Paulo Roberto Barbosa Evora

Hypomagnesemia Inhibits Nitric Oxide Release From Coronary Endothelium: Protective Role of Magnesium Infusion After Cardiac Operations

BACKGROUND Postoperative hypomagnesemia is common in patients who have undergone cardiac operations and is associated with clinically significant morbidity resulting from atrial and ventricular dysrhythmias. Magnesium supplementation may increase the cardiac index in the early postoperative period. METHODS The action of the magnesium cation on coronary vascular reactivity was studied. Segments of canine epicardial coronary artery were suspended in organ chambers to measure isometric force (95% O2/5% CO2, 37 degrees C). RESULTS In coronary segments constricted with prostaglandin F2alpha (2 x 10[-6] mol/L), acetylcholine and adenosine diphosphate (10[-9] to 10[-4] mol/L) induced vasodilation in arteries with endothelium (n=10, each group; p < 0.05). Acetylcholine-mediated vasodilation was blocked by NG-monomethyl-L-arginine (10[-4] mol/L) and NG-nitro-L-arginine (10[-4] mol/L), two inhibitors of nitric oxide synthesis from L-arginine (n=10, p < 0.05). The removal of magnesium from the organ chamber solution impaired vasodilation in response to acetylcholine and adenosine diphosphate. However, normal endothelium-dependent vasodilation could be restored by return of magnesium to the bathing solution. Vascular relaxation in response to bradykinin (10[-9] to 10[-6] mol/L), which was found to induce endothelium-dependent vasodilation independent of nitric oxide production, was unaffected by magnesium removal (n=10). CONCLUSIONS Hypomagnesemia selectively impaired the release of nitric oxide from the coronary endothelium. Because nitric oxide is a potent endogenous nitro-vasodilator and inhibitor of platelet aggregation and adhesion, hypomagnesemia could promote vasoconstriction and coronary thrombosis in the early postoperative period.

Bioassay of EDRF From Internal Mammary Arteries: Implications for Early and Late Bypass Graft Patency

To study the basal, luminal release of endothelium-derived relaxing factor, 35-mm segments of canine internal mammary artery (IMA) were cannulated and perfused at 5 mL/min in vitro with physiological salt solution. Vasoactive properties of the effluent were bioassayed on coronary artery smooth muscle. Effluent from IMAs produced significant vasodilation of the bioassay ring compared with effluent from a prosthetic conduit (n = 24; p < 0.05). The vasodilation by the effluent could be eliminated by mechanically removing the intima of the IMA, or by treating the IMA segments with NG-monomethyl-L-arginine or NG-nitro-L-arginine, two competitive inhibitors of nitric oxide synthesis from L-arginine; vasodilation was not influenced by treatment with indomethacin. In 83% of the superfusion experiments, effluent from the left IMA induced greater relaxation of the bioassay ring than did effluent from the right IMA. In addition, the average vasodilation induced by left IMA effluent was 28% +/- 2.3% versus 17.4% +/- 3.1% for the right (n = 24; p < 0.05). However, in organ chamber experiments, right and left IMAs exhibited comparable endothelium-dependent vasodilation to acetylcholine (n = 6). Because endothelium-derived relaxing factor induces vasodilation and also inhibits platelet adhesion, platelet aggregation, and atherogenesis, luminal release of endothelium-derived relaxing factor by the IMA could contribute to superior results when the artery is used in bypass grafting.

Rapid Improvement of Acute Schizophrenia Symptoms After Intravenous Sodium Nitroprusside: A Randomized, Double-blind, Placebo-Controlled Trial

IMPORTANCE The treatment of schizophrenia remains a challenge, and the currently available antipsychotic drugs are slow acting and produce a number of adverse effects. OBJECTIVE To examine the effectiveness and safety of a single intravenous administration of sodium nitroprusside (0.5 μg/kg/min for 4 hours) on the positive, negative, anxiety, and depressive symptoms in patients with schizophrenia. DESIGN Single-center, randomized, double-blind, placebo-controlled trial performed from March 9, 2007, to March 12, 2009. SETTING University teaching hospital in São Paulo, Brazil. PARTICIPANTS Twenty inpatients aged 19 to 40 years with a diagnosis of schizophrenia who were in the first 5 years of the disease who are taking antipsychotics. INTERVENTION Sodium nitroprusside administration. MAIN OUTCOME MEASURES The 18-item Brief Psychiatric Rating Scale and the negative subscale of the Positive and Negative Syndrome Scale. RESULTS After the infusion of sodium nitroprusside, a rapid (within 4 hours) improvement of symptoms was observed. The placebo and experimental groups had significant differences in the 18-item Brief Psychiatric Rating Scale total score and subscale scores, which persisted for 4 weeks after infusion. CONCLUSIONS The results clearly show a therapeutic effect of sodium nitroprusside. If this drug is approved for routine clinical use in patients with schizophrenia, this discovery will be an important advance in the pharmacologic treatment of this devastating disorder. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01548612.

