Proceedings of The Physiological Society

University of Oxford (2011) Proc Physiol Soc 23, PC274

Poster Communications

The sGC activator BAY58-2667 protects against sterile inflammatory shock in mice.

B. H. Vandendriessche1, A. Cauwels1, E. J. Rogge1, P. Brouckaert1

1. Department for Molecular Biomedical Research, VIB-UGent, Gent (Zwijnaarde), Belgium.

Reactive oxygen species can oxidize the ferric-heme prosthetic group of soluble guanylate cyclase (sGC) resulting in the formation of apo-sGC that is nitric oxide (NO)-insensitive and is proteolytically degraded. The sGC activator BAY58-2667 (1) can bind apo-sGC, thereby stabilizing it and increasing cyclic GMP production in a heme- and NO-independent manner. Starting from the observation that the hypoxic NO-donor nitrite (NO2-) (2) can sGC-dependently protect against sterile inflammatory shock (3), we decided to test BAY58-2667 in a murine model of endotoxic shock and found that it can protect against morbidity and mortality, as evidenced by a rapid return of normal resting heart rate (HR), heart rate variability (HRV), and mean arterial pressure (MAP). Female C57BL/6 mice were injected IV with LPS (10 mg/kg) to induce endotoxic shock. Treatment was either vehicle or BAY58-2667 (100 µg/kg) IV, given +3h or +8h after challenge. Rectal temperature was used as a read-out of morbidity and was improved 30h after LPS in the +8h (33.4 °C ± 0.48; n = 4) group compared to controls (27.2 °C ± 0.43, n = 4), whereas the +3h treatment exacerbated morbidity (100% mortality 30h after LPS, n = 5). Mortality 60h after LPS challenge was also lower in the +8h group compared to control and +3h group: controls (100% mortality, n = 9) versus +3h (100% mortality, n = 5) and +8h group (32.5% mortality, n = 9). Values are means ± SEM. HR, MAP, activity, and core temperature were determined using PA-C10 and ETA-F20 implantable transmitters (Data Sciences International). Female C57BL/6 mice were anesthetized using inhaled isoflurane (induction 4%, maintenance 2%). Analgesia was started 24h before the procedure until complete recovery (Ibuprofen, 200 µg/ml in drink). Following baseline measurement, implanted mice received a bolus IV injection of LPS (10 mg/kg) to induce endotoxic shock. Afterwards they were treated with vehicle or BAY58-2667, +3h or +8h after LPS. Infusion of LPS was associated with an immediate loss of activity, and progressive decline in HR, MAP and core temperature. The +3h group (n = 2) was again sensitized and did not recover, whereas the HR and MAP in the +8h group was stabilized already 24h after LPS, and HRV and circadian rhythms returned to normal 30h after LPS (n = 2). One control mouse died 50h after challenge. The second control survived but it took up to 5 days for HR and MAP to recover fully as compared to only 30-35h for the +8h treated animal. We conclude that reactivation of sGC in regions exposed to high levels of oxidative stress, as occurs during ischemia, can restore tissue metabolic homeostasis. Whether or not this (1) occurs at the level of the microcirculation of vital organs; (2) is a consequence of a direct or indirect beneficial effect on cardiac function; (3) or is a combination of both, remains to be determined.

Where applicable, experiments conform with Society ethical requirements