Simon K Jackson — Page 2

PubMed2002

Endotoxin-induced liver hypoxia: defective oxygen delivery versus oxygen consumption.

In vivo EPR was used to investigate liver oxygenation in a hemodynamic model of septic shock in mice. Oxygen-sensitive material was introduced either (i) as a slurry of fine particles which localized at the liver sinusoids (pO2 = 44.39 +/- 5.13 mmHg) or (ii) as larger particles implanted directly into liver tissue to measure average pO2 across the lobule (pO2 = 4.56 +/- 1.28 mmHg). Endotoxin caused decreases in pO2 at both sites early (5-15 min) and at late time points (6 h after endotoxin; sinusoid = 11.22 +/- 2.48 mmHg; lobule = 1.16 +/- 0.42 mmHg). The overall pO2 changes observed were similar (74.56% versus 74.72%, respectively). Blood pressures decreased transiently between 5 and 15 min (12.88 +/- 8% decrease) and severely at 6 h (59 +/- 9% decrease) following endotoxin, despite volume replacement with saline. Liver and circulatory nitric oxide was elevated at these times. Liver oxygen extraction decreased from 44% in controls to only 15% following endotoxin, despite severe liver hypoxia. Arterial oxygen saturation, blood flow (hepatic artery), and cardiac output were unaffected. Pretreatment with l-NMMA failed to improve endotoxin-induced oxygen defects at either site, whereas interleukin-13 preserved oxygenation. These site-specific measurements of pO2 provide in vivo evidence that the principal cause of liver hypoxia during hypodynamic sepsis is reduced oxygen supply to the sinusoid and can be alleviated by maintaining sinusoidal perfusion.

Animals↗

PubMed2002

Addition of candesartan to angiotensin converting enzyme inhibitor therapy in patients with chronic heart failure does not reduce levels of oxidative stress.

BACKGROUND: Angiotensin II exerts a number of harmful effects in patients with chronic heart failure (CHF) and, through an increase in oxidative stress, is thought to be critical in the development of endothelial dysfunction. Angiotensin II may be elevated in CHF despite treatment with angiotensin converting enzyme (ACE) inhibitors, producing a rationale for adjunctive angiotensin receptor blockade. We investigated whether the addition of angiotensin antagonism to ACE inhibition would reduce oxidative stress and improve endothelial function and exercise tolerance in patients with chronic heart failure. METHODS AND RESULTS: Twenty-eight heart failure patients, who were on stable ACE inhibitor therapy, were randomised to receive adjunctive therapy with candesartan or placebo. Plasma lipid-derived free radicals, TBARS and neutrophil O2-generation, markers of oxidative stress, were measured in venous blood. Arterial endothelial function was assessed as the response of the brachial artery to flow-related shear stress. Exercise capacity was determined by cardiopulmonary exercise testing. Compared with placebo, candesartan had no effect on changes in lipid derived free radicals (-0.1+/-1.2 vs. -0.1+/-1.0 units, respectively, P=NS), TBARS (-2.2+/-1.1 vs. -2.6+/-2.2 micromol/l, respectively, P=NS) or neutrophil O2-generating capacity (-7.3+/-5.1 vs. -8.4+/-7.9 mV/5x10(5) neutrophils, respectively, P=NS). There was no effect on changes in brachial artery flow-mediated dilatation (0.5+/-1.0 vs. 0.8+/-1.3%, respectively, P=NS) nor peak VO2 (1.6+/-0.7 ml/kg per min vs. 1.8+/-0.6 ml/kg per min; P=NS). CONCLUSION: The addition of the candesartan to ACE inhibitor therapy had no effect on oxidative stress and did not improve endothelial function or exercise capacity in patients with CHF.

Adult↗