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1.  Reperfusion after acute coronary occlusion in dogs impairs endothelium-dependent relaxation to acetylcholine and augments contractile reactivity in vitro. 
Journal of Clinical Investigation  1987;79(1):265-274.
Endothelial injury may contribute to the augmented coronary vascular tone seen in myocardial ischemia by impairing endothelial production or release of vasodilators. In vitro reactivity of arterial rings was studied after 60 min of coronary occlusion and 60 min of reperfusion in anesthetized dogs. Ischemia without reperfusion blunted contractile reactivity to potassium chloride (KCl), whereas ischemia plus reperfusion augmented contractile responses to both KCl and ergonovine. The response to acetylcholine, an endothelium-dependent vasodilator, was abolished in reperfused arteries, whereas the response to nitroprusside, an endothelium-independent vasodilator, was intact. Verapamil pretreatment restored KCl contractile responses to normal in reperfused coronary rings and partially restored endothelium-dependent relaxation. Electron microscopy revealed a nondenuding epicardial coronary endothelial injury in reperfused arteries. These data support the hypothesis that reperfusion of ischemic myocardium augments reactivity to vasoconstrictor agents by causing endothelial cell damage, excessive calcium influx, and loss of modulating vasodilator function.
Images
PMCID: PMC424037  PMID: 3793926
2.  Nitrite Regulates Hypoxic Vasodilation via Myoglobin–Dependent Nitric Oxide Generation 
Circulation  2012;126(3):325-334.
Background
Hypoxic vasodilation is a physiological response to low oxygen (O2) tension that increases blood supply to match metabolic demands. While this response has been characterized for more than 100 years, the underlying hypoxic sensing and effector signaling mechanisms remain uncertain. We have shown that deoxygenated myoglobin (deoxyMb) in the heart can reduce nitrite to nitric oxide (NO˙) and thereby contribute to cardiomyocyte NO˙ signaling during ischemia. Based on recent observations that Mb is expressed in the vasculature of hypoxia-tolerant fish, we hypothesized that endogenous nitrite may contribute to physiological hypoxic vasodilation via reactions with vascular Mb to form NO˙.
Methods and Results
We here show that Mb is expressed in vascular smooth muscle and contributes significantly to nitrite-dependent hypoxic vasodilation in vivo and ex vivo. The generation of NO˙ from nitrite reduction by deoxyMb activates canonical soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) signaling pathways. In vivo and ex vivo vasodilation responses, the reduction of nitrite to NO˙ and the subsequent signal transduction mechanisms were all significantly impaired in mice without myoglobin (Mb−/−). Hypoxic vasodilation studies in Mb, endothelial and inducible NO synthase knockout models (eNOS−/−, iNOS−/−) suggest that only Mb contributes to systemic hypoxic vasodilatory responses in mice.
Conclusions
Endogenous nitrite is a physiological effector of hypoxic vasodilation. Its reduction to NO˙ via the heme globin Mb enhances blood flow and matches O2 supply to increased metabolic demands under hypoxic conditions.
doi:10.1161/CIRCULATIONAHA.111.087155
PMCID: PMC3410747  PMID: 22685116
hypoxic vasodilation; myoglobin; nitrite
3.  Hypoxia induces endothelin gene expression and secretion in cultured human endothelium. 
Journal of Clinical Investigation  1991;88(3):1054-1057.
Hypoxia in vivo is associated with constriction of the distal vasculature in the lung. Uniquely situated at the interface between blood and the vessel wall proper, the vascular endothelium may release vasoactive mediators in the setting of hypoxia. Endothelin-1 is a potent vasoconstrictor released by endothelial cells that could function as a paracrine regulator of vascular tone. We found that physiologic low oxygen tension (PO2 = 30 Torr) increased endothelin secretion from cultured human endothelial cells four to eightfold above the secretion rate at ambient oxygen tension. This increase in secretion was accompanied by a corresponding increase in the transcriptional rate of the preproendothelin gene resulting in increased steady-state mRNA levels of preproendothelin. In contrast, the transcription of a number of other growth-factor-encoding genes, including transforming growth factor-beta, was unaffected by hypoxia. Endothelin transcript production increased within 1 h of hypoxia and persisted for at least 48 h. In addition, the stimulatory effects of low oxygen tension on endothelin mRNA levels were reversible upon reexposure to 21% oxygen environments. These findings suggest a role for endothelin in the control of regional blood flow in the vasculature in response to changes in oxygen tension.
Images
PMCID: PMC295521  PMID: 1885767
4.  Impaired Vascular Regulation in Patients with Obstructive Sleep Apnea 
Rationale: Impaired endothelium-dependent vasodilation has been documented in patients with sleep apnea. This impairment may result in blood flow dysregulation during apnea-induced fluctuations in arterial blood gases.
Objectives: To test the hypothesis that hypoxic and hypercapnic vasodilation in the forearm and cerebral circulation are impaired in patients with sleep apnea.
Methods: We exposed 20 patients with moderate to severe sleep apnea and 20 control subjects, to isocapnic hypoxia and hyperoxic hypercapnia. A subset of 14 patients was restudied after treatment with continuous positive airway pressure.
Measurements and Main Results: Cerebral flow velocity (transcranial Doppler), forearm blood flow (venous occlusion plethysmography), arterial pressure (automated sphygmomanometry), oxygen saturation (pulse oximetry), ventilation (pneumotachograph), and end-tidal oxygen and carbon dioxide tensions (expired gas analysis) were measured during three levels of hypoxia and two levels of hypercapnia. Cerebral vasodilator responses to hypoxia (−0.65 ± 0.44 vs. −1.02 ± 0.72 [mean ± SD] units/% saturation; P = 0.03) and hypercapnia (2.01 ± 0.88 vs. 2.57 ± 0.89 units/mm Hg; P = 0.03) were smaller in patients versus control subjects. Hypoxic vasodilation in the forearm was also attenuated (−0.05 ± 0.09 vs. −0.10 ± 0.09 unit/% saturation; P = 0.04). Hypercapnia did not elicit forearm vasodilation in either group. Twelve weeks of continuous positive airway pressure treatment enhanced hypoxic vasodilation in the cerebral circulation (−0.83 ± 0.32 vs. −0.46 ± 0.29 units/% saturation; P = 0.01) and forearm (−0.19 ± 0.15 vs. −0.02 ± 0.08 units/% saturation; P = 0.003), and hypercapnic vasodilation in the brain showed a trend toward improvement (2.24 ± 0.78 vs. 1.76 ± 0.64 units/mm Hg; P = 0.06).
