Abstract 17415: Mitochondrial Ca2+/Calmodulin-Dependent Kinase II Inhibition Changes the Calcium Homeostasis in the Endothelium and Decreases the Vascular Relaxation in Mesenteric Arteries

Introduction: The Ca2+/Calmodulin-dependent Kinase II (CaMKII) is present in mitochondria and cytosol. In mitochondria, it regulates the mitochondrial Ca 2+ uptake via the mitochondrial Ca2+ uniporter. Since endothelial nitric oxide synthase activity is regulated by intracellular [Ca2+], we hypothesized that it affects cytosolic Ca2+, NO production and ACh-dependent vasodilation. Hypothesis: Inhibition of mitochondrial CaMKII in endothelium increases the cytosolic [Ca2+], and decreases vasorelaxation by Acetylcholine. Methods: CaMKII in mitochondria was inhibited through expression of the mitochondria-targeted CaMKII inhibitor peptide (mito-CaMKIIN) in a novel transgenic mouse model (endo-mtCaMKIIN) in endothelial cells only or delivered by adenoviral transduction (Ad-mtCaMKIIN) in human Aortic Endothelium cells (HAEC). In HAEC, cytosolic Ca2+ levels (by FURA-2 AM), eNOS activation and NOx levels were measured. Results: The basal Ca2+ levels were higher in the cytosol of mitoCaMKIIN cells (1.08 ± 0.02 Fura-2 ratio normalized by control, p<0.05). Thapsigargin-induced ER Ca 2+ release was significantly higher with mitoCaMKIIN (AUC 0.252 ± 0.027 versus 0.112 ± 0.01275, p<0.05), whereas cytosolic Ca 2+ levels after ACh were reduced (AUC 0.191 ± 0.025 versus 0.435 ± 0.054). Higher levels of phosphorylation of eNOS at Ser1177 and Thr495 sites were seen at baseline. The concentration-response curve of vascular relaxation to acetylcholine and SNP shifted to the right (p<0.05) in mesenteric resistance artery of mitoCaMKIIN mice. Conclusions: The inhibition of mitochondrial CaMKII in the endothelium increases the cytosolic levels, endoplasmic reticulum storage of calcium and eNOS phosphorylation. However, there are lower calcium release and lower sensitivity to acetylcholine and SNP.

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Differential expression of α2D-adrenoceptor and eNOS in aortas from early and later stages of diabetes in Goto-Kakizaki rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01074.2003 ◽

2004 ◽

Vol 287 (1) ◽

pp. H135-H148 ◽

Cited By ~ 40

Author(s):

Tsuneo Kobayashi ◽

Takayuki Matsumoto ◽

Kazuyuki Ooishi ◽

Katsuo Kamata

Keyword(s):

Vascular Reactivity ◽

Matched Control ◽

Early Stage ◽

Vascular Dysfunction ◽

Spontaneous Diabetes ◽

Relaxation Response ◽

No Production ◽

Gk Rats ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

The aim of the present study was to compare vascular dysfunction between the early (12 wk old) and later (36 wk old) stages of spontaneous diabetes in Goto-Kakizaki (GK) rats. We also evaluated the aortic expression of the α2D-adrenoceptor and endothelial nitric oxide synthase (eNOS). Vascular reactivity was assessed in thoracic aortas from age-matched control rats and 12- and 36-wk GK rats. Using RT-PCR and immunoblots, we also examined the changes in expression of the α2D-adrenoceptor and eNOS. In aortas from GK rats (vs. those from age-matched control rats): 1) the relaxation response to ACh was enhanced at 12 wk but decreased at 36 wk; 2) the relaxation response to sodium nitroprusside was decreased at both 12 and 36 wk, 3) norepinephrine (NE)-induced contractility was decreased at 12 wk but not at 36 wk, 4) the expressions of α1B- and α1D-adrenoceptors were unaffected, whereas those of α2D-adrenoceptor and eNOS mRNAs were increased at both 12 and 36 wk; and 5) NE- and ACh-stimulated NOx (nitrite and nitrate) levels were increased at 12 wk, although at 36 wk ACh-stimulated NOx was lower, whereas NE-stimulated NOx showed no change. These results clearly demonstrate that enhanced ACh-induced relaxation and impaired NE-induced contraction, due to NO overproduction via eNOS and increased α2D-adrenoceptor expression, occur in early-stage GK rats and that the impaired ACh-induced relaxation in later-stage GK rats is due to reductions in both NO production and NO responsiveness (but not in eNOS expression).

