Neuronal nitric oxide synthase and human vascular regulation

Area of Science:

• Physiology
• Vascular Biology
• Pharmacology

Background:

• Microvascular tone regulates blood flow distribution.
• Nitric oxide (NO) is crucial for paracrine regulation of vessel tone.
• Endothelial NO synthase (eNOS) was traditionally considered the primary source of NO for vascular regulation.

Purpose of the Study:

• To investigate the role of neuronal NO synthase (nNOS) in human microvascular tone regulation.
• To challenge the conventional view of eNOS as the sole mediator of vascular NO production.
• To explore the distinct contributions of nNOS and eNOS in vivo.

Main Methods:

• First-in-human studies utilizing a selective nNOS inhibitor, S-methyl-l-thiocitrulline (SMTC).
• Administration of SMTC to assess effects on basal forearm and coronary blood flow.
• Evaluation of SMTC's impact on acetylcholine-, substance P-, and shear stress-induced vasodilation.
• Assessment of SMTC's effect on mental stress-induced vasodilation.

Main Results:

• SMTC reduced basal forearm and coronary blood flow in humans, effects reversed by l-arginine.
• SMTC did not inhibit eNOS-mediated vasodilation induced by acetylcholine, substance P, or increased shear stress.
• SMTC inhibited mental stress-induced vasodilation.
• Results suggest nNOS plays a significant role in local vascular tone regulation, independent of central nervous system effects.

Conclusions:

• eNOS and nNOS have distinct physiological roles in the in vivo regulation of human microvascular tone.
• nNOS contributes to basal blood flow regulation and stress-induced vasodilation.
• These findings necessitate further investigation into the specific roles of nNOS and eNOS in human vascular diseases.