Inhaled but not intravenous milrinone prevents pulmonary endothelial dysfunction after cardiopulmonary bypass.

OBJECTIVE: Cardiopulmonary bypass triggers a systemic inflammatory response that alters pulmonary endothelial function, which can contribute to pulmonary hypertension. Milrinone is a type III phosphodiesterase inhibitor. The objective of this study was to compare the effects of inhaled and intravenous milrinone on the pulmonary endothelium-dependent relaxations and hemodynamic and oxygenation parameters after cardiopulmonary bypass in a porcine model. METHODS: Five groups of Landrace swine were compared: (1) control group, no cardiopulmonary bypass; (2) bypass group, 90 minutes of normothermic bypass and 60 minutes of reperfusion; (3) inhaled milrinone group, bypass preceded by a 1.8-mg bolus of inhaled milrinone followed by a continuous milrinone nebulization; (4) intravenous milrinone group, bypass preceded by 2 mg of intravenous milrinone; and (5) inhaled NaCl group, bypass preceded by inhaled saline solution. After sacrifice, pulmonary arterial endothelium-dependent relaxations to acetylcholine and bradykinin were studied in organ chambers. RESULTS: Inhaled milrinone caused less hypotension ( P < .05), a lesser decrease in peripheral vascular resistances ( P < .01), and a lower heart rate ( P < .05) than intravenous milrinone. Inhaled milrinone prevented the alterations in relaxations of pulmonary arteries to acetylcholine caused by cardiopulmonary bypass, and relaxations to bradykinin were improved in the inhaled milrinone group ( P < .05) compared with the cardiopulmonary bypass and control groups. CONCLUSIONS: Inhaled milrinone prevents the occurrence of the pulmonary endothelial dysfunction seen after cardiopulmonary bypass. The hemodynamic and oxygenation profiles obtained with inhaled milrinone are safer than with intravenous milrinone. These strategies might be useful in preventing pulmonary hypertension after cardiac surgery.

Cyclosporine-induced coronary endothelial dysfunction: is tetrahydrobiopterin the solution?

BACKGROUND: Coronary endothelial dysfunction after heart transplantation is predictive of cardiac allograft vasculopathy. Immunosuppressive drugs, particularly cyclosporine may contribute to this dysfunction by a direct effect. Tetrahydrobiopterin (BH(4)) is a potent antioxidant and an essential cofactor of nitric oxide biosynthesis. The purpose of this study was to investigate whether BH(4) could reverse the endothelial dysfunction induced by cyclosporine. METHODS: A previously described in vitro model of drug incubation in Krebs-bicarbonate solution (4 degrees C, 48 hours) of porcine epicardial coronary arteries was used. Coronary endothelial function studies were performed in organ chamber experiments after incubation with cyclosporine (10(-4) mol/L) in the presence or absence of 6-methyltetrahydropterin (MH(4) [0.1 mol/L], a BH(4) analog) to assess its effect on the cyclosporine-induced endothelial dysfunction. RESULTS: The average doses of PGF2(alpha) required to attain 50% of the maximal contraction to KCl was significantly lower (P < .001) in the cyclosporine group (8.6 +/- 1.94 x 10(-6) mol/L) compared to the control group (24.8 +/- 5.2 x 10(-6) mol/L). Exposure to cyclosporine induced a significant decrease in endothelium-dependent relaxations to serotonin (5HT) (% E(max) [5HT]: 77% +/- 4%; P < .05). Addition of MH(4) significantly reversed this impaired response (% E(max) [5HT]: 62% +/- 4%; P < .05). No alterations of relaxation were observed with bradykinin in both groups. Endothelium-independent relaxations to sodium nitroprussiate were fully preserved. CONCLUSIONS: These results suggest a significant protective role of BH(4) on coronary endothelial function following exposure to cyclosporine, which could reduce the incidence of endothelial dysfunction and cardiac allograft vasculopathy following cardiac transplantation.

Inhaled prostacyclin reduces cardiopulmonary bypass-induced pulmonary endothelial dysfunction via increased cyclic adenosine monophosphate levels.