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Protein kinase Cδ regulates endothelial nitric oxide synthase expression via Akt activation and nitric oxide generation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00353.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. L582-L591 ◽

Cited By ~ 9

Author(s):

Neetu Sud ◽

Stephen Wedgwood ◽

Stephen M. Black

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Promoter Activity ◽

Dominant Negative ◽

No Production ◽

Enos Expression ◽

Akt Activation ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

In this study, we explore the roles of the delta isoform of PKC (PKCδ) in the regulation of endothelial nitric oxide synthase (eNOS) activity in pulmonary arterial endothelial cells isolated from fetal lambs (FPAECs). Pharmacological inhibition of PKCδ with either rottlerin or with the peptide, δV1-1, acutely attenuated NO production, and this was associated with a decrease in phosphorylation of eNOS at Ser1177 (S1177). The chronic effects of PKCδ inhibition using either rottlerin or the overexpression of a dominant negative PKCδ mutant included the downregulation of eNOS gene expression that was manifested by a decrease in both eNOS promoter activity and protein expression after 24 h of treatment. We also found that PKCδ inhibition blunted Akt activation as observed by a reduction in phosphorylated Akt at position Ser473. Thus, we conclude that PKCδ is actively involved in the activation of Akt. To determine the effect of Akt on eNOS signaling, we overexpressed a dominant negative mutant of Akt and determined its effect of NO generation, eNOS expression, and phosphorylation of eNOS at S1177. Our results demonstrated that Akt inhibition was associated with decreased NO production that correlated with reduced phosphorylation of eNOS at S1177, and decreased eNOS promoter activity. We next evaluated the effect of endogenously produced NO on eNOS expression by incubating FPAECs with the eNOS inhibitor 2-ethyl-2-thiopseudourea (ETU). ETU significantly inhibited NO production, eNOS promoter activity, and eNOS protein levels. Together, our data indicate involvement of PKCδ-mediated Akt activation and NO generation in maintaining eNOS expression.

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Abstract 3633: Flow-induced Dilation is Mediated by Akt-dependent Activation of eNOS-derived H2O2 in Mouse Cerebral Arteries

Circulation ◽

10.1161/circ.118.suppl_18.s_455 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Annick Drouin ◽

Eric Thorin

Keyword(s):