Conclusions: Vasodilator responses to chemical stimuli in the cerebral circulation and the forearm are impaired in many patients with obstructive sleep apnea. Some of these impairments can be improved with continuous positive airway pressure.
doi:10.1164/rccm.200903-0393OC
PMCID: PMC2784418  PMID: 19745203
hypoxia; sleep; vasodilation; cerebral vascular circulation; regional blood flow
5.  Hypoxia Impairs Vasodilation in the Lung 
Journal of Clinical Investigation  1981;67(1):238-246.
Alveolar hypoxia causes pulmonary vasoconstriction; we investigated whether hypoxia could also impair pulmonary vasodilation. We found in the isolated perfused rat lung a delay in vasodilation following agonist-induced vasoconstriction. The delay was not due to erythrocyte or plasma factors, or to alterations in base-line lung perfusion pressure. Pretreating lungs with arachidonic acid abolished hypoxic vasoconstriction, but did not influence the hypoxia-induced impairment of vasodilation after angiotensin II, bradykinin, or serotonin pressor responses. Progressive slowing of vasodilation followed angiotensin II-induced constriction as the lung oxygen tension fell progressively below 60 Torr. KCl, which is not metabolized by the lung, caused vasoconstriction; the subsequent vasodilation time was delayed during hypoxia. However, catecholamine depletion in the lungs abolished this hypoxic vasodilation delay after KCl-induced vasoconstriction. In lungs from high altitude rats, the hypoxia-induced vasodilation impairment after an angiotensin II pressor response was markedly less than it was in lungs from low altitude rats. We conclude from these studies that (a) hypoxia impairs vasodilation of rat lung vessels following constriction induced by angiotensin II, serotonin, bradykinin, or KCl, (b) hypoxia slows vasodilation following KCl-induced vasoconstriction probably by altering lung handling of norepinephrine, (c) the effect of hypoxia on vasodilation is not dependent on its constricting effect on lung vessels, (d) high altitude acclimation moderates the effect of acute hypoxia on vasodilation, and (e) the hypoxic impairment of vasodilation is possibly the result of an altered rate of dissociation of agonists from their membrane receptors on the vascular smooth muscle.
PMCID: PMC371593  PMID: 7451651
6.  Antioxidant and Vasodilatory Effects of Heme Oxygenase on Mesenteric Vasoreactivity Following Chronic Hypoxia 
Objective
Chronic hypoxia (CH) results in impaired vasoconstriction associated with increased expression of heme oxygenase (HO). We hypothesized that enhanced HO activity minimizes reactive oxygen species (ROS) in arteries from CH rats, thereby normalizing endothelium-dependent vasodilation and concurrently produces carbon monoxide (CO), resulting in tonic vasodilation.
Methods
ROS were quantified in mesenteric arteries from control and CH Sprague-Dawley rats. Reactivity to the endothelium-dependent vasodilator, acetylcholine (ACh), and the vasoconstrictor, phenylephrine (PE), were also assessed.
Results
Basal ROS levels did not differ between groups and were similarly increased by HO inhibition. In contrast, catalase inhibition increased ROS in CH rats only. Vasodilatory responses to ACh were not different between groups. Combined inhibition of catalase and HO impaired PE-induced vasoconstriction in both groups. CH-induced impairment of vasoconstriction was reversed by either catalase or HO inhibition supporting the protective roles of the HO and catalase pathways following CH. Increased vascular smooth muscle calcium was observed with inhibition in the CH group, suggesting that catalase and HO-derived CO elicit reduced calcium influx, leading to the impaired vasoconstriction.
Conclusions
Our data suggest that although the HO pathway is an important antioxidant influence, impaired vasoconstriction following CH appears to be due to effects of ROS and HO-derived CO.
doi:10.1080/10739680802342077
PMCID: PMC3003603  PMID: 19031291
hypoxia; heme oxygenase; carbon monoxide; oxidative stress; mesenteric arteries
7.  HSP20 phosphorylation and interstitial metabolites in hypoxia-induced dilation of swine coronary arteries 
Acta physiologica Scandinavica  2005;184(1):37-44.
Objective
Hypoxia induces coronary artery dilation, but the responsible mechanism is largely unknown. Many stimuli induce arterial smooth muscle relaxation by reducing ser19-myosin regulatory light chain (MLC) phosphorylation. Other stimuli can induce smooth muscle relaxation without reductions in ser19-MLC phosphorylation. This form of relaxation has been termed force suppression and appears to be associated with heat shock protein 20 (HSP20) phosphorylation on ser16. We investigated whether hypoxia-induced sustained dilation in swine coronary arteries was promoted without ser19-MLC dephosphorylation and associated with ser16-HSP20 phosphorylation. Nitroglycerin vasodilation served as control.
Methods
In a pressure myograph, the tunica media of intact pre-contracted (PGF2α;10-5 m) porcine coronary artery segments were cannulated using a microdialysis catheter. Diameter responses and interstitial lactate/pyruvate ratios were studied during 90 min hypoxia, hypoxia + reoxygenation (60 min), nitroglycerin (100 μm, 90 min), and nitroglycerin + wash-out (60 min). The arterial segments were snap-frozen and analysed for ser16-HSP20 phosphorylation and ser19-MLC phosphorylation.
