Endogenous carbon monoxide is an endothelial-derived vasodilator factor in the mesenteric circulation

2003 ◽  
Vol 284 (3) ◽  
pp. H838-H845 ◽  
Author(s):  
Jay S. Naik ◽  
Theresa L. O'Donaughy ◽  
Benjimen R. Walker
Keyword(s):  
Carbon Monoxide ◽  
Cellular Localization ◽  
Vascular Reactivity ◽  
Protoporphyrin Ix ◽  
Physiological Saline ◽  
Mesenteric Arteries ◽  
Zinc Protoporphyrin ◽  
Sprague Dawley ◽  
Vasodilator Response ◽  
Enhanced Production

Chronic hypoxia (CH) is associated with both blunted agonist-induced and myogenic vascular reactivity, possibly due to an enhanced production of heme oxygenase (HO)-derived carbon monoxide (CO). However, the cellular location of the HO responsible for these effects has not been clearly established. Therefore, we examined the response to administration of the substrate for HO, heme-l-lysinate (HLL), in endothelium-intact and endothelium-denuded small mesenteric arteries from CH male Sprague-Dawley rats. Mesenteric arteries were isolated and mounted on glass cannulas, pressurized to 60 mmHg, and superfused with physiological saline solution. All experiments were performed in the presence of 100 μM N ω-nitro-l-arginine. The vasodilator response to HLL or exogenous CO was examined. HLL experiments were performed in the presence and absence of the HO inhibitor zinc protoporphyrin IX (ZnPPIX). HLL administration resulted in a dose-dependent vasodilator response that was abolished in the presence of ZnPPIX or by endothelial removal. Exogenous CO produced a vasodilator response that was independent of an intact endothelium. Cellular localization of HO was verified through immunohistochemistry in sections of the gut and aorta from CH and control animals. Staining for HO-1, HO-2, and endothelial nitric oxide synthase was confined to the endothelium. Thus we conclude that CO is a product of HO located within the endothelium.

Heme oxygenase-mediated vasodilation involves vascular smooth muscle cell hyperpolarization

2003 ◽  
Vol 285 (1) ◽  
pp. H220-H228 ◽  
Author(s):  
Jay S. Naik ◽  
Benjimen R. Walker
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Heme Oxygenase ◽  
Vascular Reactivity ◽  
Protoporphyrin Ix ◽  
Zinc Protoporphyrin ◽  
Spin Traps ◽  
Enhanced Production ◽  
Vasodilatory Response ◽  
Presence And Absence

Chronic hypoxia is associated with both blunted agonist-induced and myogenic vascular reactivity and is possibly due to an enhanced production of heme oxygenase (HO)-derived carbon monoxide (CO). However, the mechanism of endogenous CO-meditated vasodilation remains unclear. Isolated pressurized mesenteric arterioles from chronically hypoxic rats were administered the HO substrate heme-l-lysinate (HLL) in the presence or absence of iberiotoxin, 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ), ryanodine, or free radical spin traps ( N- tert-butyl-α-phenylnitrone and 4,5-dihydroxy-1,3-benzenedisulfonic acid disodium salt). The effects of HLL administration on vascular smooth muscle (VSM) membrane potential were assessed in superior mesenteric artery strips in the presence and absence of zinc protoporphyrin IX or iberiotoxin. The vasodilatory responses to exogenous CO were assessed in the presence and absence of ODQ or iberiotoxin. HLL administration produced a dose-dependent vasodilatory response that was nearly eliminated in the presence of iberiotoxin. Neither ODQ, spin traps, nor ryanodine altered the vasodilatory response to HLL, although ODQ abolished the vasodilatory response to S-nitroso- N-acetyl-penicillamine. HLL administration produced a zinc protoporphyrin IX- and iberiotoxin-sensitive VSM cell hyperpolarization. Iberiotoxin and ODQ inhibited the vasodilatory response to exogenous CO. Thus the vasodilatory response to endogenous CO involves cGMP-independent activation of VSM large-conductance Ca2+-activated K+ channels and does not likely involve the formation of Ca2+ sparks emanating from ryanodine-sensitive stores.

