Methylene Blue for Refractory Shock in Polytraumatized Patient: A Case Report.

BACKGROUND: Methylene blue (MB) has been advocated for the treatment of shock refractory to standard measures. MB is proposed to increase blood pressure in shock by interfering with guanylate cyclase and nitric oxide synthase (NOS) activity. Several studies have evaluated the vasoconstrictive and positive inotropic effects of MB in septic shock patients. However, there is a paucity of studies involving trauma patients. CASE REPORT: A 4-year-old boy was hit by a truck while riding his bicycle and was treated with fluid resuscitation at the emergency department and then taken to the operating room for damage-control surgery. He had liver, diaphragm, rectal, and thoracic injuries. At the pediatric intensive care unit (PICU), he remained hypotensive despite volume, dopamine, epinephrine, and norepinephrine infusion. A dose of 0.5 mg/kg of i.v. MB was administered. During the next 2 h after MB administration, we were able to wean him off norepinephrine, and doses of epinephrine and dopamine were reduced. Ultimately, he was discharged from the PICU 13 days later in good condition. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Trauma patients who have experienced bleeding and survived the initial insult are still at risk of dying from continuing systemic hypoperfusion and the resultant multiple organ dysfunctions. Use of a low dose of MB as an adjuvant to treat shock might improve survival of these patients.

An adaptation for exhaled breath condensate collection in rabbits.

AIM: To set up and test the feasibility of a handmade apparatus adapted for exhaled breath condensate (EBC) collection in medium-sized animals. MATERIALS AND METHODS: The apparatus was produced using an 18-mm thick u-shaped borosilicate glass. The u-shaped tube body is 25 cm in diameter, and the horizontal portions are 12 cm in diameter. The base consists of a tube joint 14/20 or 14 mm thick by 20 cm in diameter, and has a length of 5 cm. This has a hole that is plugged for condensate flow to a 1.5 mL polypropylene microtube that stores the condensate during collection. Was placed inside a styrofoam box and immersed in crushed ice and salt to ensure cooling. The temperature was monitored and maintained throughout the collection at -10°C. One of the outputs of the u-shaped tube was connected to the expiratory limb of the ventilator. RESULTS: An experimental model of ALI, induced by oleic acid (OA) was adopted to determine the concentration of biomarkers of oxidative stress: malondialdehyde (MDA), glutathione (GSH), and nitrite/nitrate (NOx). The proposed model allows measurement of NOx, MDA, and GSH. However, the NOx and MDA levels in the EBC were not significant. It was only possible to observe an upward trend, which suggests a temporal evolution of the presence of these markers in the EBC. CONCLUSION: The EBC collection method adapted is effective to generate sufficient content that allows to determine the levels of different biomarkers, such as NOx, MDA, and GSH, that are involved in oxidative and inflammatory stress processes during respiratory diseases.

In vitro effects of extracellular hypercapnic acidification on the reactivity of rat aorta: Rat aorta vasodilation during hypercapnic acidification.

The mechanisms by which pH influences vascular tone are not entirely understood, but evidence suggests that the endothelium is involved. Here, we aimed to study the in vitro vascular responses induced by extracellular hypercapnic acidification (HA), as well as the endothelium-dependent mechanisms that are involved in the responses. We bubbled a mixture of CO2 (40%)/O2 (60%) in an organ bath; we constructed a pH-response curve (pH range 7.4-6.6) and registered isometric force simultaneously. Aortic rings from rats were pre-contracted with phenylephrine (10-6 M) and incubated for 30 min in the presence of different chemicals. The relaxations induced by HA occurred in rings with endothelium were: 1) Partially inhibited by indomethacin (10-5 M) (PGI2 pathway inhibitor); 2) Strongly inhibited by NO pathways: L-NAME (10-4 M) and L-NMMA (10-4 M) (no specific NO synthase inhibitors); L-Nil (10-3 M) (specific iNOS inhibitor); ODQ (10-4 M) (specific guanylate cyclase inhibitor), and; 4) Inhibit by tetraethylammonium (10-3 M) (non-specific potassium channel inhibitor), glibenclamide (10-5 M) (specific KATP inhibitor), aminopyridine (10-3 M) (specific Kv inhibitor) and apamin (10-6 M) (specific SKCa inhibitor). IN CONCLUSION: 1) HA causes endothelium-dependent relaxation; 2) Indomethacin failed in blocking this relaxation, but the method limitation does not allow ruling out some prostanoid role; 3) The HA vessel relaxation is mediated via cGMP/NO, and; 4) The hyperpolarization occurs by the action of potassium SKCa, KATP and Kv channels without relying on BKCa channels.

