Neuronal nitric oxide synthase and human vascular regulation

Abstract

Vascular blood flow and its distribution among different vascular beds are regulated by changes in microvascular tone. Nitric oxide (NO) plays a key role in the local paracrine regulation of vessel tone both under resting conditions and when blood flow increases in response to agonist stimulation or increased shear stress. The conventional notion that endothelial NO synthase (eNOS)-derived NO is largely responsible for both effects has been challenged by first-in-human studies with a selective inhibitor of neuronal NOS (nNOS), S-methyl-l-thiocitrulline (SMTC). These studies reveal that SMTC causes a reduction in basal blood flow in the normal human forearm and coronary circulations (that is reversed by l-arginine), without affecting the eNOS-mediated vasodilatation elicited by acetylcholine, substance P, or increased shear stress. S-methyl-l-thiocitrulline also inhibits mental stress-induced vasodilatation. These results are consistent with a significant body of experimental studies suggesting that nNOS plays an important role in the local regulation of vessel tone in other species, independent of the effects of nNOS-derived NO in the central nervous system. These emerging data suggest that eNOS and nNOS have distinct roles in the physiologic local regulation of human microvascular tone in vivo and pave the way for further detailed investigation of the relative contribution of nNOS and eNOS in vascular regulation in human disease.

Figure 1

Effects of nNOS in the human forearm. Intraarterial infusion of the nNOS-specific inhibitor STMC into the brachial artery resulted in a dose dependent reduction in forearm blood flow (panel A). Maximal reduction in forearm blood flow in response to SMTC was abolished in the presence of excess l-arginine but not d-arginine (panel B). Intraarterial infusion of the eNOS-agonist acetylcholine (ACh) resulted in a dose-dependent increase in forearm blood flow. This response was abolished in the presence of the nonselective NOS inhibitor l-NMMA but was unaffected by SMTC. S-methyl-l-thiocitrulline had no effect on NO-independent changes in blood flow in response to intraarterial sodium nitroprusside (SNP) (panel C) (adapted from Seddon et al. 2008. Circulation 117:1991-1996).

Figure 2

Effects of nNOS in the human coronary circulation. Intracoronary Doppler ultrasound traces demonstrating average peak velocity (APV) values at baseline and after infusion of the endothelial agonist substance P. Volumetric coronary blood flow can be obtained from the product of APV values and the cross-sectional area of the coronary vessel (calculated from measuring the diameter of the epicardial vessel with the use of quantitative coronary angiography [QCA]) at the time of APV recording (panel A). Doppler/QCA was used to derive changes in coronary blood flow in response to the nNOS-selective inhibitor SMTC and the nonselective NOS inhibitor l-NMMA during cardiac catheterization in patients who turned out to have unobstructed/smooth coronary vessels. As in the forearm, intracoronary infusion of the SMTC reduced coronary blood flow. This response was abolished in the presence of excess l-arginine but not d-arginine (panel B). Intracoronary infusion of the eNOS-agonist substance P increased coronary blood flow. This response was abolished in the presence of l-NMMA but was unaffected by SMTC (panel C) (adapted from Seddon et al. 2009. Circulation 119:2656-2662).

Figure 3

Potential in vivo sources of nNOS-derived NO. Schematic representation of the potential sources of nNOS and nNOS-derived NO in vivo. Neuronal NOS is known to be expressed in endothelial and smooth muscle cells within the vascular wall as well as skeletal muscle cells and perivascular nerve fibers. The nNOS-derived NO from one or more of these sources may influence vascular tone.