Results
The normalized diameter responses to hypoxia (6.1 ± 4.3%) and nitroglycerin (12.6 ± 1.6%) were both significantly greater than normoxic control arteries (-10.5 ± 1.8%, anova, P < 0.05). Ser16-HSP20 phosphorylation was increased with hypoxia and nitroglycerin treatment and ser16-HSP20 phosphorylation correlated with changes in diameters (n = 29, r2 = 0.64, P < 0.001). Ser19-MLC phosphorylation was not significantly altered by hypoxia. The lactate/pyruvate ratio was significantly increased in hypoxic arteries but did not correlate with diameters or ser16-HSP20 phosphorylation.
Conclusion
Ser16-HSP20 phosphorylation is a potential regulator of hypoxia-induced dilation in coronary arteries.
doi:10.1111/j.1365-201X.2005.01426.x
PMCID: PMC2276684  PMID: 15847642
hypoxia; metabolism; microdialysis; signal transduction; smooth muscle; vasodilation
8.  Long Term Administration of Endothelin Receptor Antagonist Improves Coronary Endothelial Function in Patients with Early Atherosclerosis 
Circulation  2010;122(10):958-966.
Background
Endothelin (ET-1) is one of the most potent vasoconstrictors, and plays a seminal role in the pathogenesis of atherosclerosis. The current study was designed to test the hypothesis that long term treatment with an endothelin-A (ETA) receptor antagonist improves coronary endothelial function in patients with early coronary atherosclerosis.
Methods and Results
Forty seven patients with multiple cardiovascular risk factors, nonobstructive coronary artery disease and coronary endothelial dysfunction were randomized in a double-blind manner to either the ETA receptor antagonist Atrasentan (10mg) or placebo for six months. Coronary endothelium-dependent vasodilation was examined by infusing acetylcholine (ACh10−6 ml/L to 10−4 mol/L) in the left anterior descending coronary artery (LAD). NG-monomethyl-L-arginine (L-NMMA) was administered to a sub group of patients. Endothelium independent coronary flow reserve (CFR) was examined using intracoronary adenosine and nitroglycerin.
Baseline characteristics and incidence of adverse effects were similar between the two groups. There was a significant improvement in percent change of coronary blood flow (% Δ CBF) in response to ACh at six months from baseline in the Atrasentan group as compared to the placebo group (39.67 % (23.23, 68.21) vs.−2.22 % (−27.37, 15.28), P<0.001). No significant difference in the percent change of coronary artery diameter or change in coronary flow reserve (Δ CFR) was demonstrated. CBF, coronary artery diameter and the effect of L-NMMA were similar between the groups at baseline and at six months.
Conclusion
This study demonstrates that six month treatment with Atrasentan improves coronary microvascular endothelial function and support the role of the endogenous endothelin system in the regulation of endothelial function in early atherosclerosis in humans.
doi:10.1161/CIRCULATIONAHA.110.967406
PMCID: PMC2946239  PMID: 20733096
endothelin-1 (ET-1); Atrasentan; endothelium dependent coronary blood flow; endothelium independent coronary flow reserve; coronary artery diameter
9.  C-Reactive Protein Impairs Coronary Arteriolar Dilation to Prostacyclin Synthase Activation: Role of Peroxynitrite 
Endothelium-derived vasodilators, i.e., nitric oxide (NO), prostacyclin (PGI2) and prostaglandin E2 (PGE2), play important roles in maintaining cardiovascular homeostasis. C-reactive protein (CRP), a biomarker of inflammation and cardiovascular disease, has been shown to inhibit NO-mediated vasodilation. The goal of this study was to determine whether CRP also affects endothelial arachidonic acid (AA)-prostanoid pathways for vasomotor regulation. Porcine coronary arterioles were isolated and pressurized for vasomotor study, as well as for molecular and biochemical analysis. AA elicited endothelium-dependent vasodilation and PGI2 release. PGI2 synthase (PGI2-S) inhibitor trans-2-phenyl cyclopropylamine blocked vasodilation to AA but not to serotonin (endothelium-dependent NO-mediated vasodilator). Intraluminal administration of a pathophysiological level of CRP (7 μg/mL, 60 minutes) attenuated vasodilations to serotonin and AA but not to nitroprusside, exogenous PGI2, or hydrogen peroxide (endothelium-dependent PGE2 activator). CRP also reduced basal NO production, caused tyrosine nitration of endothelial PGI2-S, and inhibited AA-stimulated PGI2 release from arterioles. Peroxynitrite scavenger urate failed to restore serotonin dilation, but preserved AA-stimulated PGI2 release/dilation and prevented PGI2-S nitration. NO synthase inhibitor L-NAME and superoxide scavenger TEMPOL also protected AA-induced vasodilation. Collectively, our results suggest that CRP stimulates superoxide production and the subsequent formation of peroxynitrite from basal released NO compromises PGI2 synthesis, and thus endothelium-dependent PGI2-mediated dilation, by inhibiting PGI2-S activity through tyrosine nitration. By impairing PGI2-S function, and thus PGI2 release, CRP could promote endothelial dysfunction and participate in the development of coronary artery disease.
doi:10.1016/j.yjmcc.2009.04.015
PMCID: PMC2703687  PMID: 19410579
prostaglandins; microcirculation; free radicals; vasodilation
10.  Depolarization of Mitochondria in Endothelial Cells Promotes Cerebral Vascular Vasodilation by Activation of Nitric Oxide Synthase 
Objective
Mitochondrial depolarization following ATP-sensitive potassium (mitoKATP) channel activation has been shown to induce cerebral vasodilation by the generation of ‘calcium sparks’ in smooth muscle. It is unclear, however, if mitochondrial depolarization in endothelial cells is capable of promoting vasodilation by releasing vasoactive factors. Therefore, we studied the effect of endothelial mitochondrial depolarization by mitoKATP channel activators, BMS-191095 (BMS) and diazoxide, on endothelium-dependent vasodilation.
