Experimental agents

Nitric oxide (NO) is released in large amounts in response to a septic challenge. It is a potent vasodilator and therefore has been implicated in the hypotension associated with septic shock. NO also plays a role in the maintenance of peripheral tissue perfusion and in intercellular adhesion, and has microbicidal effects. Therefore blocking NO production may restore arterial blood pressure by limiting vasodilation, but could have severe detrimental effects. Two experimental NO blockers which have undergone clinical trials are NG-monomethyl-L-arginine (L-NMMA) and methylene blue.

L-NMMA is an inhibitor of NO synthase. In septic patients, administration of L-NMMA may increase arterial blood pressure, although with an associated fall in cardiac output. The correct dosage is important, as the use of high doses may increase mortality, and timing of administration also seems to be critical with late intervention being more effective. The degree of inhibition may also be important, with specific inhibition of inducible NOS being most beneficial.

Methylene blue is an inhibitor of guanylate cyclase and therefore may specifically attenuate the hemodynamic effects of NO, which are associated with guanylate cyclase activation. Administration of methylene blue to patients with septic shock increases arterial blood pressure and left ventricular work, with no significant effect on cardiac output, and in animal models methylene blue administration has been shown to improve mesenteric blood flow selectively ( Preis.e.r.efal 1994). Further work needs to be done to to establish whether there is a place for methylene blue or L-NMMA in the treatment of septic patients.

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