The chronic gastrointestinal manifestations of Chagas disease

Chagas disease is an infectious disease caused by the protozoan Trypanosoma cruzi. The disease mainly affects the nervous system, digestive system and heart. The objective of this review is to revise the literature and summarize the main chronic gastrointestinal manifestations of Chagas disease. The chronic gastrointestinal manifestations of Chagas disease are mainly a result of enteric nervous system impairment caused by T. cruzi infection. The anatomical locations most commonly described to be affected by Chagas disease are salivary glands, esophagus, lower esophageal sphincter, stomach, small intestine, colon, gallbladder and biliary tree. Chagas disease has also been studied in association with Helicobacter pylori infection, interstitial cells of Cajal and the incidence of gastrointestinal cancer.

Protamine releases endothelium-derived relaxing factor from systemic arteries. A possible mechanism of hypotension during heparin neutralization.

BackgroundWhen used to reverse the anticoagulant effect of heparin, protamine sulfate often causes vasodilation that can lead to systemic hypotension. Protamine is rich in the basic amino acid arginine, which is the precursor of endothelial cell synthesis of nitric oxide, and nitric oxide is the active component of endothelium-derived relaxing factor (EDRF). Methods and ResultsTo determine whether the hypotensive effect of protamine could be due to stimulated release of EDRF, we studied rings (4–5 mm) of canine coronary, femoral, and renal artery suspended in organ chambers containing physiological salt solution (37°C and 95% O2–5% CO2). Arterial rings with and without endothelium were contracted with prostaglandin F2α (2×10−6 M) and exposed to increasing concentrations of protamine (final organ bath concentration, 40–400 μg/ml). In arterial segments without endothelium, protamine caused only a modest decrease in tension. However, protamine induced concentration-dependent relaxation in all arterial segments with endothelium, which was significantly greater than in segments without endothelium (p<0.05). The endothelium-dependent relaxation induced by protamine was inhibited by NG monomethyl-L-arginine (L-NMMA) (10−5 M), but L-NMMA had no effect on rings without endothelium. The action of L-NMMA could be reversed by L-arginine (10−4 M) but not D-arginine (10−4 M). ConclusionsThis study demonstrates that protamine stimulates the release of EDRF from arterial endothelium, and that endothelium-dependent vasodilation may be an important cause of systemic hypotension during protamine infusion.

Pre-and postoperative care in cardiothoracic surgery: a physiotherapeutic approach

It is well known that anesthesia and certain surgeries predispose patients to changes in respiratory function, pulmonary volumes, and gas exchange. Cardiac surgery, which is considered a major surgery, may trigger respiratory complications in the postoperative period. These complications have various causes, such as heart and lung functions in the pre-operative, the use of cardiopulmonary bypass (CPB), and the level of sedation. In these extensive thoracic procedures, respiratory dysfunction may be significant, persisting in the postoperative period. Physiotherapy is offered to patients in the ICU as part of a multidisciplinary treatment plan. It is a time-consuming treatment, and is possible at various times during the patients stay in the ICU. However, it is particularly valuable in postoperative recovery in order to avoid respiratory and motor complications. Thus, a literature review was performed, aiming to arrange current and relevant information on available resources for respiratory monitoring, as well as its importance in evaluating and treating lung function impairment, as this complication is a frequent cause of death in surgical patients.

Role of nitric oxide production in anaphylaxis and its relevance for the treatment of anaphylactic hypotension with methylene blue.

OBJECTIVE To review the role of nitric oxide production in anaphylaxis. DATA SOURCES We performed MEDLINE searches of the literature. In addition, some references known to the authors but not listed in MEDLINE, such as abstracts and a CD-ROM, were included. Finally, additional clinical details of the cases were provided by one of the authors. STUDY SELECTION Primary reports were preferentially selected for inclusion. However, some secondary publications are also cited. RESULTS Histamine along with other mediators, such as leukotrienes, tumor necrosis factor, and platelet-activating factor, induce the production of nitric oxide. Nitric oxide can inhibit the release and effects of catecholamines. Sympathetic amines may inhibit production of nitric oxide. Studies in animals have demonstrated the generation of nitric oxide during anaphylaxis. Inhibition of nitric oxide synthase improves survival in an animal model of anaphylaxis. Nitric oxide causes vasodilation indirectly by increasing the activation of guanylyl cyclase, which then causes smooth muscle relaxation by increasing the concentration of smooth muscle cyclic guanosine monophosphate. Methylene blue is an inhibitor of guanylyl cyclase, which increases systemic vascular resistance and reverses shock in animal studies. The previously reported successful treatment with methylene blue of 11 patients with anaphylactic hypotension is reviewed. CONCLUSION Nitric oxide plays a significant role in the pathophysiology of anaphylaxis. Treatment with methylene blue should be considered in patients with anaphylactic hypotension that has not responded to other interventions.