Role of CO in attenuated vasoconstrictor reactivity of mesenteric resistance arteries after chronic hypoxia

2002 ◽  
Vol 282 (1) ◽  
pp. H30-H37 ◽  
Author(s):  
Rayna J. Gonzales ◽  
Benjimen R. Walker
Keyword(s):  
Chronic Hypoxia ◽  
Protoporphyrin Ix ◽  
Aortic Ring ◽  
Mesenteric Arteries ◽  
Zinc Protoporphyrin ◽  
Sprague Dawley ◽  
Resistance Arteries ◽  
Sprague Dawley Rats ◽  
Oxide Synthase

Chronic hypoxia (CH) is associated with a persistent reduction in systemic vasoconstrictor reactivity. Experiments on aortic ring segments isolated from CH rats suggest that enhanced vascular expression of heme oxygenase (HO) and resultant production of the vasodilator carbon monoxide (CO) may underlie this attenuated vasoreactivity after hypoxia. Similar to the aorta, small arteries from CH rats exhibit blunted reactivity; however, the regulatory role of CO in the resistance vasculature has not been established. Therefore, we examined the significance of HO activity on responsiveness to phenylephrine (PE) in the mesenteric circulation of control and CH rats. To document that the mesenteric bed demonstrates reduced reactivity after CH, we determined the vasoconstrictor responses of conscious, chronically instrumented male Sprague-Dawley rats to PE under control conditions and then immediately after exposure to 48 h CH (0.5 atm). All rats showed reduced mesenteric vasoconstriction to PE after CH. To examine the role of CO in reduced reactivity, small mesenteric arteries (100–200 μm intraluminal diameter) from control and 48-h CH rats were isolated and mounted on glass cannulas, pressurized to 60 mmHg and superfused with increasing concentrations of PE under normoxic conditions. Similar to the intact circulation, vessels from CH rats exhibited reduced vasoconstrictor sensitivity to PE compared with controls that persisted in the presence of nitric oxide synthase inhibition. The HO inhibitor, zinc protoporphyrin IX (5 μM) enhanced reactivity only in CH vessels. Additionally, a range of concentrations of the HO substrate heme-l-lysinate caused vasodilation in CH vessels but not in controls. Thus we conclude that CO contributes a significant vasodilator influence in resistance vessels after CH that may account for diminished vasoconstrictor responsiveness under these conditions.

Renal vasodilatory influence of endogenous carbon monoxide in chronically hypoxic rats

2000 ◽  
Vol 279 (6) ◽  
pp. H2908-H2915 ◽  
Author(s):  
Theresa L. O'Donaughy ◽  
Benjimen R. Walker
Keyword(s):  
Carbon Monoxide ◽  
Chronic Hypoxia ◽  
Protoporphyrin Ix ◽  
Renal Tissue ◽  
Zinc Protoporphyrin ◽  
Renal Vasculature ◽  
Conscious Rats ◽  
Enhanced Production ◽  
Renal Vascular ◽  
And Control

