Protection against TNF-induced lethal shock by soluble guanylate cyclase inhibition requires functional inducible nitric oxide synthase

Hypotension and shock observed in sepsis, SIRS, and tumor necrosis factor ( TNF) or cytokine-based cancer treatment are the consequence of excessive ni tric oxide (NO) production and subsequent soluble guanylate cyclase (sGC)-m ediated vascular smooth muscle relaxation. We demonstrate here that, while NO synthase (NOS) inhibitors exacerbated toxicity, inhibitors of sGC activa tion 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 obse rved that no protection against TNF toxicity could be obtained in the absen ce of NO. These data imply that iNOS- (and not eNOS-) derived NO is an endo genous protective molecule indispensable to survive a TNF challenge and exe rting this beneficial effect via sGC-independent mechanisms.