Methods and Results
Diameter studies in isolated rat cerebral arteries showed BMS and diazoxide induced vasodilations that were diminished by endothelial denudation. Mitochondrial depolarization-induced vasodilation was reduced by inhibition of mitoKATP channels, phosphoinositide-3 kinase (PI3K) or nitric oxide synthase (NOS). Scavenging of reactive oxygen species (ROS), however, diminished vasodilation induced by diazoxide but not by BMS. Fluorescence studies in cultured rat brain microvascular endothelial cells (CMVECs) showed that BMS elicited mitochondrial depolarization, and enhanced nitric oxide (NO) production; diazoxide exhibited largely similar effects, but unlike BMS, increased mitochondrial ROS production. Measurements of intracellular calcium ([Ca2+]i) in CMVECs and arteries showed that both diazoxide and BMS increased endothelial [Ca2+]i. Western blot analyses revealed increased phosphorylation of Akt and endothelial NOS (eNOS) by BMS and diazoxide. Increased phosphorylation of eNOS by diazoxide was abolished by PI3K inhibition. Electron spin resonance spectroscopy confirmed vascular NO generation in response to diazoxide and BMS.
Conclusions
Pharmacological depolarization of endothelial mitochondria promotes activation of eNOS by dual pathways involving increased [Ca2+]i as well as by PI3K-Akt-induced eNOS phosphorylation. Both mitochondrial ROS-dependent and –independent mechanisms mediate activation of eNOS by endothelial mitochondrial depolarization.
doi:10.1161/ATVBAHA.112.300560
PMCID: PMC3628534  PMID: 23329133
mitochondrial ATP-sensitive potassium channels; diazoxide; BMS-191095; membrane potential and superoxide
11.  Preserved Coronary Endothelial Function by Inhibition of δ Protein Kinase C in a Porcine Acute Myocardial Infarction Model 
International journal of cardiology  2008;133(2):256-259.
Background
Previous studies demonstrate impairment of endothelial-dependent vasodilation after ischemia/reperfusion (I/R). Though we have demonstrated that inhibition of δ protein kinase C (δPKC) at reperfusion reduces myocyte damage and improves cardiac function in a porcine acute myocardial infarction (AMI) model, impact of the selective δPKC inhibitor on epicardial coronary endothelial function remains unknown.
Methods
Either δPKC inhibitor (δV1-1, n=5) or saline (n=5) was infused into the left anterior descending artery at the last 1 minute of the 30-minute ischemia by balloon occlusion. In vivo responses to bradykinin (endothelium-dependent vasodilator) or nitroglycerin (endothelium-independent vasodilator) were analyzed at 24 h after I/R using intravascular ultrasound. Vascular responses were calculated as the ratio of vessel area at each time point (30, 60, 90 and 120 seconds after the infusion), divided by values at baseline (before the infusion).
Results
In control pigs, endothelial-dependent vasodilation following bradykinin infusion in infarct-related epicardial coronary artery was impaired, whereas in δPKC inhibitor treated-pigs the endothelial-dependent vasodilation was preserved. Nitroglycerin infusion caused similar vasodilatory responses in the both groups.
Conclusions
This is the first demonstration that a δPKC inhibitor preserves vasodilator capacity in epicardial coronary arteries in an in vivo porcine AMI model. Because endothelial dysfunction correlates with worse outcome in patients with AMI, this preserved endothelial function in epicardial coronary arteries might result in a better clinical outcome.
doi:10.1016/j.ijcard.2007.11.021
PMCID: PMC2688394  PMID: 18242734
ultrasonography; angioplasty; myocardial infarction; protein kinases; endothelium
12.  Endothelin-1, aging and hypertension 
Current opinion in cardiology  2008;23(4):350-355.
Purpose of review
Endothelin-1 system activation plays an important role in the etiology of atherosclerotic vascular disease. Aging and hypertension are two independent cardiovascular risk factors that have been shown to exhibit increased endothelin-1 system activation. This review focuses on the cardiovascular effects of the endothelin system, its relation to aging and hypertension, as well as potential treatment options.
Recent findings
Many of the cardiovascular complications associated with both aging and hypertension are attributable, in part, to endothelial dysfunction, particularly vasomotor dysregulation. To date most studies have focused on the effects of aging and hypertension on endothelium-dependent nitric oxide-mediated vasodilation. However, endothelin-1-mediated vasoconstrictor tone increases with age and contributes to the pathogenesis of hypertension. Pharmacologic approaches to reduce endothelin-1 system activation have produced limited results and are largely disease-specific. In contrast, regular aerobic exercise has been shown to be extremely effective at reducing endothelin-1 system activity.
Summary
Both aging and hypertension represent important cardiovascular disease risk factors that are characterized by increased endothelin-1-mediated vasoconstrictor tone. Future studies are needed to elucidate pharmacologic options for reducing endothelin-1 system activity especially in older hypertensive adults, though regular aerobic exercise must continue to be a point of emphasis for maintaining/improving vascular health.
doi:10.1097/HCO.0b013e328302f3c6
PMCID: PMC2430763  PMID: 18520719
aging; endothelin-1; endothelium; hypertension
13.  Pivotal role of Cu,Zn-superoxide dismutase in endothelium-dependent hyperpolarization 
Journal of Clinical Investigation  2003;112(12):1871-1879.
The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating factors, including prostacyclin, NO, and endothelium-derived hyperpolarizing factor (EDHF). We have recently identified that endothelium-derived H2O2 is an EDHF in mesenteric arteries of mice and humans and in porcine coronary microvessels. However, the mechanism for the endothelial production of H2O2 as an EDHF remains to be elucidated. In this study, we tested our hypothesis that Cu,Zn-superoxide dismutase (Cu,Zn-SOD) plays a pivotal role in endothelium-dependent hyperpolarization, using control and Cu,Zn-SOD–/– mice. In mesenteric arteries, EDHF-mediated relaxations and hyperpolarizations were significantly reduced in Cu,Zn-SOD–/– mice with no inhibitory effect of catalase, while endothelium-independent relaxations and hyperpolarizations were preserved. Endothelial H2O2 production also was significantly reduced in Cu,Zn-SOD–/– mice. In Langendorff isolated heart, bradykinin-induced increase in coronary flow was significantly reduced in Cu,Zn-SOD–/– mice, again with no inhibitory effect of catalase. The exogenous SOD mimetic tempol significantly improved EDHF-mediated relaxations and hyperpolarizations and coronary flow response in Cu,Zn-SOD–/– mice. These results prove the novel concept that endothelial Cu,Zn-SOD plays an important role as an “EDHF synthase” in mice, in addition to its classical role to scavenge superoxide anions.
doi:10.1172/JCI200319351
PMCID: PMC296996  PMID: 14679182
14.  Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery. Alterations after prolonged hypoxia in the rat. 
