Hemodynamic and cardiovascular effects of nitric oxide modulation in the therapy of septic shock.
Nitric oxide synthase (NOS) of the inducible subtype (iNOS) plays a pivotal role in vasodilation associated with sepsis. Various biochemical pathways are involved, revealing targets for inhibiting the consequence of iNOS activation. Interactions of transcription factors, inducers, cofactors, and regulators of iNOS are important in understanding the development of iNOS inhibitors. Inhibition through L-arginine analogs, depletion of arginine, inhibition of cofactors, modulating gene transcription, and scavenging nitric oxide have been studied. Human studies were conducted only with nonselective L-arginine analogs. Reduction of mortality from sepsis was not reported. It is anticipated that iNOS-specific compounds will be clinically useful. The focus of future human trials will be on these agents. Although ideal therapy for treating vasodilation from sepsis is not available, research into the pathophysiology of NOS in sepsis clarified the complexities surrounding this therapeutic dilemma.
Schoonover
L L
LL
Department of Pharmacy Practice, College of Pharmacy, Washington State University, Spokane 99201-3899, USA.
Stewart
A S
AS
Clifton
G D
GD
D000818:Animals; D016166:Free Radical Scavengers; D006801:Humans; D009569:Nitric Oxide / Q000009:adverse effects* / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000627:therapeutic use*
D016166:Free Radical Scavengers; D014665:Vasodilator Agents; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II