The human coronary vasodilatory response to acute mental stress is mediated by neuronal nitric oxide synthase

Mental stress-induced ischemia approximately doubles the risk of cardiac events in patients with coronary artery disease, yet the mechanisms underlying changes in coronary blood flow in response to mental stress are poorly characterized. Neuronal nitric oxide synthase (nNOS) regulates basal coronary blood flow in healthy humans and mediates mental stress-induced vasodilation in the forearm. However, its possible role in mental stress-induced increases in coronary blood flow is unknown. We studied 11 patients (6 men and 5 women, mean age: 58 ± 14 yr) undergoing elective diagnostic cardiac catheterization and assessed the vasodilator response to mental stress elicited by the Stroop color-word test. Intracoronary substance P (20 pmol/min) and isosorbide dinitrate (1 mg) were used to assess endothelium-dependent and -independent vasodilation, respectively. Coronary blood flow was estimated using intracoronary Doppler recordings and quantitative coronary angiography to measure coronary artery diameter. Mental stress increased coronary flow by 34 ± 7.0% over the preceding baseline during saline infusion ( P < 0.01), and this was reduced to 26 ± 7.0% in the presence of the selective nNOS inhibitor S-methyl-l-thiocitrulline (0.625 µmol/min, P < 0.001). Mental stress increased coronary artery diameter by 6.9 ± 3.7% ( P = 0.02) and 0.5 ± 2.8% ( P = 0.51) in the presence of S-methyl-l-thiocitrulline. The response to substance P did not predict the response to mental stress ( r2 = −0.22, P = 0.83). nNOS mediates the human coronary vasodilator response to mental stress, predominantly through actions at the level of coronary resistance vessels. NEW & NOTEWORTHY Acute mental stress induces vasodilation of the coronary microvasculature. Here, we show that this response involves neuronal nitric oxide synthase in the human coronary circulation. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/nnos-and-coronary-flow-during-mental-stress/ .

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Faculty Opinions recommendation of Effects of neuronal nitric oxide synthase on human coronary artery diameter and blood flow in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1159746.621155 ◽

2009 ◽

Author(s):

Michael Frenneaux ◽

Julian Ormerod

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Coronary Artery ◽

Nitric Oxide Synthase ◽

Neuronal Nitric Oxide Synthase ◽

Human Coronary Artery ◽

Coronary Artery Diameter ◽

Oxide Synthase

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Effects of Neuronal Nitric Oxide Synthase on Human Coronary Artery Diameter and Blood Flow In Vivo

Circulation ◽

10.1161/circulationaha.108.822205 ◽

2009 ◽

Vol 119 (20) ◽

pp. 2656-2662 ◽

Cited By ~ 87

Author(s):

Michael Seddon ◽

Narbeh Melikian ◽

Rafal Dworakowski ◽

Husain Shabeeh ◽

Benyu Jiang ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Coronary Artery ◽

Nitric Oxide Synthase ◽

Neuronal Nitric Oxide Synthase ◽

Human Coronary Artery ◽

Coronary Artery Diameter ◽

Oxide Synthase

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Effects of estrogen in vivo on coronary vascular resistance in perfused rabbit hearts

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1995.269.6.r1333 ◽

1995 ◽

Vol 269 (6) ◽

pp. R1333-R1338 ◽

Cited By ~ 3

Author(s):

G. I. Gorodeski ◽

T. Yang ◽

M. N. Levy ◽

J. Goldfarb ◽

W. H. Utian

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Nitric Oxide Synthase ◽

Coronary Blood Flow ◽

Coronary Flow ◽

Coronary Vascular Resistance ◽

Intravenous Injections ◽

Oxide Synthase ◽

Perfused Hearts

Estrogen or its vehicle was given daily to three groups of ovariectomized rabbits for various lengths of time, after which coronary flow was measured in their isolated perfused hearts. In one group, intramuscular injections of estrogen (40 micrograms/kg) for 7 or 14 days increased coronary flow by 40-50% (P < 0.05). In rabbits given estrogen intramuscularly for 7 days, the coronary flow returned to the basal level within 7 days after the estrogen injections were discontinued. In a second group of animals, intravenous injections of estrogen (10 micrograms/kg) for 4 days increased the coronary flow by 45% (P < 0.01). In a third group, we administered the estrogen transdermally for 4 days, and we measured the plasma estrogen levels at the end of this period. The coronary flow in this group was increased by 52% (P < 0.001), and the plasma estrogen levels ranged from 39 to 800 pg/ml. In all groups of experiments, the increments in coronary flow evoked by estrogen were virtually abolished by NG-nitro-L-arginine, an inhibitor of nitric oxide synthase. We conclude that estrogen regulates coronary blood flow, in part by upregulating nitric oxide synthase in the coronary vasculature.