Journal of Clinical Investigation  1991;88(2):447-455.
Prostacyclin is a critical mediator of structure and function in the pulmonary circulation, causing both the inhibition of vascular smooth muscle growth and vasodilation via the stimulation of adenylate cyclase. To examine the potential role of alterations in prostacyclin production or mechanism of action in chronic hypoxic pulmonary hypertension, we determined the effects of prolonged (7 d) in vivo hypoxia on in vitro prostacyclin synthesis and mediation of adenylate cyclase activity in rat main pulmonary arteries. In control arteries prostacyclin production exceeded that of prostaglandin (PG) E2 by 25-fold, with 42% originating from the endothelium. Studies utilizing indomethacin revealed that endogenous prostaglandins mediate at least 69% of basal adenylate cyclase activity. Prostacyclin-stimulated enzyme activity was enhanced by exogenous GTP, indicating that this is a receptor-mediated process involving G protein amplification. Comparable dose-related responses to prostacyclin and PGE2 suggest that these agents may activate a common receptor. After 7 d of in vivo hypoxia there was a 2.7-fold increase in in vitro prostacyclin production, with equivalent increases in synthesis in the endothelium and vascular smooth muscle. However, despite this increase there was no change in basal adenylate cyclase activity, and this was associated with attenuated sensitivity of the enzyme to prostacyclin stimulation. Concomitant diminution of the response to beta-adrenergic stimulation, with previously-demonstrated beta receptor downregulation and unaltered postreceptor-mediated activity, suggests that the blunted response to prostacyclin is due to receptor downregulation. Parallel studies of the thoracic aorta indicated that these changes are specific to the pulmonary artery. It is postulated that attenuation of the response of adenylate cyclase to prostacyclin may contribute to the structural changes and hypertension observed in the pulmonary vasculature of the rat with chronic hypoxia.
PMCID: PMC295357  PMID: 1864958
15.  Role of Insulin Resistance in Endothelial Dysfunction 
Insulin resistance is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular diseases. Insulin exerts pro- and anti-atherogenic actions on the vasculature. The balance between nitric oxide (NO)-dependent vasodilator actions and endothelin-1- dependent vasoconstrictor actions of insulin is regulated by phosphatidylinositol 3-kinase-dependent (PI3K) - and mitogen-activated protein kinase (MAPK)-dependent signaling in vascular endothelium, respectively. During insulin-resistant conditions, pathway-specific impairment in PI3K-dependent signaling may cause imbalance between production of NO and secretion of endothelin-1 and lead to endothelial dysfunction. Insulin sensitizers that target pathway-selective impairment in insulin signaling are known to improve endothelial dysfunction. In this review, we discuss the cellular mechanisms in the endothelium underlying vascular actions of insulin, the role of insulin resistance in mediating endothelial dysfunction, and the effect of insulin sensitizers in restoring the balance in pro- and anti-atherogenic actions of insulin.
doi:10.1007/s11154-012-9229-1
PMCID: PMC3594115  PMID: 23306778
Nitric Oxide; Insulin Resistance; Endothelial Dysfunction; Metabolic Syndrome
16.  High arterial compliance in cirrhosis is related to low adrenaline and elevated circulating calcitonin gene related peptide but not to activated vasoconstrictor systems 
Gut  2001;49(1):112-118.
BACKGROUND AND AIMS—Static and dynamic functions of the wall of large arteries are largely unknown in cirrhosis in vivo. The present study was undertaken to determine arterial compliance (COMPart) in relation to vasodilator and vasoconstrictor systems in patients with cirrhosis. In addition, vasoactivity was manipulated by inhalation of oxygen.
STUDY POPULATION AND METHODS—In 20 patients with alcoholic cirrhosis and 12 controls we determined COMPart (stroke volume relative to pulse pressure), cardiac output, plasma volume, systemic vascular resistance, central circulation time, plasma catecholamines, renin activity, endothelin-1, and calcitonin gene related peptide (CGRP) at baseline and during oxygen inhalation.
RESULTS—COMPart was significantly increased in cirrhotic patients compared with controls (1.32 v 1.06 ml/mm Hg; p< 0.05) and inversely related to plasma adrenaline levels (r=−0.53; p<0.02) but positively related to circulating levels of CGRP (r=0.58; p<0.01). No significant relation was found for plasma noradrenaline, renin activity, or endothelin-1. COMPart was positively related to plasma volume (r=0.50; p<0.02) and inversely to systemic vascular resistance (r=−0.69; p<0.001) and central circulation time (r=−0.49; p<0.02). During oxygen inhalation, COMPart decreased (−13%; p<0.005) and systemic vascular resistance increased (+10%; p<0.001) towards normal values without significant changes in mean arterial pressure. Plasma adrenaline (−16%; p<0.01) decreased and the relation to COMPart disappeared. The relation of COMPart to CGRP and circulatory variables remained unchanged.
CONCLUSION—Elevated arterial compliance in cirrhosis is related to low adrenaline, high CGRP, and systemic hyperdynamics but not to indicators of the activated vasoconstrictor systems (noradrenaline, renin, endothelin-1). Thus the altered static and dynamic characteristics of the wall of large arteries are intimately associated with circulatory and vasodilatory derangement in cirrhosis but biomanipulation indicates that the changes are, at least in part, reversible during isobaric conditions.


