, and metabolic and endocrine profiles of the animals were recorded. Curves to noradrenaline were obtained in absence and presence of nitric oxide synthase inhibitor (L-NAME, 3×10-4M) on intact and denuded thoracic aorta from C and OB rats. RESULTS: Body weight, adiposity index, leptin and insulin levels were increased in OB, while blood pressure was unchanged. Obesity also produced glucose tolerance and insulin resistance. Reactivity to noradrenaline of intact aorta was similar in C and OB rats. L-NAME presence produced a similar increase in maximal responses, but a higher leftward shift of noradrenaline responses in intact aorta from C than in OB rats [EC50 (x10-7M): C = 1.84 (0.83-4.07), O = 2.49 (1.41-4.38); L-NAME presence C = 0.02 (0.01-0.04)*, O = 0.21 (0.11-0.40)*†,*p < 0.05 vs respective control, †p < 0.05 vs control plus L-NAME, n = 6-7]. None of the protocols altered the reactivity to noradrenaline of denuded aortas. CONCLUSION: High-fat diet-induced obesity promotes metabolic and vascular alterations. The vascular alteration involved an endothelial L-arginine/NO pathway improvement was probably correlated to diet-induced hyperinsulinemia and hyperleptinemia. The greater resistance to L-NAME effects in aorta of obese rats raises concerns about the lower cardiovascular vulnerability of obese individuals in the presence of associated pathologies that impair NO-system activity.

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