Endothelial Nitric Oxide Synthase ◽

Fluorescent Dyes ◽

Cerebral Arteries ◽

Physiological Role ◽

No Production ◽

Flow Mediated Dilation ◽

Enos Activity ◽

Maximal Diameter ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Introduction . Endothelial nitric oxide synthase (eNOS) produces superoxide leading to H 2 O 2 -dependent dilations to acetylcholine (ACh) in isolated mouse cerebral and human coronary arteries. Akt increases eNOS activity responsible for flow-mediated dilation (FMD). It is unknown, however, if endogenous H 2 O 2 mediates FMD. Hypothesis . Akt-dependent activation of eNOS leads to the production of functionally relevant levels of H 2 O 2 responsible for FMD. Methods . Cerebral arteries (100 to 150 μm in diameter) were isolated from 12±2 week-old C57Bl/6 male mice. FMD (0 to 10 μl/min, 2-mu;l step-increase at constant internal pressure of 60 mm Hg; shear stress = 0 to 50 dyn/cm 2 ) were induced in vessels pre-constricted with phenylephrine (30 μM) at a pO 2 value of 150 mm Hg using a gas mixture of 12% O 2 , 5% CO 2 , 83% N 2 . Simultaneously to diameter acquisition, H 2 O 2 or NO production was detected by the fluorescent dyes CMH 2 CFDA or DAF-2, respectively. Results are expressed as mean±SEM of n = 6 to 8 mice per experiment. Results . FMD (at 10 μl/min, 25±3% of maximal diameter) were reduced (P<0.05) by endothelial removal (6±1%) or eNOS inhibition with N-nitro-L-arginine (L-NNA; 11±1%), but not by the specific NO scavenger 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl3-oxide (PTIO; 24±3%). Likewise, FMD was not associated with a rise in NO-associated fluorescence, while addition of PEG-catalase and silver diethyldithio-carbamate (DETC; superoxide dismutase inhibitor) reduced (P<0.05) FMD to 10±2% and 15±1%, respectively, suggestive of the implication of H 2 O 2 in FMD. Accordingly, a rise in H 2 O 2 -associated fluorescence (+133±19 a.u.) was observed simultaneously to FMD, and was reduced by L-NNA, PEG-catalase and DETC (+55±10, +64±4 and +50±10 a.u., respectively; P<0.05). Furthermore, specific inhibition of Akt by triciribine (1 μM) prevented FMD together with H 2 O 2 -associated rise in fluorescence (3±1% and +23±4 a.u., respectively, P<0.05). Triciribine, however, neither limited ACh-induced dilation nor the rise in H 2 O 2 -associated fluorescence. Conclusion . In C57Bl/6 mouse cerebral arteries, Akt-dependent activation of eNOS-derived H 2 O 2 accounts for flow-mediated dilation. This suggests a physiological role for eNOS-derived free radicals.

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Effects of homocysteine on endothelial nitric oxide production

AJP Renal Physiology ◽

10.1152/ajprenal.2000.279.4.f671 ◽

2000 ◽

Vol 279 (4) ◽

pp. F671-F678 ◽

Cited By ~ 135

Author(s):

Xiaohui Zhang ◽

Hong Li ◽

Haoli Jin ◽

Zachary Ebin ◽

Sergey Brodsky ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Redox State ◽

Calcium Ionophore ◽

No Production ◽

Cellular Redox ◽

A Cell ◽

Oxide Synthase ◽

Endothelial Nitric Oxide ◽

Peroxynitrite Scavengers

Hyperhomocysteinemia (HHCy) is an independent and graded cardiovascular risk factor. HHCy is prevalent in patients with chronic renal failure, contributing to the increased mortality rate. Controversy exists as to the effects of HHCy on nitric oxide (NO) production: it has been shown that HHCy both increases and suppresses it. We addressed this problem by using amperometric electrochemical NO detection with a porphyrinic microelectrode to study responses of endothelial cells incubated with homocysteine (Hcy) to the stimulation with bradykinin, calcium ionophore, or l-arginine. Twenty-four-hour preincubation with Hcy (10, 20, and 50 μM) resulted in a gradual decline in responsiveness of endothelial cells to the above stimuli. Hcy did not affect the expression of endothelial nitric oxide synthase (eNOS), but it stimulated formation of superoxide anions, as judged by fluorescence of dichlorofluorescein, and peroxynitrite, as detected by using immunoprecipitation and immunoblotting of proteins modified by tyrosine nitration. Hcy did not directly affect the ability of recombinant eNOS to generate NO, but oxidation of sulfhydryl groups in eNOS reduced its NO-generating activity. Addition of 5-methyltetrahydrofolate restored NO responses to all agonists tested but affected neither the expression of the enzyme nor formation of nitrotyrosine-modified proteins. In addition, a scavenger of peroxynitrite or a cell-permeant superoxide dismutase mimetic reversed the Hcy-induced suppression of NO production by endothelial cells. In conclusion, electrochemical detection of NO release from cultured endothelial cells demonstrated that concentrations of Hcy >20 μM produce a significant indirect suppression of eNOS activity without any discernible effects on its expression. Folates, superoxide ions, and peroxynitrite scavengers restore the NO-generating activity to eNOS, collectively suggesting that cellular redox state plays an important role in HCy-suppressed NO-generating function of this enzyme.

