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Tetrahydrobiopterin as another EDRF in man
A Schaffner1, N Blau, M Schneemann
1Department of Medicine, University Hospital of Zürich, Switzerland.
Biochemical and Biophysical Research Communications
|November 30, 1994
Summary
Inflammatory conditions alter nitric oxide (NO) production by human cells. Tetrahydrobiopterin (BH4) secreted by endothelial cells supports NO production in smooth muscle cells, leading to vasodilatation.
Area of Science:
- Vascular biology
- Cellular signaling
- Biochemistry
Background:
- Sepsis involves complex changes in nitric oxide synthase (NOS) expression and activity.
- Endotoxin and inflammatory cytokines modulate NOS isoforms in endothelial and smooth muscle cells.
- Compartmentalized nitric oxide (NO) production is suggested under septic conditions.
Purpose of the Study:
- To investigate the compartmentalization of NO production in human vascular cells.
- To determine the role of tetrahydrobiopterin (BH4) in regulating NOS activity.
- To explore the mechanism of endothelium-derived factor (EDRF)-mediated vasodilatation.
Main Methods:
- Dual chamber cell cultures of inflammatory-activated human endothelial cells.
- Measurement of tetrahydrobiopterin (BH4) secretion.
- Laser Doppler velocimetry for intraarterial infusion studies in humans.
- Assays for L-arginine consumption and cyclic GMP production.
Main Results:
- Endothelial cells secrete BH4 directionally towards underlying smooth muscle cells.
- Intraarterial infusion of BH4 induces significant vasodilatation in humans.
- Increased L-arginine consumption and cyclic GMP production indicate NO mediation.
- BH4 acts as a cofactor for NOS, facilitating NO production.
Conclusions:
- BH4 is an endothelium-derived factor that regulates NOS activity.
- Endothelial cells supply BH4 to smooth muscle cells, enabling NO-dependent vasodilatation.
- This mechanism reconciles the concept of an inflammatory EDRF with NO-mediated effects.