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The Role of Neuronal Nitric Oxide Synthase in Regulation of Cerebral Blood Flow in Normocapnia and Hypercapnia in Rats

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1995.97 ◽

1995 ◽

Vol 15 (5) ◽

pp. 774-778 ◽

Cited By ~ 128

Author(s):

Qiong Wang ◽

Dale A. Pelligrino ◽

Verna L. Baughman ◽

Heidi M. Koenig ◽

Ronald F. Albrecht

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Nitric Oxide Synthase ◽

Inhibitory Action ◽

Neuronal Nitric Oxide Synthase ◽

Muscarinic Agonist ◽

Doppler Flowmetry ◽

Nos Inhibitors ◽

Oxide Synthase

The nitric oxide synthase (NOS) inhibitors, nitro-L-arginine, its methyl ester, and N-monomethyl-L-arginine, have been shown to attenuate resting CBF and hypercapnia-induced cerebrovasodilation. Those agents nonspecifically inhibit the endothelial and neuronal NOS (eNOS and nNOS). In the present study, we used a novel nNOS inhibitor, 7-nitroindazole (7-NI) to examine the role of nNOS in CBF during normocapnia and hypercapnia in fentanyl/N2O-anesthetized rats. CBF was monitored using laser-Doppler flowmetry. Administration of 7-NI (80 mg kg−1 i.p.) reduced cortical brain NOS activity by 57%, the resting CBF by 19–27%, and the CBF response to hypercapnia by 60%. The 60% reduction was similar in magnitude to the CBF reductions observed in previous studies in which nonspecific NOS inhibitors were used. In the present study, 7-NI did not increase the MABP. Furthermore, the CBF response to oxotremorine, a blood–brain barrier permeant muscarinic agonist that induces cerebrovasodilation via endothelium-derived NO, was unaffected by 7-NI. These results confirmed that 7-NI does not influence eNOS; they also indicated that the effects of 7-NI on the resting CBF and on the CBF response to hypercapnia in this study were solely related to its inhibitory action on nNOS. The results further suggest that the NO synthesized by the action of nNOS participates in regulation of basal CBF and is the major, if not the only, category of NO contributing to the hypercapnic CBF response.

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Exercise training enhances multiple mechanisms of relaxation in coronary arteries from ischemic hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00531.2013 ◽

2013 ◽

Vol 305 (9) ◽

pp. H1321-H1331 ◽

Cited By ~ 13

Author(s):

Rachel R. Deer ◽

Cristine L. Heaps

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Coronary Artery ◽

Nitric Oxide Synthase ◽

Exercise Training ◽

Coronary Arteries ◽

Vascular Function ◽

Channel Inhibition ◽

Oxide Synthase ◽

Endothelium Dependent Relaxation

Exercise training of coronary artery disease patients is of considerable interest, since it has been shown to improve vascular function and, thereby, enhance blood flow into compromised myocardial regions. However, the mechanisms underlying exercise-induced improvements in vascular function have not been fully elucidated. We tested the hypothesis that exercise training increases the contribution of multiple mediators to endothelium-dependent relaxation of coronary arteries in the underlying setting of chronic coronary artery occlusion. To induce gradual occlusion, an ameroid constrictor was placed around the proximal left circumflex coronary artery in Yucatan miniature swine. At 8 wk postoperatively, pigs were randomly assigned to sedentary or exercise (treadmill, 5 days/wk) regimens for 14 wk. Exercise training significantly enhanced the contribution of nitric oxide, prostanoids, and large-conductance Ca2+-dependent K+ (BKCa) channels to endothelium-dependent, bradykinin-mediated relaxation in nonoccluded and collateral-dependent arteries. Combined nitric oxide synthase, prostanoid, and BKCa channel inhibition ablated the enhanced relaxation associated with exercise training. Exercise training significantly increased nitric oxide levels in response to bradykinin in endothelial cells isolated from nonoccluded and collateral-dependent arteries. Bradykinin treatment significantly increased PGI2 levels in all artery treatment groups and tended to be further enhanced after nitric oxide synthase inhibition in exercise-trained pigs. No differences were found in whole cell BKCa channel currents, BKCa channel protein levels, or arterial cyclic nucleotide levels. Although redundant, upregulation of parallel vasodilator pathways appears to contribute to enhanced endothelium-dependent relaxation, potentially providing a more refined control of blood flow after exercise training.