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Endothelin stimulates endothelial nitric oxide synthase expression in the thick ascending limb

AJP Renal Physiology ◽

10.1152/ajprenal.00413.2003 ◽

2004 ◽

Vol 287 (2) ◽

pp. F231-F235 ◽

Cited By ~ 38

Author(s):

Marcela Herrera ◽

Jeffrey L. Garvin

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Receptor Antagonist ◽

Endothelial Nitric Oxide Synthase ◽

No Production ◽

Thick Ascending Limb ◽

Enos Expression ◽

No Release ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Endothelin-1 (ET-1) acutely inhibits NaCl reabsorption by the thick ascending limb (THAL) by activating the ETB receptor, stimulating endothelial nitric oxide synthase (eNOS), and releasing nitric oxide (NO). In nonrenal tissue, chronic exposure to ET-1 stimulates eNOS expression via the ETB receptor and activation of phosphatidylinositol 3-kinase (PI3K). We hypothesized that ET-1 increases eNOS expression in the THAL by binding to ETB receptors and stimulating PI3K. In primary cultures of medullary THALs treated for 24 h, eNOS expression increased by 36 ± 18% with 0.01 nM ET-1, 123 ± 30% with 0.1 nM ( P < 0.05; n = 5), and 71 ± 30% with 1 nM, whereas 10 nM had no effect. BQ-788, a selective ETB receptor antagonist, completely blocked stimulation of eNOS expression caused by 0.1 nM ET-1 (12 ± 25 vs. 120 ± 40% for ET-1 alone; P < 0.05; n = 5). BQ-123, a selective ETA receptor antagonist, did not affect the increase in eNOS caused by 0.1 nM ET-1. Sarafotoxin c (S6c; 0.1 μM), a selective ETB receptor agonist, increased eNOS expression by 77 ± 30% ( P < 0.05; n = 6). Wortmannin (0.01 μM), a PI3K inhibitor, completely blocked the stimulatory effect of 0.1 μM S6c (77 ± 30 vs. −28 ± 9%; P < 0.05; n = 6). To test whether the increase in eNOS expression heightens activity, we measured NO release in response to simultaneous treatment with l-arginine, ionomycin, and clonidine using a NO-sensitive electrode. NO release by control cells was 337 ± 61 and 690 ± 126 pA in ET-1-treated cells ( P < 0.05; n = 5). Taken together, these data suggest that ET-1 stimulates THAL eNOS, activating ETB receptors and PI3K and thereby increasing NO production.

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Aging induces muscle-specific impairment of endothelium-dependent dilation in skeletal muscle feed arteries

Journal of Applied Physiology ◽

10.1152/japplphysiol.00461.2002 ◽

2002 ◽

Vol 93 (5) ◽

pp. 1685-1690 ◽

Cited By ~ 79

Author(s):

Christopher R. Woodman ◽

Elmer M. Price ◽

M. Harold Laughlin

Keyword(s):

Skeletal Muscle ◽

Mrna Expression ◽

Vascular Function ◽

Fischer 344 ◽

Old Rats ◽

The Right ◽

Oxide Synthase ◽

Endothelial Nitric Oxide ◽

Feed Arteries ◽

Skeletal Muscle Feed Arteries

We tested the hypothesis that aging decreases endothelium-dependent vasodilation in feed arteries perfusing rat skeletal muscle. In addition, we tested the hypothesis that attenuated vasodilator responses are associated with decreased endothelial nitric oxide synthase (eNOS) and superoxide dismutase-1 (SOD-1) expression. Soleus feed arteries (SFA) and gastrocnemius feed arteries (GFA) were isolated from young (4 mo) and old (24 mo) male Fischer 344 rats. Feed arteries from the right hindlimb were cannulated with two glass micropipettes for examination of endothelium-dependent [acetylcholine (ACh)] and endothelium-independent [adenosine (Ado) or sodium nitroprusside (SNP)] vasodilator function. Feed arteries from the left hindlimb were frozen and used to assess eNOS and SOD-1 protein and mRNA expression. In SFA, endothelium-dependent dilation to ACh was reduced in old rats (0.9 ± 0.04 vs. 0.8 ± 0.03), whereas dilator responses to Ado and SNP were similar in SFA of young and old rats. In GFA, vasodilator responses to ACh, Ado, and SNP were not altered by age. eNOS and SOD-1 protein expression declined with age in SFA (−71 and −54%, respectively) but not in GFA. eNOS and SOD-1 mRNA expression were not altered by age in SFA or GFA. Collectively, these data indicate aging induces muscle-specific impairment of endothelium-dependent vascular function in SFA.