OBJECTIVE: Cardiopulmonary bypass triggers a systemic inflammatory response that alters pulmonary endothelial function, which can contribute to pulmonary hypertension. This study was designed to demonstrate that inhaled prostacyclin, a selective pulmonary vasodilator prostaglandin, prevents pulmonary arterial endothelial dysfunction induced by cardiopulmonary bypass. METHODS: Three groups of Landrace swine were compared: control without cardiopulmonary bypass (control group); 90 minutes of normothermic cardiopulmonary bypass (bypass group); 90 minutes of cardiopulmonary bypass and treated with prostacyclin during cardiopulmonary bypass (continuous nebulization with continuous positive airway pressure until the end of the cardiopulmonary bypass; prostacyclin group). After 60 minutes of reperfusion, swine were put to death and pulmonary arteries harvested. After contraction to phenylephrine, endothelium-dependent relaxation to bradykinin and acetylcholine was studied in standard organ chamber experiments. The pulmonary artery intravascular cyclic adenosine monophosphate content was compared between the 3 groups (post-cardiopulmonary bypass). RESULTS: There was a statistically significant improvement of the endothelium-dependent relaxation to bradykinin in the prostacyclin group when compared with the bypass group (P <.05). There was no statistically significant difference for endothelium-dependent relaxation to acetylcholine (P >.05) between the prostacyclin and the bypass groups. There was a statistically significant decrease in the cyclic adenosine monophosphate content and a statistically significant increase of the mean pulmonary artery pressure in the bypass group only (P <.05). CONCLUSION: Prophylactic use of inhaled prostacyclin has a favorable impact on the pulmonary endothelial dysfunction induced by cardiopulmonary bypass associated with preservation of pulmonary intravascular cyclic adenosine monophosphate content and the pulmonary vascular tone.

Stabilization of blood homocysteine in an epidemiological setting.

The major problem in the determination of homocysteine (Hcy), which is thought to be a risk factor in colorectal cancer, is the rise in its concentration if blood is not centrifuged immediately after collection. We assess the interference of 3-deazaadenosine (which inhibits conversion of S-adenosylhomocysteine into Hcy within the erythrocyte), using the fluorescence polarization immunoassay (FPIA) assay, the stabilizing effect of 3-deazaadenosine and the impact of temperature on Hcy stabilization. To assess interference of 3-deazaadenosine, 12 blood samples were extracted; two aliquots were obtained from each and one of them was added 3-deazaadenosine (50 micromol/l). To assess the stabilizing value of 3-deazaadenosine, as well as the effect of temperature, two blood samples were extracted from 24 volunteers. One of the tubes was immediately placed on ice and centrifuged (reference concentration). To the second tube was immediately added 3-deazaadenosine (50 micromol/l), producing six aliquots, three of which were kept at room temperature (25 degrees C) for 1, 4 and 6 hours, the other three kept at 37 degrees C. The mean values (standard deviation) obtained for methodological interference were: 7.32 (3.58) micromol/l without stabilizer, and 7.11 (3.61) micromol/l with stabilizer. There were no statistically significant differences (P = 0.104) and intraclass correlation coefficient was 0.989, suggesting no methodological interference. We did not find any significant differences regarding our reference value in the samples kept at room temperature during the interval studied. A high Pearson correlation coefficient was obtained. Nevertheless, in those samples kept at 37 degrees C, a slight increase was observed in the 4-hour period (P = 0.009). The addition of 3-deazaadenosine may avoid problems in the critical pre-analytical phase in the Hcy measurement. There is no interference with the FPIA assay, nor any dilution effect, and new reference values are not necessary.

[Systemic inflammation during exacerbations of chronic obstructive pulmonary disease]. / Inflamación sistémica durante las agudizaciones de la enfermedad pulmonar obstructiva crónica.

OBJECTIVE: The circulating blood levels of several inflammatory cytokines and acute phase proteins are higher in patients with stable chronic obstructive pulmonary disease (COPD). However, whether or not these inflammatory markers increase during COPD exacerbation or are modified by corticosteroid treatment has not been investigated. The objective of this study was therefore 1) to describe changes in several inflammatory markers in systemic circulation during COPD exacerbation, and 2) to assess the potential effects of corticosteroid treatment during exacerbation. METHODS: Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), interleukin 8 (IL-8) and C-reactive protein (CRP) were determined for 10 patients (65 2 years old) with severe COPD (FEV1 35 4% reference) who were hospitalized for acute respiratory failure (PaO2 57 2 mm Hg; PaCO2 48 3 mm Hg). Blood samples were obtained in the emergency room (before starting intravenous corticosteroid treatment), during the first 24 hours of admission, upon discharge and two months later. Eight healthy non-smokers of a similar age (54 3 years) were also studied as control subjects. RESULTS: The COPD patients had higher concentrations of IL-6 (5.1 1.6 vs. 1.8 0.5 pg/mL, p < 0.05) and CRP (2.2 0.4 vs. 0.6 0.2 mg/dL, p < 0.005) than did controls, but the concentrations of IL-8 were similar (29 11.3 vs. 34.7 10.3 pg/mL, p = ns). No statistically significant changes were seen either during recovery, in spite of intravenous corticosteroid treatment, or two months after discharge.The ELISA test used was unable to detect TNF-alpha in any of the samples obtained from either patients or controls. CONCLUSION: The results show that 1) there is evidence of systemic inflammation during exacerbation of COPD, and 2) such systemic inflammation does not appear to be influenced significantly by intravenous corticosteroid treatment.