Differential role of endothelial versus neuronal nitric oxide synthase in the regulation of coronary blood flow during pacing-induced increases in cardiac workload

Endothelial nitric oxide synthase (eNOS) was assumed to be the only source of nitric oxide (NO) involved in the regulation of human coronary blood flow (CBF). However, our recent first-in-human study using the neuronal NOS (nNOS)-selective inhibitor S-methyl-L-thiocitrulline (SMTC) showed that nNOS-derived NO also plays a role. In this study, we investigated the relative contribution of nNOS and eNOS to the CBF response to a pacing-induced increase in cardiac workload. Incremental right atrial pacing was undertaken in patients with angiographically normal coronary arteries during intracoronary infusion of saline vehicle and then either SMTC or NG-monomethyl-l-arginine (l-NMMA; which inhibits both eNOS and nNOS). Intracoronary SMTC (0.625 μmol/min) and l-NMMA (25 μmol/min) reduced basal CBF to a similar extent (−19.2 ± 3.2% and 25.0 ± 2.7%, respectively; n = 10 per group). Pacing-induced increases in CBF were significantly blunted by l-NMMA (maximum CBF: 83.5 ± 14.2 ml/min during saline vs. 61.6 ± 9.5 ml/min during l-NMMA; P < 0.01). By contrast, intracoronary SMTC had no effect on the maximum CBF during pacing (98.5 ± 12.9 ml/min during saline vs. 102.1 ± 16.6 ml/min during SMTC; P = not significant). l-NMMA also blunted the pacing-induced increase in coronary artery diameter ( P < 0.001 vs. saline), whereas SMTC had no effect. Our results confirm a role of nNOS in the regulation of basal CBF in humans but show that coronary vasodilation in response to a pacing-induced increase in cardiac workload is exclusively mediated by eNOS-derived NO.

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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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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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A Unique Role of NO in the Control of Blood Flow

Physiology ◽

10.1152/physiologyonline.1999.14.2.74 ◽

1999 ◽

Vol 14 (2) ◽

pp. 74-80 ◽

Cited By ~ 5

Author(s):

Ulrich Pohl ◽

Cor de Wit

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Nitric Oxide Synthase ◽

Vascular Conductance ◽

Unique Role ◽

Nos Inhibitors ◽

Oxide Synthase

Nitric oxide synthase (NOS) inhibitors induce significant vasoconstriction, suggesting an indispensable role of NO as a local vasodilator. This is due mainly to its effects on large arterioles that significantly control arterial conductance while scarcely being regulated by metabolites. NO’s role in adapting vascular conductance to flow is pronounced during (re)active hyperemia and autoregulation.

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Erection Capability Is Potentiated by Long-Term Sildenafil Treatment: Role of Blood Flow-Induced Endothelial Nitric-Oxide Synthase Phosphorylation

Molecular Pharmacology ◽

10.1124/mol.104.010678 ◽

2005 ◽

Vol 68 (1) ◽

pp. 226-232 ◽

Cited By ~ 70

Author(s):

Biljana Musicki ◽

Hunter C. Champion ◽

Robyn E. Becker ◽

Tongyun Liu ◽

Melissa F. Kramer ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

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Endothelial nitric oxide synthase genotype modulates the improvement of coronary blood flow by pravastatin: a placebo-controlled PET study

Journal of Molecular Medicine ◽

10.1007/s00109-002-0398-3 ◽

2002 ◽

Vol 80 (12) ◽

pp. 802-807 ◽

Cited By ~ 18

Author(s):

Tarja A. Kunnas ◽

Terho Lehtimäki ◽

Reijo Laaksonen ◽

Erkki Ilveskoski ◽

Tuula Janatuinen ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Nitric Oxide Synthase ◽

Coronary Blood Flow ◽

Endothelial Nitric Oxide Synthase ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

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2380Mechanisms of myocardial ischemia during exercise in microvascular angina

European Heart Journal ◽

10.1093/eurheartj/ehz748.0143 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

H Rahman ◽

M Ryan ◽

M Lumley ◽

H McConkey ◽

F Khan ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Nitric Oxide Synthase ◽