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Nitric oxide function in atherosclerosis

Mediators of Inflammation ◽

10.1080/09629359791875 ◽

1997 ◽

Vol 6 (1) ◽

pp. 3-21 ◽

Cited By ~ 29

Author(s):

K. E. Matthys ◽

H. Bult

Keyword(s):

Nitric Oxide ◽

Leukocyte Adhesion ◽

Atherosclerotic Lesion ◽

Vascular Wall ◽

Early Event ◽

No Production ◽

Oxygen Intermediates ◽

Atherosclerotic Lesions ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Atherosclerosis is a chronic inflammatory process in the intima of conduit arteries, which disturbs the endothelium-dependent regulation of the vascular tone by the labile liposoluble radical nitric oxide (NO) formed by the constitutive endothelial nitric oxide synthase (eNOS). This defect predisposes to coronary vasospasm and cardiac ischaemia, with anginal pain as the typical clinical manifestation. It is now appreciated that endothelial dysfunction is an early event in atherogenesis and that it may also involve the microcirculation, in which atherosclerotic lesions do not develop. On the other hand, the inflammatory environment in atherosclerotic plaques may result in the expression of the inducible NO synthase (iNOS) isozyme. Whether the dysfunction in endothelial NO production is causal to, or the result of, atherosclerotic lesion formation is still highly debated. Most evidence supports the hypothesis that constitutive endothelial NO release protects against atherogenesis e.g. by preventing smooth muscle cell proliferation and leukocyte adhesion. Nitric oxide generated by the inducible isozyme may be beneficial by replacing the failing endothelial production but excessive release may damage the vascular wall cells, especially in combination with reactive oxygen intermediates.

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Cilostazol Induces eNOS and TM Expression via Activation with Sirtuin 1/Krüppel-like Factor 2 Pathway in Endothelial Cells

International Journal of Molecular Sciences ◽

10.3390/ijms221910287 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10287

Author(s):

Chih-Hsien Wu ◽

Yi-Lin Chiu ◽

Chung-Yueh Hsieh ◽

Guo-Shiang Tsung ◽

Lian-Shan Wu ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Endothelial Nitric Oxide Synthase ◽

Umbilical Vein ◽

Sirtuin 1 ◽

No Production ◽

Beneficial Effects ◽

Umbilical Vein Endothelial Cells ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Cilostazol was suggested to be beneficial to retard in-stent atherosclerosis and prevent stent thrombosis. However, the mechanisms responsible for the beneficial effects of cilostazol are not fully understood. In this study, we attempted to verify the mechanism of the antithrombotic effect of cilostazol. Human umbilical vein endothelial cells (HUVECs) were cultured with various concentrations of cilostazol to verify its impact on endothelial cells. KLF2, silent information regulator transcript-1 (SIRT1), endothelial nitric oxide synthase (eNOS), and endothelial thrombomodulin (TM) expression levels were examined. We found cilostazol significantly activated KLF2 expression and KLF2-related endothelial function, including eNOS activation, Nitric oxide (NO) production, and TM secretion. The activation was regulated by SIRT1, which was also stimulated by cilostazol. These findings suggest that cilostazol may be capable of an antithrombotic and vasculoprotective effect in endothelial cells.