Interleukins and inflammatory markers in in-stent restenosis after femoral percutaneous transluminal angioplasty.

BACKGROUND: Inflammatory activity may influence results of percutaneous transluminal angioplasty (PTA). The purpose of this study was to evaluate the relationship between (1) proinflammatory markers (interleukin [IL]-6, IL-8, tumor necrosis factor α (TNF-α), and highly sensitive C-reactive protein [CRP]); (2) type 1 T helper cell marker (IL-12); and (3) Type 2 T helper cell marker (transforming growth factor-ß [TGF-ß]) and in-stent restenosis, 6 months after femoral PTA with stent implantation. METHODS: We performed a single-center prospective study with 26 patients with peripheral artery disease requiring PTA and stenting. As control, we studied 26 patients who were submitted to diagnostic angiography. Serum samples were collected before stent implantation, 24 hr and 6 months after the procedure. To detect restenosis, a new angiography was obtained at 6 months. RESULTS: Restenosis was observed in 10 (38.5%) patients who underwent PTA and stenting. There was a trend to increased levels of IL-6, TNF-α, TGF-ß, and IL-12 24 hr after PTA and stenting compared with pretreatment. IL-8 levels showed a statistically significant reduction 24 hours after versus pretreatment (P < 0.05), 6 months vs. pretreatment, and 6 months vs. 24 hr (P < 0.01). There was no statistical difference between cytokine levels when comparing restenosis and no restenosis groups. CRP levels were already high at pretreatment. CONCLUSIONS: No inflammatory marker was independently identified as risk factor for in-stent restenosis, 6 months after femoral PTA with stent implantation. The question that remains is whether acute phase reactants will be clinically useful to predict the individual risk for in-stent restenosis.

In vitro effects of the organophosphorus pesticide malathion on the reactivity of rat aorta.

BACKGROUND AND PURPOSE: There is a remarkable paucity of studies analyzing the role of the endothelium-derived relaxing factors on the vascular effects of organophosphates. This study was carried out to evaluate the vascular effects of malathion and the role of nitric oxide (NO) and prostacyclin (PGI2). METHODS: Vascular reactivity measuring isometric forces in vitro ('organ chambers') and flow cytometry (cells loaded with DAF-FM DA) were used. RESULTS: In rat thoracic aorta segments contracted with phenylephrine (Phe) (10(-7) mol/l), malathion (10(-10) to 10(-5) mol/l) induced concentration-dependent relaxation in arteries with intact endothelium (n = 7; p < 0.05). Malathion-mediated relaxation was blocked by N-nitro-L-arginine methyl ester (L-NAME; 10(-4) mol/l), a nonspecific NO synthase inhibitor, and/or indomethacin (10(-5) mol/l), a nonspecific cyclooxygenase inhibitor (n = 10, p < 0.05). In thoracic aorta rings, with and without endothelium, Phe (10(-10) to 10(-5) mol/l) evoked concentration-dependent contraction, which was reduced in the presence of malathion. In rings with or without endothelium, incubated with malathion, L-NAME and indomethacin, the Phe-induced contraction was restored. The role of NO was confirmed using flow cytometry. Malathion evokes endothelium-dependent relaxation through the M1 muscarinic receptor, since this relaxation was clearly blocked by atropine (M1 and M2 blocker) and pirenzepine (M1 blocker), but was less blocked by gallamine (M2 blocker) or 4-DAMP (M3 blocker). CONCLUSIONS: These findings suggest that the organophosphate compound effects on vascular reactivity depend of NO and PGI2.