Keywords: arterial compliance; calcitonin gene related peptide; catecholamines; endothelin 1; hypoxia; renin; systemic vascular resistance
doi:10.1136/gut.49.1.112
PMCID: PMC1728353  PMID: 11413119
17.  Evidence for altered vascular responses to exogenous endothelin-1 in patients with advanced cirrhosis with restoration of the normal vasoconstrictor response following successful liver transplantation 
Gut  2003;52(10):1505-1510.
Background and aims: There is evidence that dampened responses to endogenous vasoconstrictors contribute to the hyperdynamic circulation that is characteristic of advanced cirrhosis. The aim of this study was to determine whether there is an altered vascular responsiveness to the endothelium derived constricting factor endothelin-1 (ET-1) in patients with decompensated chronic liver disease which might contribute to this abnormal circulatory state, and whether normal endothelin responses are restored following liver transplantation.
Methods: Using forearm plethysmography, we studied the vascular response to an intra-arterial ET-1 infusion in six patients with end stage cirrhosis, before and after liver transplantation, compared with six normal control subjects. Responses to the selective endothelin A (ETA) receptor subtype antagonist, BQ123, were also examined.
Results: The forearm vessels of patients with cirrhosis vasodilated in response to ET-1 infusion while in healthy controls a marked vasoconstriction response was observed (p<0.0001, area under the curve time-blood flow was normal compared with the cirrhosis groups, ANOVA). Prior to commencement of liver transplant surgery, cirrhotic patients were confirmed to have a hyperdynamic circulation with a high cardiac index (4.07 (0.23) l/min/m2 (normal range 2.8–3.6 l/min/m2)) and low systemic vascular resistance index (1284 (115) dyn×s/cm5/m2 (normal range 1760–2600 dyn×s/cm5/m2)). Following transplantation, normal vasoconstrictor responses to ET-1 were restored. Responses to BQ123 were not different in patients with advanced cirrhosis compared with controls.
Conclusion: In patients with end stage cirrhosis, ET-1 produces vasodilatation at a dose that causes marked vasoconstriction in normal control subjects. This effect is not attributable to impairment of ETA receptor responses. Our findings suggest that altered endothelin responses may contribute to the generalised dilatation of the circulation that occurs in patients with advanced liver disease.
PMCID: PMC1773833  PMID: 12970146
endothelin; forearm plethysmography; cirrhosis; liver transplantation
18.  Enhanced External Counterpulsation Improves Peripheral Artery Flow Mediated Dilation in Patients With Chronic Angina: A Randomized Sham-Controlled Study 
Circulation  2010;122(16):1612-1620.
Background
Mechanisms responsible for anti-ischemic benefits of enhanced external counterpulsation (EECP) remain unknown. This was the first randomized, sham controlled study to investigate the extra-cardiac effects of EECP on peripheral artery flow mediated dilation.
Methods and Results
Forty-two symptomatic patients with coronary artery disease (CAD) were randomized (2:1 ratio) to either 35 1-hr sessions of EECP (n=28) or Sham-EECP (n=14). Flow-mediated dilation of the brachial and femoral arteries was performed using ultrasound. Plasma levels of nitrate and nitrite (NOx), 6-keto prostaglandin F1α (PGF1α), endothelin-1 (ET-1), asymmetric dimethylarginine (ADMA), tumor necrosis factor–α (TNF-α), monocyte chemoattractant protein–1 (MCP-1), vascular cell adhesion molecule (sVCAM), C-reactive protein (hsCRP), and 8-Isoprostane (8-iso-PGF2α) were measured. EECP increased brachial (+51% vs. +2%) and femoral (+30% vs. +3%) artery flow mediated dilation, the nitric oxide turnover/production marker NOx (+36% vs. +2%) and PGF1α (+71% vs. +1%), while decreasing ET-1 (-25% vs. +5%) and the nitric oxide synthase inhibitor ADMA (-28% vs. +0.2%) in treatment vs. sham, respectively (all p<0.05). EECP decreased the pro-inflammatory cytokines TNF-α (-16% vs. +12%), MCP-1 (-13% vs. +0.2%), sVCAM-1 (-6% vs. +1%), hsCRP (-32% vs. +5%), and the lipid peroxidation marker 8-iso-PGF2α (-21% vs. +1.3%) in treatment vs. sham, respectively (all p<0.05). EECP reduced angina classification (-62% vs 0%; p<0.001) in treatment vs. sham, respectively.
Conclusions
Our findings provide novel mechanistic evidence that EECP has a beneficial effect on peripheral artery flow mediated dilation and endothelial-derived vasoactive agents in patients with symptomatic CAD.
doi:10.1161/CIRCULATIONAHA.109.923482
PMCID: PMC2963100  PMID: 20921442
angina; nitric oxide; endothelin; inflammation; vasodilation
19.  Hypoxia–Reoxygenation Triggers Coronary Vasospasm in Isolated Bovine Coronary Arteries via Tyrosine Nitration of Prostacyclin Synthase 
The role of peroxynitrite in hypoxia–reoxygenation-induced coronary vasospasm was investigated in isolated bovine coronary arteries. Hypoxia–reoxygenation selectively blunted prostacyclin (PGI2)-dependent vasorelaxation and elicited a sustained vasoconstriction that was blocked by a cyclooxygenase inhibitor, indomethacin, and SQ29548, a thromboxane (Tx)A2/prostaglandin H2 receptor antagonist, but not by CGS13080, a TxA2 synthase blocker. The inactivation of PGI2 synthase, as evidenced by suppressed 6-keto-PGF1α release and a decreased conversion of 14C-prostaglandin H2 into 6-keto-PGF1α, was paralleled by an increased nitration in both vascular endothelium and smooth muscle of hypoxia–reoxygenation-exposed vessels. The administration of the nitric oxide (NO) synthase inhibitors as well as polyethylene-glycolated superoxide dismutase abolished the vasospasm by preventing the inactivation and nitration of PGI2 synthase, suggesting that peroxynitrite was implicated. Moreover, concomitant administration to the organ baths of the two precursors of peroxynitrite, superoxide, and NO mimicked the effects of hypoxia–reoxygenation, although none of them were effective when given separately. We conclude that hypoxia–reoxygenation elicits the formation of superoxide, which causes loss of the vasodilatory action of NO and at the same time yields peroxynitrite. Subsequently, peroxynitrite nitrates and inactivates PGI2 synthase, leaving unmetabolized prostaglandin H2, which causes vasospasm, platelet aggregation, and thrombus formation via the TxA2/prostaglandin H2 receptor.
