Oxidative stress triggers hyperdynamic circulation via central neural activation in portal hypertensive rats

Abstract

Background: Hyperdynamic circulation in portal hypertension (PHT) depends on central neural activation. However, the initiating mechanism that signals PHT to the central neural cardiovascular-regulatory centers remains unclear. We aimed to test the hypothesis that oxidative stress in the gut initiates the signal that activates central cardiovascular nuclei in portal hypertensive rats.

Methods: Two groups of rats were used. One had portal hypertension produced by partial portal vein ligation, while controls underwent sham operation. Hemodynamics including portal pressure, cardiac output, mean arterial pressure (MAP) and peripheral vascular resistance were measured. Activation of central cardiovascular nuclei was determined by immunohistochemical Fos expression in the paraventricular nucleus (PVN) of the hypothalamus. Myeloperoxidase activity, an oxidative stress marker, was measured in the jejunum. Hydrogen peroxide, the antioxidant N-acetyl-cysteine (NAC) or saline controls were administered for 12-14 days by gavage or osmotic minipumps placed in the peritoneal cavity.

Results: Compared with controls, PHT rats showed increased cardiac output (54.2 ± 9.5 vs 33.6 ± 2.4 ml/min/100 g BW, p < 0.01), decreased MAP (96.2 ± 6.4 mmHg vs 103.2 ± 7.8, p < 0.01) and systemic vascular resistance (1.84 ± 0.28 vs 3.14 ± 0.19 mmHg/min/ml/100 g BW, p < 0.01). PHT rats had increased jejunal myeloperoxidase and PVN Fos expression. NAC treatment eliminated the hyperdynamic circulation, decreased jejunal myeloperoxidase and PVN Fos expression in PHT rats, but had no effect on sham controls. H₂O₂ significantly increased PVN Fos expression and decreased MAP.

Conclusion: These results indicate that in PHT, mesenteric oxidative stress is the initial signal that activates chemoreceptors and triggers hyperdynamic circulation by central neural cardiovascular-regulatory centers.

Keywords: Antioxidant; Cardiac output; Central neural cardiovascular-regulatory centers; Hyperdynamic circulation; Intestinal congestion; Nitric oxide; Oxidative stress; Portal hypertension; Portal vein stenosis; Systemic vascular resistance; Vagal nerve.