The lignan (-)-cubebin inhibits vascular contraction and induces relaxation via nitric oxide activation in isolated rat aorta.

Cubebin, the most abundant lignan in Piper cubeba, has been described as having several effects as trypanocidal, antimycobacterial, antispasmodic, antimicrobial, anti-inflammatory, and analgesic. This study investigated the vasorelaxant effect produced by (-)-cubebin in isolated rat aortic rings pre-contracted with phenylephrine (Phe), and the possible mechanism involved in this event was evaluated. Endothelium-dependent relaxation was evoked by acetylcholine and (-)-cubebin in intact aortic rings, while endothelium-independent vasorelaxation was elicited by sodium nitroprusside and (-)-cubebin in denuded rings. Cumulative concentration-response curves for Phe (10(-10) -10(-5) M) were determined for endothelium-intact and endothelium-denuded aortic rings in either the presence or absence of (-)-cubebin. Dose-response curves were also constructed for pre-incubation of vascular rings with Nω-nitro-L-arginine methyl ester (L-NAME) (a non-specific nitric oxide synthase inhibitor), indomethacin (an unspecific cyclooxygenase inhibitor), and 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ) (a guanylyl cyclase inhibitor). (-)-Cubebin was found to exert a vasorelaxant effect irrespective of the presence of endothelium, which was abolished by pretreatment with L-NAME and ODQ, but not with indomethacin. In addition, (-)-cubebin was able to reduce Phe contraction in the case of intact rings. These results suggest that (-)-cubebin promotes vasorelaxation via NO/cGMP pathway in rat aorta, without prostacyclin involvement.

Coronary Artery Bypass Grafting: A Comparative Exercise between Patients from the BYPASS Registry and Patients from a University Hospital.

INTRODUCTION: The coronary artery bypass grafting (CABG) data provided by the Brazilian Registry of Cardiovascular Surgeries in Adults (BYPASS) Registry is a Brazilian reality. OBJECTIVE: To carry out a comparative exercise between the BYPASS Registry published data and data from patients operated on in a randomly chosen period (2013-2015) at Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP-USP). METHODS: This is a retrospective study reviewing 173 electronic medical records of CABG patients from the HCFMRP-USP. These data were compared with the BYPASS Registry published data. Chi-square test was used to verify the changes within the prevalence of adequate/inadequate biochemical tests before and after surgery. The sample was divided into groups consistent with cardiopulmonary bypass (CPB) time (CPB ≤ 120 minutes and CPB > 120 minutes). For the complications, prevalence by the chi-square test was adopted. Significant P-values are < 0.05. RESULTS: The comparative operative data of the BYPASS Registry and the HCFMRP-USP patients were quite similar, except for the isolate use of only arterial grafts, which was more frequent on HCFMRP-USP patients (30.8% vs. 15.9%), and the use of radial artery, also more frequent on HCFMRP-USP patients (48.8% vs. 1.1%). CONCLUSION: The comparative study suggested that the BYPASS Registry should be a reference for CABG quality control.

Methylene Blue to Neonatal Septic Shock treatment in neonate pigs.