PMCID: PMC2195551  PMID: 10429677
peroxynitrite; nitric oxide; superoxide anions; prostaglandin; thromboxane A2/prostaglandin H2 receptor
20.  Increased Nitric Oxide-Mediated Vasodilation of Bone Resistance Arteries Is Associated With Increased Trabecular Bone Volume After Endurance Training In Rats 
Bone  2009;46(3):813-819.
Old age-associated osteoporosis is related to diminished bone blood flow and impaired nitric oxide (NO)-mediated vasodilation of the bone vasculature. Endurance exercise training restores the age-associated reduction of vasodilation in numerous vascular beds, as well as improving bone properties. The purpose of this study was to determine whether functional improvements in the bone vasculature are associated with increased bone properties after an endurance training intervention. Young adult (4–6mo) and old (24–26 mo) male Fischer-344 rats remained sedentary or were trained (15 m/min walking, 15° incline, 5 days/wk, 10–12 wk). Endothelium-dependent vasodilation of the femoral principal nutrient artery (PNA) was assessed in vitro using acetylcholine (ACh) and inhibitors of NO synthase (NOS) and cyclooxygenase (COX). PNA endothelium-dependent vasodilation was greater after training by 16% in young and by 24% in old animals. The NOS-mediated contribution to endothelium-dependent vasodilation was enhanced by 77% after training in old rats. Distal femur trabecular bone volume (BV/TV, %) was lower with old age in sedentary animals (young: 27±2%, old: 23±1%; P<0.05). Exercise-induced elevations in bone and marrow blood flow and the NOS signaling pathway were associated with greater BV/TV (young trained: 34±2%, old trained: 26±1%; P<0.05) relative to sedentary groups. These data demonstrate that training-induced increases in bone properties are associated with enhanced endothelium-dependent vasodilation through a NOS signaling pathway in the bone vasculature.
doi:10.1016/j.bone.2009.10.029
PMCID: PMC2823927  PMID: 19892040
Blood Flow; Nitric Oxide; Vasculature; Exercise; Aging
21.  Circulating and Vascular Bioactive Factors during Hypertension in Pregnancy 
Current bioactive compounds  2010;6(1):60-75.
Normal pregnancy is associated with significant vascular remodeling in the uterine and systemic circulation in order to meet the metabolic demands of the mother and developing fetus. The pregnancy-associated vascular changes are largely due to alterations in the amount/activity of vascular mediators released from the endothelium, vascular smooth muscle and extracellular matrix. The endothelium releases vasodilator substances such as nitric oxide, prostacyclin and hyperpolarizing factor as well as vasoconstrictor factors such as endothelin, angiotensin II and thromboxane A2. Vascular smooth muscle contraction is mediated by intracellular free Ca2+ concentration ([Ca2+]i), and [Ca2+]i sensitization pathways such as protein kinase C, Rho-kinase and mitogen-activated protein kinase. Extracellular matrix and vascular remodeling are regulated by matrix metalloproteases. Hypertension in pregnancy and preeclampsia are major complications and life threatening conditions to both the mother and fetus, precipitated by various genetic, dietary and environmental factors. The initiating mechanism of preeclampsia and hypertension in pregnancy is unclear; however, most studies have implicated inadequate invasion of cytotrophoblasts into the uterine artery, leading to reduction in the uteroplacental perfusion pressure and placental ischemia/hypoxia. This placental hypoxic state is thought to induce the release of several circulating bioactive factors such as growth factor inhibitors, anti-angiogenic proteins, inflammatory cytokines, reactive oxygen species, hypoxia-inducible factors, and vascular receptor antibodies. Increases in the plasma levels and vascular content of these factors during pregnancy could cause an imbalance in the vascular mediators released from the endothelium, smooth muscle and extracellular matrix, and lead to severe vasoconstriction and hypertension. This review will discuss the interactions between the various circulating bioactive factors and the vascular mediators released during hypertension in pregnancy, and provide an insight into the current and future approaches in the management of preeclampsia.
doi:10.2174/157340710790711737
PMCID: PMC2856945  PMID: 20419111
cytokines; endothelium; nitric oxide; vascular smooth muscle; calcium; preeclampsia
22.  Impaired coronary microvascular dilation correlates with enhanced vascular smooth muscle MLC phosphorylation in Diabetes 
Objective
Impaired endothelium-independent vasodilation is a known consequence of type-1 and 2 diabetes, and the mechanism of impaired vasodilation is not well understood. The following study investigated the effects of type-1 and 2 diabetes in endothelial-independent vasodilation associated with coronary vascular smooth muscle (VSM) relaxation and contractile signaling mechanisms.
Methods
Type-1 diabetes was induced in Yucatan mini-swine via alloxan injection and treated with or without insulin(DM and IDM). Non-diabetic swine served as controls(ND). Expression and/or phosphorylation of determinants of VSM relaxation and contraction signaling were examined in coronary arteries and microvessels. Coronary microvessel relaxation was assessed using sodium nitroprusside(SNP). In addition, SNP-induced vasodilation and myosin light chain (MLC) phosphorylation was determined in coronary microvessels isolated from ND and type-2 diabetic human atrial appendage.
Results
Diabetic impairment in SNP-induced relaxation was completely normalized by insulin. Soluble guanylate cyclase (sGC) VSM expression decreased in both DM and IDM groups and did not correlate with vasorelaxation. Phosphorylation of MLC and myosin phosphatase increased in the DM group and MLC phosphorylation strongly correlated with impaired VSM relaxation(r=.670, p<0.01). Coronary microvessels from type-2 diabetic human patients exhibited similarly impaired vasodilation and enhanced VSM MLC phosphorylation.