Impaired endothelium-dependent relaxation after coronary reperfusion injury : evidence for G-protein dysfunction

This study was done to determine whether abnormal receptor-dependent release of endothelium-derived relaxing factor (EDRF) might be caused by G-protein dysfunction. Dogs were exposed to global myocardial ischemia (45 minutes, induced by aortic cross-clamping) followed by reperfusion (60 minutes) while on cardiopulmonary bypass, and coronary arteries were then studied in vitro in organ chamber experiments. After reperfusion, endothelium-dependent relaxation to the receptor-dependent agonists adenosine diphosphate and acetyl-choline was significantly impaired as well as to sodium fluoride, which acts on a pertussis toxin-sensitive G-protein. In contrast, endothelium-dependent relaxations to the receptor-independent agonists A23187 and phospholipase C were normal. Furthermore, endothelium-dependent relaxation to poly-L-arginine (molecular weight, 139,200), which appears to induce endothelium-dependent relaxation of the canine coronary artery by a nonnitric oxide pathway, was unaffected by ischemia and reperfusion. These experiments suggest that global myocardial ischemia and reperfusion selectively impair receptor-mediated release of EDRF (nitric oxide) but that the ability of the endothelial cell to produce EDRF or generate endothelium-dependent relaxation to nonnitric oxide-dependent agonists remains intact. We hypothesize that coronary reperfusion injury leads to G-protein dysfunction in the endothelium.

Diabetes and Vascular Disease: Basic Concepts of Nitric Oxide Physiology, Endothelial Dysfunction, Oxidative Stress and Therapeutic Possibilities

The vascular manifestations associated with diabetes mellitus (DM) result from the dysfunction of several vascular physiology components mainly involving the endothelium, vascular smooth muscle and platelets. It is also known that hyperglycemia-induced oxidative stress plays a role in the development of this dysfunction. This review considers the basic physiology of the endothelium, especially related to the synthesis and function of nitric oxide. We also discuss the pathophysiology of vascular disease associated with DM. This includes the role of hyperglycemia in the induction of oxidative stress and the role of advanced glycation end-products. We also consider therapeutic strategies.

Protamine induces endothelium-dependent vasodilatation of the pulmonary artery

BACKGROUND Protamine sulfate, which is used for heparin neutralization, has been reported to induce catastrophic pulmonary vasoconstriction after infusion. However, in the systemic circulation, protamine infusion induces hypotension due to peripheral vasodilation. METHODS To determine whether protamine also could induce vasodilation in the pulmonary circulation, third-order canine pulmonary artery segments were studied in vitro in organ chambers. RESULTS In pulmonary artery segments that were caused to contract with phenylephrine (10(-5) mol/L), protamine sulfate (40 to 400 micrograms/mL, final organ bath concentration) produced concentration-dependent relaxation in canine pulmonary artery segments with endothelium (to 74% +/- 7% of the initial contraction to phenylephrine) that was significantly greater (p < 0.05) than in segments without endothelium (30% +/- 6% of the initial phenylephrine contraction). Pretreatment of arterial segments with NG-monomethyl-L-arginine (10(-5) mol/L), the competitive inhibitor of nitric oxide synthesis from L-arginine, did not change tension of arterial segments, but NG-monomethyl-L-arginine attenuated the relaxation to protamine. The inhibitory effect of NG-monomethyl-L-arginine could be reversed by the addition of L-arginine (10(-4) mol/L) but not D-arginine (10(-4) mol/L). Endothelium-dependent vasodilation to protamine (40 to 400 micrograms/mL) also could be inhibited by heparin (8 U/mL, final organ bath concentration). However, the inhibitory effect of heparin could be overcome by adding higher concentrations of protamine. CONCLUSIONS Protamine-mediated pulmonary vasodilatation could be an important mechanism to protect against the constrictive effects of autocoids generated during heparin neutralization. Such a mechanism might be dysfunctional in certain persons and put them at risk for pulmonary vasoconstriction after protamine infusion.