OBJECTIVE: The authors design an animal model of neonatal sepsis to analyze the treatment of neonatal septic shock with Methylene Blue (MB) in a swine model. METHODS: The study design included twenty male newborn pigs divided into four groups: 1) The control group; 2) The sepsis group (induced with lipopolysaccharide); 3) The MB group, and 4) The MB-treated sepsis group. Septic shock was defined as Blood Pressure (BP) dropping 20% below the baseline value. Continuous Blood Pressure (BP), Nitric Oxide (NO) levels, cyclic Guanosine Monophosphate (cGMP), malondialdehyde acid, base excess, lactate, arterial blood gases, hematocrit, and echocardiography were analyzed. RESULTS: The BP of the sepsis group treated with MB showed a slight improvement in the first hour after treatment; however, a significant difference was not observed compared to the untreated sepsis group. Besides hemodynamic stability, the current study did not show symptomatic pulmonary hypertension, suggesting that MB was safe in neonates and children. An improvement in Base Excel (BE) levels after MB administration in septic animals may indicate a possible improvement in microcirculation. CONCLUSION: The MB improved biomarkers related to septic shock prognosis, although an improvement in the blood levels could not be detected. MB might be a beneficial drug for hemodynamic instability in infants.

Atrial Septal Aneurysm and Atrial Septal Defect Association - an Uncommon But Well- Recognized Association.

Atrial septal aneurysm (ASA) is an uncommon but wellrecognized cardiac abnormality. This educational text reviews the case of a 54-year-old female presenting an ASA related to a small ostium secundum atrial septal defect. The considerable signs and symptoms, interestingly, have not been justified by the clinical and hemodynamic investigations. So, we opted for a better imaging investigation with cardiac catheterization and transesophageal echocardiography. The surgical process was earlier indicated and performed with aid of cardiopulmonary bypass.

Frailty Among Non-Elderly Patients Undergoing Cardiac Surgery. / Fragilidade entre Pacientes não Idosos Submetidos à Cirurgia Cardíaca.

BACKGROUND: Usually viewed as a characteristic of old age, frailty may also occur in non-elderly people, primarily in those suffering from chronic disease. Frailty may increase operative risk. OBJECTIVES: To determine the prevalence of frailty patients undergoing coronary artery bypass (CABG) and/or heart valve replacement or reconstruction and/or heart valve surgery, as well as the influence of frailty on postoperative outcomes. METHODS: Our study comprised 100 adults who underwent consecutive elective cardiac operations. Frailty was assessed using the Fried scale. Patients also performed a 6-minute walk test, and we measured maximal inspiratory and expiratory pressures. A p value <0.05 was considered significant. RESULTS: Of a cohort of 100 patients, based on the Fried frailty criteria, 17 patients (17%) were considered frail, 70 (70%) pre-frail and only 13 (13%) were non-frail. Among patients with valvular heart disease, 11 (18.6%) were considered frail and 43 (73%) pre-frail. Fifty three percent of the patients considered frail were less than 60 years old (median=48 years old). The differences in frailty phenotype between patients with valvular heart disease and coronary artery disease were not statistically significant (p=0.305). A comparison between non-frail, pre-frail, and frail patients showed no significant difference in the distribution of comorbidities and cardiac functional status, regardless of their cardiac disease. However, hospital mortality was significantly higher in frail patients (29.4%, p=0.026) than in pre-frail patients (8.6%) and non-frail patients (0%). CONCLUSIONS: Frailty is prevalent even among non-elderly patients undergoing CABG or valvular heart surgery and is associated with higher postoperative hospital mortality.