Conclusions
Impaired vasodilation in type-1 diabetes correlates with enhanced VSM MLC phosphorylation. In addition, enhanced VSM MLC phosphorylation is associated with impaired vasodilation in type 2 diabetes in humans.
doi:10.1080/10739680802461950
PMCID: PMC3044647  PMID: 19152178
23.  Concentration of circulating plasma endothelin in patients with angina and normal coronary angiograms. 
British Heart Journal  1995;74(6):620-624.
BACKGROUND--Some patients with angina pectoris and normal coronary arteriograms have reduced coronary flow reserve and abnormal endothelium dependent vasodilator responses. Endothelin-1 (ET-1), a potent vasoconstrictor, is an important modulator of microvascular function and may also have algogenic properties. METHOD--Plasma ET-1 was measured in peripheral venous blood in 40 patients (30 women) (mean (SD) age 56 (8) years) with angina and normal coronary arteriograms and 21 normal controls (17 women) (mean (SD) age 53 (7) years). Patients with systemic hypertension, left ventricular hypertrophy, or coronary spasm were excluded. Plasma ET-1 was measured using radioimmunoassay. RESULTS--Thirty five patients had > or = 1 mm ST segment depression during exercise. Left bundle branch block was present in four patients at rest and in one during exercise. Mean (SD) (range) concentration of ET-1 (pg/ml) was higher in patients than in controls (3.84 (1.25) (1.97-7.42) v 2.88 (0.71) (1.57-4.48) P < 0.0001). In patients with "high" (> control mean (one SD)) ET-1 concentrations (n = 23), the time to onset of chest pain during exercise was significantly shorter (6.21 (3.9) v 9.03 (3.9) min; p = 0.01) than in patients with "low" ET-1 concentrations. Of the five patients with left bundle branch block, four had plasma ET-1 concentration > 4.0 pg/ml. CONCLUSION--Plasma endothelin is raised in patients with angina and normal coronary arteriograms and is consistent with the demonstration of endothelial dysfunction in such patients. The association between "high" plasma ET-1 and an earlier onset of chest pain during exercise suggests that endothelin may also have a role in the genesis of chest pain in patients with normal coronary arteries.
PMCID: PMC484117  PMID: 8541166
24.  Nanoparticle Inhalation Impairs Coronary Microvascular Reactivity via a Local Reactive Oxygen Species-Dependent Mechanism 
Cardiovascular toxicology  2010;10(1):27-36.
We have shown that nanoparticle inhalation impairs endothelium-dependent vasodilation in coronary arterioles. It is unknown whether local reactive oxygen species (ROS) contribute to this effect. Rats were exposed to TiO2 nanoparticles via inhalation to produce a pulmonary deposition of 10 µg. Coronary arterioles were isolated from the left anterior descending artery distribution, and responses to acetylcholine, arachidonic acid, and U46619 were assessed. Contributions of nitric oxide synthase and prostaglandin were assessed via competitive inhibition with NG-Monomethyl-L-Arginine (L-NMMA) and indomethacin. Microvascular wall ROS were quantified via dihydroethidium (DHE) fluorescence. Coronary arterioles from rats exposed to nano-TiO2 exhibited an attenuated vasodilator response to ACh, and this coincided with a 45% increase in DHE fluorescence. Coincubation with 2,2,6,6-tetramethylpiperidine-N-oxyl and catalase ameliorated impairments in ACh-induced vasodilation from nanoparticle exposed rats. Incubation with either L-NMMA or indomethacin significantly attenuated Ach-induced vasodilation in sham-control rats, but had no effect in rats exposed to nano-TiO2. Arachidonic acid induced vasoconstriction in coronary arterioles from rats exposed to nano-TiO2, but dilated arterioles from sham-control rats. These results suggest that nanoparticle exposure significantly impairs endothelium-dependent vasoreactivity in coronary arterioles, and this may be due in large part to increases in microvascular ROS. Furthermore, altered prostanoid formation may also contribute to this dysfunction. Such disturbances in coronary microvascular function may contribute to the cardiac events associated with exposure to particles in this size range.
doi:10.1007/s12012-009-9060-4
PMCID: PMC2825710  PMID: 20033351
Microcirculation; Nanoparticle; Coronary; Arteriole; Vasodilation; Titanium dioxide; Inhalation; Reactive oxygen species
25.  Endogenous adipose-derived factors diminish coronary endothelial function via inhibition of nitric oxide synthase 
Adipocytokines may be the molecular link between obesity and vascular disease. However, the effects of these factors on coronary vascular function have not been discerned. Accordingly, the goal of this investigation was to delineate the mechanisms by which endogenous adipose-derived factors affect coronary vascular endothelial function. Both isolated canine coronary arteries and coronary blood flow in anesthetized dogs were studied with and without exposure to adipose tissue. Infusion of adipose-conditioned buffer directly into the coronary circulation did not change baseline hemodynamics; however, endothelial-dependent vasodilation to bradykinin was impaired both in vitro and in vivo. Coronary vasodilation to sodium nitroprusside was unaltered by adipose tissue. Oxygen radical formation did not cause the impairment because quantified dihydroethidium staining was decreased by adipose tissue and neither a superoxide dismutase mimetic nor catalase improved endothelial function. Inhibition of nitric oxide (NO) synthase with L-NAME diminished bradykinin-mediated relaxations and eliminated the subsequent vascular effects of adipose tissue. In vitro measurement of NO demonstrated that adipose tissue exposure quickly lowered baseline NO and abolished bradykinin-induced NO production. The results indicate that adipose tissue releases factor(s) that selectively impair endothelial-dependent dilation via inhibition of NO synthase-mediated NO production.
doi:10.1080/10739680701858447
PMCID: PMC3042130  PMID: 18574744
coronary circulation; perivascular adipose tissue; vascular endothelium; adipocytokine; nitric oxide

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