Myocardial Perfusion ◽

Coronary Blood Flow ◽

Coronary Perfusion ◽

Fractional Flow ◽

Microvascular Angina ◽

Flow Reserve ◽

Oxide Synthase

Abstract Background Coronary microvascular dysfunction (MVD) is defined by impaired flow augmentation in response to a vasodilator, the pathophysiological basis of which is unclear. This study sought to address two major gaps in our understanding of MVD: firstly, whether diminished flow reserve is due to structural changes within the microvasculature or potentially reversible dysfunction and secondly to unravel the mechanism of exercise-induced ischemia in the absence of obstructive disease. Methods Simultaneous intracoronary pressure and flow velocity recordings were made in the left anterior descending artery of patients with angina and no obstructive epicardial disease (Fractional Flow Reserve >0.80). Measurements were made at rest, during adenosine-mediated hyperaemia and supine bicycle exercise. Wave intensity analysis was used to quantify waves that accelerate and decelerate coronary blood flow, coronary perfusion efficiency being defined as the proportion of total wave energy that accelerates blood flow. Patients were prospectively classified into MVD (coronary flow reserve <2.5) and controls with researchers blinded to the classification throughout the protocol. Myocardial perfusion and vascular function were assessed by 3T cardiac MRI and venous occlusion plethysmography with forearm blood flow (FBF) assessment during serial infusions of acetylcholine, adenosine and the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). Results 78 patients were enrolled (42 patients had MVD and 36 were controls), with no differences in cardiovascular risk factors between groups. The MVD group had elevated coronary blood flow (21.3±6.4 vs. 15.1±4.5cm s–1; p<0.001) and global myocardial perfusion (1.36±0.37 vs. 1.13±0.22ml/min/g; p=0.01) at rest. Maximum coronary and myocardial blood flow during hyperaemia was similar in both groups. During exercise, MVD patients achieved similar peak flow (30.5±10.0 vs. 26.3±7.7cm s–1; p=0.07) despite a higher rate-pressure product (20777±5205 vs. 17450±4710bpm.mmHg; p=0.01). Coronary perfusion efficiency, decreased with exercise in the MVD group (61±11% vs. 44±10% p<0.001) but was unchanged in controls. On MRI, MVD had lower hyperaemic endo-epicardial perfusion ratio than controls (0.94±0.08 vs. 1.04±0.13; p=0.001). Augmentation of FBF with acetylcholine was attenuated in MVD patients compared to controls (p=0.02) but the response to adenosine was similar (p=0.13). Infusion of L-NMMA caused a significantly greater reduction in FBF in MVD patients compared to controls (p<0.001). Exercise Physiology in MVD Conclusion Impaired flow reserve in MVD represents a dysfunctional state, characterised by inappropriately elevated resting flow due to increased nitric-oxide synthase mediated vasodilatation. There is abnormal flow distribution in the myocardium predisposing to subendocardial ischaemia, associated with and exacerbated by impaired cardiac-coronary coupling during exercise. These novel findings may represent distinct therapeutic targets. Acknowledgement/Funding British Heart Foundation

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00745.2016 ◽

2017 ◽

Vol 313 (3) ◽

pp. H578-H583 ◽

Cited By ~ 5

Author(s):

Sitara G. Khan ◽

Narbeh Melikian ◽

Husain Shabeeh ◽

Ana R. Cabaco ◽

Katherine Martin ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Coronary Artery ◽

Nitric Oxide Synthase ◽

Coronary Blood Flow ◽

Mental Stress ◽

Coronary Flow ◽

Neuronal Nitric Oxide Synthase ◽

Coronary Artery Diameter ◽

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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Intracoronary Genistein Acutely Increases Coronary Blood Flow in Anesthetized Pigs through β-Adrenergic Mediated Nitric Oxide Release and Estrogenic Receptors

Endocrinology ◽

10.1210/en.2007-1361 ◽

2008 ◽

Vol 149 (5) ◽

pp. 2678-2687 ◽

Cited By ~ 23

Author(s):

Elena Grossini ◽

Claudio Molinari ◽

David A. S. G. Mary ◽

Francesca Uberti ◽

Philippe Primo Caimmi ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Nitric Oxide Synthase ◽