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Dysregulation of l-arginine metabolism and bioavailability associated to free plasma heme

AJP Cell Physiology ◽

10.1152/ajpcell.00405.2009 ◽

2010 ◽

Vol 299 (1) ◽

pp. C148-C154 ◽

Cited By ~ 38

Author(s):

F. Omodeo-Salè ◽

L. Cortelezzi ◽

Z. Vommaro ◽

D. Scaccabarozzi ◽

A. M. Dondorp

Keyword(s):

Nitric Oxide ◽

Severe Malaria ◽

Protoporphyrin Ix ◽

Plasmodium Falciparum Malaria ◽

No Production ◽

Cationic Amino Acid ◽

Rbc Membrane ◽

Free Heme ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Severe Plasmodium falciparum malaria is associated with hypoargininemia, which contributes to impaired systemic and pulmonary nitric oxide (NO) production and endothelial dysfunction. Since intravascular hemolysis is an intrinsic feature of severe malaria, we investigated whether and by which mechanisms free heme [Fe(III)-protoporphyrin IX (FP)] might contribute to the dysregulation of l-arginine (l-Arg) metabolism and bioavailability. Carrier systems “y+” [or cationic amino acid transporter (CAT)] and “y+L” transport l-Arg into red blood cells (RBC), where it is hydrolyzed to ornithine and urea by arginase (isoform I) or converted to NO· and citrulline by endothelial nitric oxide synthase (eNOS). Our results show a significant and dose-dependent impairment of l-Arg transport into RBC pretreated with FP, with a strong inhibition of the system carrier y+L. Despite the impaired l-Arg influx, higher amounts of l-Arg-derived urea are produced by RBC preexposed to FP caused by activation of RBC arginase I. This activation appeared not to be mediated by oxidative modifications of the enzyme. We conclude that l-Arg transport across RBC membrane is impaired and arginase-mediated l-Arg consumption enhanced by free heme. This could contribute to reduced NO production in severe malaria.

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Recombinant Gene Transfer of Endothelial Nitric Oxide Synthase Augments Coronary Artery Relaxations During Hypoxia

Circulation ◽

10.1161/circ.100.suppl_2.ii-335 ◽

1999 ◽

Vol 100 (suppl_2) ◽

Author(s):

David G. Cable ◽

Vincent J. Pompili ◽

Timothy O’Brien ◽

Hartzell V. Schaff

Keyword(s):

Nitric Oxide ◽

Coronary Artery ◽

Nitric Oxide Synthase ◽

Gene Transfer ◽

Coronary Arteries ◽

Endothelial Nitric Oxide Synthase ◽

No Production ◽

Viral Control ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Background —Coronary arteries respond to hypoxia with transient relaxations, which increases coronary blood flow, in part, by release of nitric oxide. We hypothesized that increased expression of nitric oxide synthase might further augment blood vessel relaxation during hypoxia. The present study examined the effect of adenovirus-mediated transfer of bovine endothelial nitric oxide synthase (eNOS) on hypoxia-induced transient relaxations in canine coronary arteries. Methods and Results —Paired segments of coronary arteries were exposed to vehicle (phosphate-buffered saline with albumin) or an adenovirus encoding either E coli β-galactosidase (Ad.CMVLacZ, viral control; 10 10 pfu/mL) or eNOS (Ad.CMVeNOS; 10 10 pfu/mL) for 2 hours at 37°C. Immunohistochemistry with a monoclonal antibody specific for eNOS documented both endothelial and adventitial expression in Ad.CMVeNOS arteries, whereas vehicle and viral controls demonstrated only constitutive expression. Levels of cGMP were increased 5-fold in Ad.CMVeNOS arteries compared with controls. In arteries exposed to Ad.CMVeNOS, maximum contraction to prostaglandin F 2α was reduced compared with viral controls, and this effect was eliminated by pretreatment with a competitive inhibitor of eNOS ( N G -monomethyl- l -arginine, 10 −3 mol/L). Hypoxia-induced transient relaxation (95% N 2 -5% CO 2 ) in Ad.CMVeNOS arteries (45.2±8.8%, n=6) was augmented compared with vehicle (26.3±6.0%) or viral (27.2±7.1%) controls. Conclusions —Adenovirus-mediated gene transfer of nitric oxide synthase reduces receptor-dependent contractions and augments hypoxia-induced relaxations in canine coronary arteries; this method of augmentation of NO production might be advantageous for reduction of coronary artery vasospasm.

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