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Neuronal nitric oxide synthase and human vascular regulation.

Melikian N, Seddon MD, Casadei B, Chowienczyk PJ, Shah AM - Trends Cardiovasc. Med. (2009)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, London, United Kingdom.

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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).
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fig2: 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).

Mentions: In further studies, Seddon et al. (Seddon et al. 2009) also investigated the potential role of local nNOS in the human coronary circulation. The effects of intracoronary infusion of SMTC were studied in patients undergoing cardiac catheterization who turned out to have angiographically normal coronary arteries. In these subjects, SMTC caused a significant reduction in basal blood flow as assessed by intracoronary Doppler and angiography. However, SMTC had no effect on the increases in flow elicited by intracoronary substance P infusion, which in contrast was inhibited by l-NMMA (Seddon et al. 2009) (Figure 2). These data indicate that the effects of SMTC on basal flow extend to the coronary circulation.


Neuronal nitric oxide synthase and human vascular regulation.

Melikian N, Seddon MD, Casadei B, Chowienczyk PJ, Shah AM - Trends Cardiovasc. Med. (2009)

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).
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Related In: Results  -  Collection

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fig2: 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).
Mentions: In further studies, Seddon et al. (Seddon et al. 2009) also investigated the potential role of local nNOS in the human coronary circulation. The effects of intracoronary infusion of SMTC were studied in patients undergoing cardiac catheterization who turned out to have angiographically normal coronary arteries. In these subjects, SMTC caused a significant reduction in basal blood flow as assessed by intracoronary Doppler and angiography. However, SMTC had no effect on the increases in flow elicited by intracoronary substance P infusion, which in contrast was inhibited by l-NMMA (Seddon et al. 2009) (Figure 2). These data indicate that the effects of SMTC on basal flow extend to the coronary circulation.

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, London, United Kingdom.

Show MeSH
Related in: MedlinePlus