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106 Role of neuronal vs endothelial nitric oxide synthase in the coronary blood flow response to pacing

Heart ◽

10.1136/heartjnl-2012-301877b.106 ◽

2012 ◽

Vol 98 (Suppl 1) ◽

pp. A60.2-A61

Author(s):

H Shabeeh ◽

N Melikian ◽

R Dworakowski ◽

B Casadei ◽

P Chowienczyk ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Nitric Oxide Synthase ◽

Coronary Blood Flow ◽

Endothelial Nitric Oxide Synthase ◽

Blood Flow Response ◽

Flow Response ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

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Neuronal nitric oxide synthase and splanchnic blood flow in anaesthetized rats

Acta Physiologica Scandinavica ◽

10.1111/j.1365-201x.2004.01396.x ◽

2005 ◽

Vol 183 (3) ◽

pp. 257-262 ◽

Cited By ~ 12

Author(s):

L. Jansson ◽

P.-O. Carlsson ◽

B. Bodin ◽

A. Andersson ◽

O. Kallskog

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Nitric Oxide Synthase ◽

Neuronal Nitric Oxide Synthase ◽

Splanchnic Blood Flow ◽

Anaesthetized Rats ◽

Oxide Synthase

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Isoflurane-induced Cerebral Hyperemia Is Partially Mediated by Nitric Oxide and Epoxyeicosatrienoic Acids in Mice In Vivo

Anesthesiology ◽

10.1097/00000542-200212000-00027 ◽

2002 ◽

Vol 97 (6) ◽

pp. 1528-1533 ◽

Cited By ~ 20

Author(s):

Franz Kehl ◽

Hui Shen ◽

Carol Moreno ◽

Neil E. Farber ◽

Richard J. Roman ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Nitric Oxide Synthase ◽

Neuronal Nitric Oxide Synthase ◽

Epoxyeicosatrienoic Acids ◽

Acute Administration ◽

Doppler Flowmetry ◽

Cortical Blood Flow ◽

Oxide Synthase ◽

Cerebral Cortical Blood Flow

Background Despite intense investigation, the mechanism of isoflurane-induced cerebral hyperemia is unclear. The current study was designed to determine the contributions of neuronal nitric oxide synthase, prostaglandins, and epoxyeicosatrienoic acids to isoflurane-induced cerebral hyperemia. Methods Regional cerebral cortical blood flow was measured with laser Doppler flowmetry during stepwise increases of isoflurane from 0.0 to 1.2, 1.8, and 2.4 vol% end-tidal concentration in alpha-chloralose-urethane-anesthetized, C57BL/6 mice before and 45 min after administration of the neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI, 40 mg/kg, intraperitoneal), the cyclooxygenase inhibitor indomethacin (INDO, 10 mg/kg, intravenous), and the cytochrome P450 epoxygenase inhibitor N-methylsulfonyl-6-(2-proparglyoxyphenyl)hexanoic acid (PPOH, 20 mg/kg, intravenous). Results Isoflurane increased regional cerebral cortical blood flow by 9 +/- 3, 46 +/- 21, and 101 +/- 26% (SD) at 1.2, 1.8, and 2.4 vol%, respectively. The increases in regional cerebral cortical blood flow were significantly (*P < 0.05) smaller after 7-NI (5 +/- 6, 29 +/- 19*, 68 +/- 15%*) or PPOH (4 +/- 8, 27 +/- 17*, 67 +/- 30%*), but not after administration of INDO (4 +/- 4, 33 +/- 18 [NS], 107 +/- 35% [NS]). The effect of combined treatment with 7-NI, PPOH, and INDO was not additive and was equal to that of either 7-NI or PPOH alone (5 +/- 5, 30 +/- 12*, 76 +/- 24%*). Chronic treatment of mice for 5 days with 7-NI (2 x 40 mg/kg, intraperitoneal) produced similar decreases in regional cerebral cortical blood flow as those seen with acute administration. Neither PPOH nor INDO conferred a significant additional block of the hyperemia in these animals. Conclusions Nitric oxide and epoxyeicosatrienoic acids contribute to isoflurane-induced hyperemia. However, only approximately one third of the cerebral hyperemic response to isoflurane is mediated by autacoids. The remaining part of this response appears to be mediated by a direct action of isoflurane on smooth muscle by some yet-unknown mechanism.

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