Chronic hypoxia (CH) attenuates systemic vasoconstriction to a variety of agonists in conscious rats. Recent evidence suggests that similarly diminished responses to vasoconstrictors in aortic rings from CH rats may be due to increased endothelial heme oxygenase (HO) activity and enhanced production of the vasodilator carbon monoxide (CO). Thus we hypothesized that a hypoxia-induced increase in HO activity is responsible for decreased vasoconstrictor responsiveness observed in conscious CH rats. CH (4 wk at 0.5 atm) and control rats were renal denervated and instrumented for the measurement of renal blood flow (RBF) and blood pressure. First, renal vasoconstrictor responses to graded intravenous infusion of phenylephrine (PE) were assessed in conscious rats. CH rats demonstrated significantly diminished renal vasoconstrictor responses to PE compared with control responses that persisted even with acute restoration of normoxia. In additional experiments, CH rats exhibited increased renal vascular resistance and decreased RBF in response to the HO inhibitor zinc protoporphyrin IX (11 μmol/kg iv), whereas renal hemodynamics were unaffected by the inhibitor in control animals. Furthermore, we demonstrated greater HO enzyme activity in renal tissue from CH rats compared with controls. These data suggest that enhanced HO activity contributes a tonic vasodilatory influence in the renal vasculature of CH rats that may be responsible for the diminished sensitivity to vasoconstrictor agonists observed under these conditions.

Heme Oxygenase-1/Carbon Monoxide-regulated Mitochondrial Dynamic Equilibrium Contributes to the Attenuation of Endotoxin-induced Acute Lung Injury in Rats and in Lipopolysaccharide-activated Macrophages

2016 ◽  
Vol 125 (6) ◽  
pp. 1190-1201 ◽  
Author(s):  
Jianbo Yu ◽  
Jia Shi ◽  
Dan Wang ◽  
Shuan Dong ◽  
Yuan Zhang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Carbon Monoxide ◽  
Lung Injury ◽  
Mitochondrial Dynamics ◽  
Protoporphyrin Ix ◽  
Zinc Protoporphyrin ◽  
Oxygen Species ◽  
Sprague Dawley ◽  
Mitochondrial Dynamic ◽  
Sprague Dawley Rats

Abstract Background Sepsis-associated acute lung injury remains the major cause of mortality in critically ill patients and is characterized by marked oxidative stress and mitochondrial dysfunction. Mitochondrial dynamics are indispensable for functional integrity. Additionally, heme oxygenase (HO)-1/carbon monoxide conferred cytoprotection against end-organ damage during endotoxic shock. Herein, we tested the hypothesis that HO-1/carbon monoxide played a critical role in maintaining the dynamic process of mitochondrial fusion/fission to mitigate lung injury in Sprague-Dawley rats or RAW 264.7 macrophages exposed to endotoxin. Methods The production of reactive oxygen species, the respiratory control ratio (RCR), and the expressions of HO-1 and mitochondrial dynamic markers were determined in macrophages. Concurrently, alterations in the pathology of lung tissue, lipid peroxidation, and the expressions of the crucial dynamic proteins were detected in rats. Results Endotoxin caused a 31% increase in reactive oxygen species and a 41% decrease in RCR levels (n = 5 per group). In parallel, the increased expression of HO-1 was observed in lipopolysaccharide-stimulated macrophages, concomitantly with excessive mitochondrial fission. Furthermore, carbon monoxide-releasing molecule-2 or hemin normalized mitochondrial dynamics, which were abrogated by zinc protoporphyrin IX. Additionally, impaired mitochondrial dynamic balance was shown in Sprague-Dawley rats that received lipopolysaccharide, accompanied by pathologic injury, elevated malondialdehyde contents, decreased manganese superoxide dismutase activities, and lowered RCR levels in rat lung mitochondria. However, the above parameters were augmented by zinc protoporphyrin IX and were in turn reversed by hemin. Conclusions The HO-1/carbon monoxide system modulated the imbalance of the dynamic mitochondrial fusion/fission process evoked by lipopolysaccharide and efficiently ameliorated endotoxin-induced lung injury in vivo and in vitro.

scholarly journals Inhaled carbon monoxide does not cause pulmonary vasodilation in the late-gestation fetal lamb

2000 ◽  
Vol 278 (4) ◽  
pp. L779-L784 ◽  
Author(s):  
Theresa R. Grover ◽  
Robyn L. Rairigh ◽  
Jeanne P. Zenge ◽  
Steven H. Abman ◽  
John P. Kinsella
Keyword(s):  
Carbon Monoxide ◽  
Blood Flow ◽  
Pulmonary Artery ◽  
Vascular Tone ◽  
Ductus Arteriosus ◽  
Protoporphyrin Ix ◽  
Left Lung ◽  
Late Gestation ◽  
Zinc Protoporphyrin ◽  
Pulmonary Vasodilation