FUNDAMENTO: Geralmente vista como uma característica da velhice, a fragilidade também pode ocorrer em pessoas não idosas, principalmente naquelas que sofrem de doenças crônicas. A fragilidade pode aumentar o risco operatório. OBJETIVOS: Determinar a prevalência de fragilidade em pacientes submetidos à cirurgia de revascularização do miocárdio (CRM) e/ou troca ou reconstrução valvar e/ou cirurgia valvar, bem como a influência da fragilidade nos desfechos pós-operatórios. MÉTODOS: Nosso estudo incluiu 100 adultos que foram submetidos a operações cardíacas eletivas consecutivas. A fragilidade foi avaliada por meio da escala de Fried. Os pacientes também realizaram um teste de caminhada de 6 minutos, e medimos as pressões inspiratória e expiratória máximas. Um valor de p < 0,05 foi considerado significativo. RESULTADOS: De uma coorte de 100 pacientes, com base nos critérios de fragilidade de Fried, 17 pacientes (17%) foram considerados frágeis, 70 (70%) pré-frágeis e apenas 13 (13%) não frágeis. Entre os portadores de valvopatia, 11 (18,6%) foram considerados frágeis e 43 (73%) pré-frágeis. Cinquenta e três por cento dos pacientes considerados frágeis tinham menos de 60 anos (mediana=48 anos). As diferenças no fenótipo de fragilidade entre os pacientes com valvopatia e doença arterial coronariana não foram estatisticamente significativas (p=0,305). A comparação entre pacientes não frágeis, pré-frágeis e frágeis não mostrou diferença significativa na distribuição das comorbidades e do estado funcional cardíaco, independentemente da doença cardíaca. No entanto, a mortalidade hospitalar mostrou-se significativamente maior em pacientes frágeis (29,4%, p=0,026) que em pacientes pré-frágeis (8,6%) e não frágeis (0%). CONCLUSÕES: A fragilidade é prevalente mesmo entre pacientes não idosos submetidos a CRM ou cirurgia cardíaca valvar e está associada a maior mortalidade hospitalar pós-operatória.

Comparative study between fructose 1-6 bisphosphate and histidine-tryptophan-ketoglutarate in liver preservation in rats submitted to total cold ischemia.

Purpose To compare Fructose-1,6-Bisphosphate (FBP) to Histidine-Tryptophan-Ketoglutarate (HTK) in liver preservation at cold ischemia. Methods Male rats (Sprague-Dawley: 280-340g) divided into three groups (n=7): Control; Fructose-1,6-bisphosphate (FBP); Histidine-Tryptophan-Ketoglutarate (HTK). Animals underwent laparotomy-thoracotomy for perfusion of livers with saline. Livers were removed and deposited into solutions. Mitochondria were isolated to determine State 3 (S3), State 4 (S4), Respiratory Control Ratio (RCR) and Swelling (S). Liver enzymes (AST, ALT, LDH) were determined in solution. At tissue, Malondialdehyde (MDA) and Nitrate (NOx) were determined. All parameters were analyzed at 0.6 and 24 hours of hypothermic preservation. Statistics analysis were made by Mann-Whitney test (p<0.05). Results Regarding ALT, there was a difference between FBP-6h/HTK-6h, lower in HTK. Regarding AST, there was a significant difference between FBP-24h/HTK-24h, lower in FBP. Regarding NOx, there was a difference between 0h and 6h, as well as 0h and 24h for both solutions. Regarding S3, there was a significant difference in 24h compared to Control-0h for both solutions, and a significant difference between FBP-6h/FBP-24h. Regarding S4, there was a difference between Control-0h/HTK-24h and FBP-24h/HTK-24h, higher in HTK. There was a difference between Control-0h/FBP-24h for Swelling, higher in FBP. Conclusion Fructose-1,6-Bisphosphate showed better performance at nitrate and aspartate aminotransferase compared to histidine-tryptophan-ketoglutarate.

Effect of Diterpene Manool on the Arterial Blood Pressure and Vascular Reactivity in Normotensive and Hypertensive Rats. / Efeito do Diterpeno Manool sobre a Pressão Arterial e Reatividade Vascular em Ratos Normotensos e Hipertensos.

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.

