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Published on: May 4, 2021
Hemodynamic and cardiovascular effects of nitric oxide modulation in the therapy of septic shock
L L Schoonover1, A S Stewart, G D Clifton
1Department of Pharmacy Practice, College of Pharmacy, Washington State University, Spokane 99201-3899, USA.
Abstract:
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.
Insights
Inducible nitric oxide synthase (iNOS) drives sepsis vasodilation. While iNOS inhibitors are researched, specific compounds are needed for effective sepsis treatment and reduced mortality.
Area of Science:
- Pharmacology
- Pathophysiology
- Biochemistry
Background:
- Inducible nitric oxide synthase (iNOS) is central to sepsis-induced vasodilation.
- Understanding iNOS biochemical pathways reveals targets for therapeutic intervention.
- Complex interactions of iNOS regulators influence inhibitor development.
Purpose of the Study:
- To review the pathophysiology of nitric oxide synthase (NOS) in sepsis.
- To explore therapeutic strategies targeting iNOS activation.
- To assess the clinical utility of iNOS inhibitors.
Main Methods:
- Review of biochemical pathways involved in iNOS activation.
- Analysis of various inhibition strategies: L-arginine analogs, cofactor inhibition, gene transcription modulation, nitric oxide scavenging.
- Evaluation of human studies using nonselective L-arginine analogs.
Main Results:
- Nonselective L-arginine analogs have been used in human sepsis studies.
- No reduction in sepsis mortality was reported with current nonselective agents.
- iNOS-specific compounds are anticipated to be clinically useful.
Conclusions:
- Current therapies for sepsis-induced vasodilation are inadequate.
- Research into iNOS pathophysiology has clarified therapeutic complexities.
- Future human trials will focus on iNOS-specific compounds for improved sepsis treatment.
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