Biomedical subjects
Paulo Roberto B Evora
Publications and source records attributed to Paulo Roberto B Evora.
Methylene blue as drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass.
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Effect of arginine vasopressin on the canine epicardial coronary artery: experiments on V1-receptor-mediated production of nitric oxide.
OBJECTIVE: To determine whether arginine vasopressin releases endothelium-derived nitric oxide (EDNO) from the epicardial coronary artery. METHODS: We studied segments of canine left circumflex coronary arteries suspended in organ chambers to measure isometric force. The coronary artery segments were contracted with prostaglandin F2alpha (2 x 10-6M) and exposed to a unique, strong arginine vasopressin concentration (10-6M) or titrated concentrations (10-9 a 10-5 M). RESULTS: The unique dose of arginine vasopressin concentration (10-6M) induced transient, but significant (p<0.05), relaxation in arterial segments with endothelium, and an increase, not significant, in tension in arteries without endothelium. Endothelium-dependent relaxation to arginine vasopressin was inhibited by Ng-monomethyl-L-arginine (L-NMMA, 10-5M) or N G-nitro-L-arginine (L-NOARG) (10-4M), 2 inhibitors of nitric oxide synthesis from L-arginine. Exogenous L-arginine (10-4M), but not D-arginine (10-4M), reversed the inhibitory effect of L-NMMA on vasopressin-mediated vasorelaxation. Endothelium dependent relaxation to vasopressin was also reversibly inhibited by the vasopressin V1-receptor blocker d(CH2)5Try(Me) arginine vasopressin (10-6M) (n=6, P<0.05). CONCLUSION: Vasopressin acts through V1 endothelial receptors to stimulate nitric oxide release from L-arginine.
Catastrophic cardiovascular adverse reactions to protamine are nitric oxide/cyclic guanosine monophosphate dependent and endothelium mediated: should methylene blue be the treatment of choice?
Clinical and experimental observations prove that heparin-neutralizing doses of protamine increase pulmonary artery pressures and decrease systemic BP. Protamine also increases myocardial oxygen consumption, cardiac output, and heart rate, and decreases systemic vascular resistance. These cardiovascular effects have clinical consequences that have justified studies in this area. Protamine adverse reactions usually have three different categories: systemic hypotension, anaphylactoid reactions, and catastrophic pulmonary vasoconstriction. The precise mechanism that explains protamine-mediated systemic hypotension is unknown. Four experimental protocols performed at Mayo Clinic, Rochester, MN, studied the intrinsic mechanism of protamine vasodilation. The first study reported in vitro systemic and coronary vasodilation after protamine infusion. The second in vitro study suggested that the pulmonary circulation is extensively involved in the protamine-mediated effects on endothelial function. The third study, carried out in anesthetized dogs, reported the methylene blue and nitric oxide synthase blockers neutralization of the protamine vasodilatatory effects. The fourth study suggested that protamine also causes endothelium-dependent vasodilation in heart microvessels and conductance arteries by different mechanisms including hyperpolarization. Reviewing these experimental results and our clinical experience, we suggest methylene blue as a novel approach to prevent and treat hemodynamic complications caused by the use of protamine after cardiopulmonary bypass. In the absence of prospective clinical trials, a growing body of cumulative clinical evidence suggests that methylene blue may be strongly considered as a therapeutic approach in the treatment of distributive shock.
Inferior canine hindlimb ischemia and reperfusion impairs femoral artery endothelium-dependent wall relaxation.
This experimental investigation was carried out to study the endothelium-dependent ischemia-reperfusion injury upon the release of nitric oxide (NO) in the canine femoral artery. The tested experimental model was the inferior canine hindlimb ischemia induced by infrarenal abdominal aortic clamping followed by reperfusion. The research protocol was standardized in four experimental groups (n=6): (1) Control group; (2) Ischemia (120 minutes) group; (3) Ischemia (90 minutes) and reperfusion (60 minutes) group; and (4) Ischemia (120 minutes) and reperfusion (90 minutes) group. The femoral artery vascular reactivity was studied in vitro with the aid of an eight "organ chambers'' setup, where segments from 4 to 5 mm, with and without endothelium, were suspended and connected to force transducers. The fundamental data of this study were as follows: (1) Ischemia caused by 120 minutes of infrarenal aortic clamping did not cause femoral artery endothelium dysfunction. (2) Ischemia caused by 90 minutes of clamping followed by 60 minutes of reperfusion also did not cause endothelium dysfunction, with an observed tendency to signal transduction impairment (studied by the sodium fluoride dose response curves). (3) Ischemia caused by 120 minutes of clamping followed by 90 minutes of reperfusion caused endothelium dysfunction, observed by the femoral artery impaired capacity of the endothelium-dependent NO release evoked by acetylcholine, adenosine diphosphate, and sodium fluoride. The present pharmacologic in vitro observations are concordant with the evidence that the NO-release impairment, caused by inferior canine hindlimb ischemia followed by reperfusion, is a consequence of endothelium cell membrane receptors, and G-proteins signal transduction dysfunction.
The cytoprotective effect of a nitric oxide donor drug on gastric mucous membrane of rats treated with ketoprofen, a non-steroidal anti-inflammatory drug.
BACKGROUND: Non-steroidal anti-inflammatory drugs are considered today a very important group of medication, with a wide variety of therapeutic use, in different areas of modern medicine. Despite their beneficial effects on the patient, these drugs show a high incidence of side effects, mainly in the gastrointestinal tract. The physiopathological mechanisms of non-steroidal anti-inflammatory drugs induced lesions and the gastric mucosa defense mechanism became an important source for medical research, especially those which try to evaluate the role of nitric oxide as a cytoprotective agent. AIM: To define a possible cytoprotective effect of a nitric oxide donor, isosorbide dinitrate, on the gastric mucous of rats submitted to non-steroidal anti-inflammatory drugs ketoprofen treatment. METHODS: Adult male Wistar rats, previously submitted to starvation for 24 hours and divided in three groups: group I (standard): animals that received isotonic saline solution intragastric by gavage and intravenous. Group II (control-ketoprofen): animals that received isotonic saline solution intragastric by gavage and ketoprofen intravenous. Group III (nitrate/ketoprofen): animals that received 2mM solution of isosorbide dinitrate intragastric by gavage and ketoprofen intravenous. Later on, these animals were sacrificed and had their stomach removed and submitted to macroscopical, microscopical and biochemical studies. The evaluated parameters were: a) gastric lesion index; b) gastric mucous layer thickness; c) gastric tissue nitrate/nitrite (NOx) concentration and d) gastric tissue malondialdehyde concentration. RESULTS: a) Gastric lesion index evaluation showed a smaller statistically significant incidence on the animals of group III; b) group III showed a thicker mucous layer, which also was statistically significant, when compared to group II; c) the variation on tissue nitrate/nitrite concentration was similar in all three groups, without statistical significance when compared to each other. CONCLUSION: Isosorbide dinitrate has a cytoprotective activity on the gastric mucosa of rats submitted to ketoprofen action.