FUNDAMENTO: Diversos estudos têm mostrado que as classes de diterpenos exercem efeito significativo no sistema cardiovascular. Os diterpenos, em particular, estão entre os principais compostos associados às propriedades cardiovasculares, como a propriedade vasorrelaxante, inotrópica, diurética e a atividade hipotensora. Embora o mecanismo de vasorrelaxamento do manool seja visível, seu efeito sobre a pressão arterial (PA) ainda é desconhecido. OBJETIVO: Avaliar o efeito hipotensor in vivo do manool e verificar o efeito de vasorrelaxamento ex vivo em anéis aórticos de ratos. MÉTODOS: Os animais foram divididos aleatoriamente em dois grupos: normotensos e hipertensos. O grupo normotenso foi submetido à cirurgia sham e adotou-se o modelo 2R1C para o grupo hipertenso. Realizou-se monitoramento invasivo da PA para testes com manool em diferentes doses (10, 20 e 40 mg/kg). Foram obtidas curvas de concentração-resposta para o manool nos anéis aórticos, com endotélio pré-contraído com fenilefrina (Phe) após incubação com Nω-nitro-L-arginina metil éster (L-NAME) ou oxadiazolo[4,3-a]quinoxalina-1-ona (ODQ). Os níveis plasmáticos de óxido nítrico (NOx) foram medidos por ensaio de quimioluminescência. RESULTADOS: Após a administração de manool, a PA se reduziu nos grupos normotenso e hipertenso, e esse efeito foi inibido pelo L-NAME em animais hipertensos apenas na dose de 10 mg/kg. O manool ex vivo promoveu vasorrelaxamento, inibido pela incubação de L-NAME e ODQ ou remoção do endotélio. Os níveis plasmáticos de NOx aumentaram no grupo hipertenso após a administração de manool. O manool induz o relaxamento vascular dependente do endotélio na aorta de ratos, mediado pela via de sinalização NO/cGMP e redução da PA, e também pelo aumento plasmático de NOx. Esses efeitos combinados podem estar envolvidos na modulação da resistência periférica, contribuindo para o efeito anti-hipertensivo do diterpeno. CONCLUSÃO: Esses efeitos em conjunto podem estar envolvidos na modulação da resistência periférica, contribuindo para o efeito anti-hipertensivo do diterpeno.

Evaluation of Indigo carmine on hepatic ischemia and reperfusion injury.

PURPOSE: To evaluate the effects of treatment with Indigo Carmine (IC) on rat livers subjected to ischemia-reperfusion injury. METHODS: The animals were subdivided into 4 groups: 1.SHAM group(SH) - saline; 2.SHAM group with IC-2mg/Kg(SHIC); 3.IR group - rats submitted to ischemia and reperfusion with saline(IR); 4.IR group with IC-2mg/Kg(IRIC). The IR protocol consists of liver exposure and administration of drug or saline intravenously, followed by 60 minutes of ischemia and 15 of reperfusion. Liver samples were collected for biochemical analysis. RESULTS: State 3 of mitochondrial respiration showed a significant worsening of the IRIC group in relation to all others. State 4 showed a difference between IRIC and SHIC. The Respiratory Control Ratio showed statistical decrease in IR and IRIC versus Sham. The osmotic swelling showed significant difference between SHxIR; SHICxIRIC and SHxIRIC. There was a significant increase in ALT in the IRIC group in relation to all the others. Concerning the nitrate dosage, there was a decrease in the group treated with IC(IRxIRIC). There was no difference regarding the dosage of Malondialdehyde. CONCLUSION: IC was not able to protect mitochondria from IR injury and proved to be a potentiating agent, acting in synergy with the IR injury promoting damage to the hepatocyte membranes.

Effect of the effluent released from the canine internal mammary artery after intraluminal and extraluminal perfusion of acetylcholine and adenosine diphosphate.