As observed with nitric oxide (NO), carbon monoxide (CO) binds and may activate soluble guanylate cyclase and increase cGMP levels in smooth muscle cells in vitro. Because inhaled NO (INO) causes potent and sustained pulmonary vasodilation, we hypothesized that inhaled CO (ICO) may have similar effects on the perinatal lung. To determine whether ICOcan lower pulmonary vascular resistance (PVR) during the perinatal period, we studied the effects of ICOon late-gestation fetal lambs. Catheters were placed in the main pulmonary artery, left pulmonary artery (LPA), aorta, and left atrium to measure pressure. An ultrasonic flow transducer was placed on the LPA to measure blood flow to the left lung. After baseline measurements, fetal lambs were mechanically ventilated with a hypoxic gas mixture (inspired O2fraction < 0.10) to maintain a constant fetal arterial [Formula: see text]. After 60 min (baseline), the lambs were treated with ICO[5–2,500 parts/million (ppm)]. Comparisons were made with INO(5 and 20 ppm) and combined INO(5 ppm) and ICO(100 and 2,500 ppm). We found that ICOdid not alter left lung blood flow or PVR at any of the study doses. In contrast, low-dose INOdecreased PVR by 47% ( P < 0.005). The combination of INOand ICOdid not enhance the vasodilator response to INO. To determine whether endogenous CO contributes to vascular tone in the fetal lung, zinc protoporphyrin IX, an inhibitor of heme oxygenase, was infused into the LPA in three lambs. Zinc protoporphyrin IX had no effect on baseline PVR, aortic pressure, or the pressure gradient across the ductus arteriosus. We conclude that ICOdoes not cause vasodilation in the near-term ovine transitional circulation, and endogenous CO does not contribute significantly to baseline pulmonary vascular tone or ductus arteriosus tone in the late-gestation ovine fetus.

Correlation of HO-1 expression with onset and reversal of hypoxia-induced vasoconstrictor hyporeactivity

2001 ◽  
Vol 281 (1) ◽  
pp. H298-H307 ◽  
Author(s):  
Nikki L. Jernigan ◽  
Theresa L. O'Donaughy ◽  
Benjimen R. Walker
Keyword(s):  
Carbon Monoxide ◽  
Blood Flow ◽  
Chronic Hypoxia ◽  
Protoporphyrin Ix ◽  
Hypoxic Exposure ◽  
Zinc Protoporphyrin ◽  
Protein Levels ◽  
Hypoxic Induction ◽  
Vasoconstrictor Response ◽  
Renal Vascular

Rats exposed to chronic hypoxia (CH; 4 wk at 0.5 atm) exhibit attenuated renal vasoconstrictor reactivity to phenylephrine (PE). Preliminary studies from our laboratory suggest that this response is mediated by hypoxic induction of heme oxygenase (HO) and subsequent release of the endogenous vasodilator carbon monoxide. Because vascular HO mRNA is increased within hours of hypoxic exposure, we hypothesized that the onset of reduced reactivity may occur fairly rapidly and correlate with HO expression. Therefore, we examined the onset of attenuated vasoconstriction on CH exposure as well as the duration of hyporeactivity on return to a normoxic environment. Renal vascular resistance (RVR) responses to graded intravenous infusion of PE were measured in conscious rats under control conditions and after 24 h, 48 h, and 4 wk of CH exposure. Vasoreactivity responses were also determined in 4-wk CH rats 1, 5, 24, and 96 h after return to normoxia. We found that RVR responses to PE were significantly blunted after 48 h and 4 wk but not after 24 h of hypoxic exposure. Inhibition of HO with zinc protoporphyrin IX increased RVR and decreased renal blood flow in 48-h CH rats but not controls. Although reactivity to PE was gradually restored after 4 wk of CH, responsiveness was still slightly blunted at 96 h after return to normoxia. Western blot analysis demonstrated a correlation between HO-1 protein levels and attenuated vasoconstrictor response in CH and posthypoxic rats. These data suggest that the onset and offset of physiologically relevant vascular HO expression occur within 2–3 days.