Coronary Blood Flow ◽

Adrenergic Receptors ◽

Primary Effect ◽

No Production ◽

Concomitant Treatment ◽

Vascular Effects ◽

Oxide Synthase

Various studies have suggested that the phytoestrogen genistein has beneficial cardioprotective and vascular effects. However, there has been scarce information regarding the primary effect of genistein on coronary blood flow and its mechanisms including estrogen receptors, autonomic nervous system, and nitric oxide (NO). The present study was planned to determine the primary effect of genistein on coronary blood flow and the mechanisms involved. In anesthetized pigs, changes in left anterior descending coronary artery caused by intracoronary infusion of genistein at constant heart rate and arterial pressure were assessed using ultrasound flowmeters. In 25 pigs, genistein infused at 0.075 mg/min increased coronary blood flow by about 16.3%. This response was graded in a further five pigs by increasing the infused dose of the genistein between 0.007 and 0.147 mg/min. In the 25 pigs, blockade of cholinergic receptors (iv atropine; five pigs) and α-adrenergic receptors (iv phentolamine; five pigs) did not abolish the coronary response to genistein, whose effects were prevented by blockade of β2-adrenergic receptors (iv butoxamine; five pigs), nitric oxide synthase (intracoronary Nω-nitro-l-arginine methyl ester; five pigs) and estrogenic receptors (ERs; ERα/ERβ; intracoronary fulvestrant; five pigs). In porcine aortic endothelial cells, genistein induced the phosphorylation of endothelial nitric oxide synthase and NO production through ERK 1/2, Akt, and p38 MAPK pathways, which was prevented by the concomitant treatment by butoxamine and fulvestrant. In conclusion, genistein primarily caused coronary vasodilation the mechanism of which involved ERα/ERβ and the release of NO through vasodilatory β2-adrenoreceptor effects.

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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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Abstract 1138: Endogenous Adipocyte-Derived Factors Diminish Coronary Endothelial-Dependent Vasodilation Via Inhibition Of Nitric Oxide Synthase

Circulation ◽

10.1161/circ.116.suppl_16.ii_229-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Gregory A Payne ◽

Lena Borbouse ◽

Gregory M Dick ◽

Johnathan D Tune

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Nitric Oxide Synthase ◽

Coronary Blood Flow ◽

Vascular Function ◽

Vascular Dysfunction ◽

Dependent Manner ◽

Pericardial Adipose Tissue ◽

Oxide Synthase

Adipocytokines may be the molecular link between obesity and vascular disease; however, effects of these factors on coronary vascular function have not been delineated. Accordingly, this study was designed to examine mechanisms by which endogenous adipocyte-derived factors impair coronary endothelial-dependent vasodilation in vivo . Experiments were conducted in open-chest anesthetized dogs (n = 16) before and during treatment with endogenous adipocyte-derived factors. Phosphate buffered saline was conditioned in a shaking water bath with parietal pericardial adipose tissue (3 g/ml) for 30 min at 37°C. The conditioned buffer was then filtered (0.2 μm) and infused directly into the coronary circulation (0.3 ml/min). Conditioned buffer did not significantly affect baseline coronary blood flow (0.50 ± 0.01 vs. 0.61 ± 0.05 ml/min/g, p = 0.68), mean arterial pressure (103 ± 6 vs. 96 ± 9 mmHg, p = 0.74), or heart rate (87 ± 13 vs. 110 ± 24 beats/min, p = 0.44). Conditioned buffer had no effect on responses to intracoronary angiotensin II (2.5 – 750 ng; 74 vs. 70% vasoconstriction). Under control conditions, bradykinin (0.03 – 3 μg/min) increased coronary blood flow (303 ± 65%) to 2.02 ± 0.31 ml/min/g in a dose-dependent manner. Conditioned buffer attenuated maximum bradykinin vasodilation to 1.64 ± 0.26 ml/min/g (167 ± 33% increase; p < 0.05). This decrease in endothelial-dependent dilation was not due to increases in superoxide production, as administration of the superoxide dismutase mimetic Tempol (10 mg/min, ic) did not improve bradykinin vasodilation (120 ± 27% increase; p < 0.05). Inhibition of nitric oxide synthase with L-NAME (150 μg/min, ic) reduced maximum bradykinin vasodilation to 0.93 ± 0.04 ml/min/g (p < 0.05) and endogenous adipocyte-derived factors had no further inhibitory effect (0.82 ± 0.09 ml/min/g, p = 0.24). These data indicate that endogenous adipocyte-derived factors diminish endothelial-dependent coronary vasodilation via inhibition of nitric oxide synthase rather than a reduction in nitric oxide bioavailability by superoxide. Our findings importantly link endogenous adipocyte-derived factors with pro-atherogenic coronary vascular dysfunction in vivo .

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