Segments of the canine internal mammary artery (35 mm in length) were suspended in vitro in an organ chamber containing physiological salt solution (95% O2/5% CO2, pH = 7.4, 37 degrees C). Segments were individually cannulated and perfused at 5 ml/minute using a roller pump. Vasorelaxant activity of the effluent from the perfused internal mammary arteries was bioassayed by measuring the decrease in tension induced by the effluent of the coronary artery endothelium-free ring which had been contracted with prostaglandin F2alpha (2 x 10(-6) M). Intraluminal perfusion of adenosine diphosphate (10(-5) M) induced significant increase in relaxant activity in the effluent from the perfused blood vessel. However, when adenosine diphosphate (10(-5) M) was added extraluminally to the internal mammary artery, no change in relaxant activity in the effluent was noted. In contrast, acetylcholine produced significant increase in the relaxant activity on the effluent of the perfused internal mammary artery with both intraluminal and extraluminal perfusion. The intraluminal and extraluminal release of endothelium-derived relaxing factor (EDRF) by acetylcholine (10(-5) M) can be inhibited by site-specific administration of atropine (10(-5) M). These experiments indicate that certain agonists can induce the release of EDRF only by binding to intravascular receptors while other agonists can induce endothelium-dependent vasodilatation by acting on neural side receptors.

Asymmetric dimethylarginine endogenous inhibition of nitric oxide synthase causes differential vasculature effects.

BACKGROUND: Asymmetric dimethylarginine (ADMA), produced during protein metabolism, is an endogenous inhibitor of nitric oxide synthase, but little is known about its direct vasoactive properties in different arterial beds. MATERIAL/METHODS: Segments of canine coronary, renal, and femoral arteries were pretreated with increasing concentrations of ADMA, and endothelial function was evaluated in organ chambers. RESULTS: In precontracted canine coronary arteries, the highest concentrations of ADMA inhibited endothelium-dependent relaxation mediated by acetylcholine (n=7), but no concentration of ADMA inhibited receptor-independent relaxation mediated by calcium ionophore (n=7) (P<.001). The effect of ADMA on acetylcholine-mediated relaxation was shown to be competitive inhibition of the nitric oxide synthase pathway, because the addition of L-arginine (10(-3) M), but not D-arginine (10(-3) M), reversed the effect produced by 10-5 M ADMA. Further, ADMA did not alter endothelium-independent relaxation mediated by sodium nitroprusside (10(-9) to 10(-6) M; n=7). Femoral arteries (n=7) and renal arteries (n=7) were more sensitive to ADMA than were coronary arteries, and they demonstrated significant ADMA inhibition to receptor dependent relaxation induced by acetylcholine (P=.03 and P=.01, respectively) and to receptor-independent relaxation induced by calcium ionophore (P=.02 and P=.01, respectively). CONCLUSIONS: Endothelium-dependent relaxation mediated by ADMA is more marked in femoral and renal arteries than in coronary arteries. The response in coronary arteries may be overall protective. Considering these different effects in various artery types, the role of ADMA as a confiable and specific cardiovascular risk factor is questioned.

In vitro evidence that endothelium-dependent vasodilatation induced by clozapine is mediated by an ATP-sensitive potassium channel.

BACKGROUND: There is a definite association between antipsychotic drugs and arterial hypertension. However, endothelium functions are scarcely considered. This investigation was carried out to study the mechanisms involved in clozapine endothelium-dependent vascular reactivity. METHODS: The experimental animals were male Wistar rats with a mean age of 70-90 days (250-300 g). The endothelium-dependent vascular reactivity was studied by measuring the isometric force and then constructing clozapine concentration-response curves. The force registrations were obtained in the aorta rings with and without the endothelium precontracted with phenylephrine (PE10-6M) treatment; this followed incubation for 30 min in "organ chambers" with different inhibitors: l- NAME (nitric oxide/cGMP); indomethacin (PGI2/cAMP); tetraethylammonium (TEA), and specific hyperpolarization blockers (paxillin, apamin, glibenclamide). The data were presented as the mean ± standard error of the mean (SEM) and were compared by one-way ANOVA or two-way ANOVA followed by the Bonferroni post-test. RESULTS: The primary outcomes were: 1) Clozapine-induced endothelium-dependent relaxation was not inhibited by indomethacin, l-NAME, ODQ, and methylene blue (MB); 2) The combination of l-NAME + indomethacin partially prevented the relaxation; 3) Clozapine did not induce relaxation in vessels contracted with KCl; 4) TEA did not block the clozapine-induced relaxation in vessels precontracted with PE (10-6 M); 5) The potassium channel blockers paxillin and apamin did not prevent relaxation but glibenclamide did. CONCLUSION: Concerning the mechanisms involved in clozapine endothelium-dependent vascular reactivity, the present study suggests that there is synergistic participation that probably occurs through a crosstalk mechanism of the cAMP, cGMPpathways and hyperpolarization.