Coronary vascular reactivity is improved by endothelin A receptor blockade in DOCA-salt hypertensive rats

1998 ◽  
Vol 274 (6) ◽  
pp. R1613-R1618 ◽  
Author(s):  
Ararat D. Giulumian ◽  
David M. Pollock ◽  
Natalie Clarke ◽  
Leslie C. Fuchs
Keyword(s):  
Vascular Reactivity ◽  
Chronic Treatment ◽  
Vascular Dysfunction ◽  
Mesenteric Arteries ◽  
Intraluminal Pressure ◽  
Receptor Blockade ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Small Arteries ◽  
Salt Hypertension

Endothelin-1 (ET-1) is thought to play an important role in the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Because hypertension is associated with an increased incidence of coronary artery disease, this study was designed to determine if coronary vascular contraction to ET-1 is altered in DOCA-salt hypertensive rats and to determine the effect of chronic treatment of DOCA-salt rats with the selective ETA receptor antagonist A-127722. Male Sprague-Dawley rats were divided into four groups: DOCA, Placebo, DOCA + A-127722, and Placebo + A-127722. A-127722 was administered in drinking water at a concentration of 8 mg/100 ml. After 3 wk, mean arterial pressure (MAP) was significantly enhanced in DOCA-salt compared with Placebo rats. A-127722 significantly inhibited the increase in MAP. Contraction to ET-1 (10−11 to 3 × 10−8 M) was measured in isolated coronary and mesenteric small arteries (200–300 μm, intraluminal diameter) maintained at a constant intraluminal pressure of 40 mmHg and was significantly impaired in vessels from DOCA-salt compared with Placebo rats. Dose-dependent contractions to KCl were also inhibited in coronary, but only minimally impaired in mesenteric, arteries of DOCA-salt rats. Inhibition of nitric oxide synthase activity did not restore contraction to ET-1 in coronary small arteries. However contractions to ET-1 were enhanced in mesenteric small arteries. Chronic treatment with A-127722 significantly restored contraction to ET-1 in coronary, but not in mesenteric, arteries of DOCA-salt rats. Because ETAreceptor blockade impairs the development of hypertension and improves coronary vascular reactivity, these data indicate that ET-1 plays an important role in coronary vascular dysfunction associated with DOCA-salt hypertension.

scholarly journals Endogenous estrogen mediates vascular reactivity and distensibility in pregnant rat mesenteric arteries

2001 ◽  
Vol 280 (3) ◽  
pp. H956-H961 ◽  
Author(s):  
Yunlong Zhang ◽  
Ken G. Stewart ◽  
Sandra T. Davidge
Keyword(s):  
Vascular Reactivity ◽  
Pressor Response ◽  
Virgin Female ◽  
Mesenteric Arteries ◽  
Female Rats ◽  
Tamoxifen Treatment ◽  
Sprague Dawley ◽  
Arterial Distensibility ◽  
Pregnant Rat ◽  
Endogenous Estrogen

