Protection against TNF-Induced Lethal Shock by Soluble Guanylate Cyclase Inhibition Requires Functional Inducible Nitric Oxide Synthase

Abstract

Hypotension and shock observed in sepsis, SIRS, and tumor necrosis factor (TNF) or cytokine-based cancer treatment are the consequence of excessive nitric oxide (NO) production and subsequent soluble guanylate cyclase (sGC)-mediated vascular smooth muscle relaxation. We demonstrate here that, while NO synthase (NOS) inhibitors exacerbated toxicity, inhibitors of sGC activation protected against TNF-induced lethality, bradycardia, and hypotension. Importantly, sGC inhibition did not interfere with the antitumor activity of TNF. Using NOS inhibitors or iNOS-deficient animals, we furthermore observed that no protection against TNF toxicity could be obtained in the absence of NO. These data imply that iNOS- (and not eNOS-) derived NO is an endogenous protective molecule indispensable to survive a TNF challenge and exerting this beneficial effect via sGC-independent mechanisms.

Anaphylactic shock depends on PI3K and eNOS-derived NO

“…Nevertheless, MB (15 mg/kg) did not prevent PAF shock to the same degree as l-NAME treatment, implying that sGC-independent NO activities are also involved ( Figure 1, B and C). In comparison, MB provided 100% protection in a mouse model of TNF-induced shock as well as in a model of hyperacute shock induced by TNF in combination with the caspase inhibitor zVAD-fmk, as reported previously (24,29). Also, lower doses of MB (5 and 10 mg/kg) still provided partial protection (data not shown).…”

“…injection (MB; Sterop) was used at a dose of 15 mg/kg unless otherwise stated. All of these treatments were based on the protective effects observed in our previous studies (24,29). ODQ (Tocris Bioscience) was used i.p.…”

“…Rectal body temperature was recorded with an electronic thermometer (model 2001; Comark). Blood pressure and heart rate were measured continuously in conscious, permanently catheterized C57BL/6 mice, as described (24,29). Briefly, a heat-stretched piece of polyethylene tubing was inserted into the right femoral artery.…”

Detection of human papillomavirus L1 gene DNA fragments in postmortem blood and spleen after Gardasil<sup>®</sup> vaccination—A case report

“…phages [41][42][43][44][45][46] is to cause release of various cytokines, including tumor necrosis factor (TNF), a recognized myocardial depressant [47][48][49][50][51]. TNF-induced hypotensive shock is a documented observation among animals Base-calling electropherogram of DNA sequencing on HPV PCR amplicon from postmortem splenic DNA.…”

Description and Mapping of the Resistance of DBA/2 Mice to TNF-Induced Lethal Shock

“…However, exploiting this cytokine in systemic antitumor therapies is impossible due to the massive induction of SIRS accompanied mainly by a blood pressure drop and hepatotoxicity (4,32). In contrast, TNF also plays a detrimental role in the progression and final outcome of many important diseases such as RA, MS, hepatitis, Crohn's disease and many others (33).…”