Right Atrium Tumor Extension Through the Inferior Vena Cava. Considerations About Nine Cases Operated Under Cardiopulmonary Bypass.

INTRODUCTION: Adrenocortical and renal cell carcinomas rarely invade the right atrium (RA). These neoplasms need surgical treatment, are very aggressive and have poor prognostic and surgical outcomes. CASE SERIES: We present a retrospective cohort of nine cases of RA invasion through the inferior vena cava (four adrenocortical carcinomas and five renal cell carcinomas). Over 13 years (2002-2014), nine patients were operated in collaboration with the team of urologists. Surgery was possible in all patients with different degrees of technical difficulty. All patients were operated considering the imaging examinations with the aid of CPB. In all reported cases (renal or suprarenal), the decision to use CPB with deep hypothermic circulatory arrest (DHCA) on surgical strategy was decided by the team of urological and cardiac surgeons. CONCLUSION: Data retrospectively collected from patients of public hospitals reaffirm: 1) Low incidence with small published series; 2) The selected cases did not represent the whole historical casuistry of the hospital, since they were selected after the adoption of electronic documentation; 3) Demographic data and references reported in the literature were presented as tables to avoid wordiness; 4) The series highlights the propensity to invade the venous system; 5) Possible surgical treatment with the aid of CPB in collaboration with the urology team; 6) CPB with DHCA is a safe and reliable option; 7) Poor prognosis with disappointing late results, even considering the adverse effects of CPB on cancer prognosis are expected but not confirmed.

Use of Methylene Blue to Treat Hypovolemic Shock Followed by Ischemia-Reperfusion Injury in the Postoperative Orthotopic Liver Transplant Patient: A Case Report.

A 57-year-old female patient received elective liver transplant due to nonalcoholic steatohepatitis complicated by hepatocellular carcinoma. Her preoperative Model for End-Stage Liver Disease score was 11. The total transplant ischemic time was 10 hours and 35 minutes, and the warm ischemic time was 35 minutes. Even with aggressive fluid overload and use of high concentrations of vasoactive amines, the patient developed possible primary graft dysfunction with poor response to fluids and vasopressor support, suggesting vasoplegic syndrome. On the basis of the hypothesis of vasoplegic syndrome, the patient received methylene blue intravenously (100 mg bolus for 12 h/1.5 mg/kg). The catastrophic situation was controlled. The patient's urine output markedly improved, she was subsequently weaned from vasoactive support, and mechanical ventilation was discontinued 2 days later. The patient was discharged on the 20th postoperative day.

The cardiopulmonary bypass and cancer dissemination puzzle1.

Early cancer diagnosis, new therapies that increased survival of patients, besides the increasingly elderly population are some factors would be associated with possible cancer dissemination in patients under cardiopulmonary bypass (CPB) cardiac surgery. Also, the benefits, and risks, regarding long-term survival, have not yet been established. Therefore, cardiac surgery morbimortality may be superior in patients with cancer disease. Also, immunologic and inflammatory changes secondary to CPB can also increase tumor recurrence. After a brief introduction and CPB immunologic the two main topic subjects included: 1) Combined heart surgery and lung resection and; 2) Possible influence of neoplasia type. After observing the relative literature scarcity, we keep the opinion that "CPB has a modest association with cancer progression" and that "CPB and cancer dissemination should be a logical but unlikely association."