The role of estrogen in the maternal systemic cardiovascular adaptations during pregnancy is still controversial. Female Sprague-Dawley rats were implanted at day 14 of pregnancy with either a 50-mg tamoxifen pellet (estrogen receptor blocker, n = 10) or placebo pellet ( n = 10). Virgin female rats were a nonpregnant control ( n = 7). At days 20–22 of pregnancy, resistance-sized mesenteric arteries were mounted onto a dual-chamber arteriograph system. Pregnancy significantly blunted the pressor response to phenylephrine [measurement of the effective concentration that yielded 50% maximum response (EC50) values were 1.5 ± 0.22 vs. 0.69 ± 0.16 μM ( P < 0.05)] and enhanced vasodilation to ACh [EC50 = 1.13 ± 2.53 vs. 3.13 ± 6.04 nM ( P < 0.05)] compared with nonpregnant rats. However, tamoxifen treatment during pregnancy reversed these effects. Inhibition of nitric oxide (NO) synthase with N G-monomethyl-l-arginine (250 μM) shifted only the responses of the placebo-treated pregnant group to both phenylephrine and ACh. Arterial distensibility in the placebo-treated pregnant group was also significantly increased ( P < 0.05) compared with nonpregnant and tamoxifen-treated pregnant animals. In summary, endogenous estrogen during pregnancy increases NO-dependent modulation of vessel tone and arterial distensibility.

scholarly journals Role of endogenous carbon monoxide in the control of breathing in zebrafish (Danio rerio)

2016 ◽  
Vol 311 (6) ◽  
pp. R1262-R1270 ◽  
Author(s):  
Velislava Tzaneva ◽  
Steve F. Perry
Keyword(s):  
Carbon Monoxide ◽  
Danio Rerio ◽  
Larval Fish ◽  
Protoporphyrin Ix ◽  
Control Of Breathing ◽  
Zinc Protoporphyrin ◽  
Hypoxic Conditions ◽  
First Time

Carbon monoxide (CO) is a gaseous signaling molecule and is produced in vivo from the intracellular breakdown of heme via the heme oxygenase (HO) family of enzymes. In this study we investigated the role of the HO-1/CO system in the control of ventilation in zebrafish, Danio rerio. Immunohistochemistry revealed the presence of HO-1 in the chemoreceptive neuroepithelial cells (NECs) of larvae (4 days postfertilization) and adults, indicating the potential for endogenous CO production in the NECs. Hypoxia (20 min, water Po2 of 30 mmHg) caused a significant increase in HO-1 activity in whole larvae and in the gills of adult fish. Zebrafish with reduced HO-1 activity (via HO-1 knockdown in larvae or zinc protoporphyrin IX treatment in adults) exhibited increased ventilation frequency ( Vf) under normoxic but not hypoxic conditions. The addition of exogenous CO restored resting Vf in fish with diminished CO production, and in some cases (e.g., hypoxic sham larvae) CO modestly reduced Vf below resting levels. Larval fish were treated with phenylhydrazine (PHZ) to eliminate the potential confounding effects of CO-hemoglobin interactions that might influence ventilation. PHZ treatment did not cause changes in Vf of normoxic larvae, and the addition of CO to PHZ-exposed larvae resulted in a significant decrease in sham and HO-1-deficient fish under normoxic conditions. This study demonstrates for the first time that CO plays an inhibitory role in the control of breathing in larval and adult zebrafish.

Roles of Carbon Monoxide in Leukocyte and Platelet Dynamics in Rat Mesentery during Sevoflurane Anesthesia

2001 ◽  
Vol 95 (1) ◽  
pp. 192-199 ◽  
Author(s):  
Hiroshi Morisaki ◽  
Tomihiro Katayama ◽  
Yoshifumi Kotake ◽  
Masaharu Ito ◽  
Takuya Tamatani ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Carbon Monoxide ◽  
Protoporphyrin Ix ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Sevoflurane Anesthesia ◽  
Mechanically Ventilated ◽  
Rat Mesentery ◽  
Platelet Dynamics

Background Heme oxygenase 1 (HO-1), induced by a variety of stressors, provides endogenous carbon monoxide (CO) and bilirubin, both of which play consequential roles in organs. The current study aimed to examine whether induction of HO-1 and its by-products modulated endothelial interaction with circulating leukocytes and platelets evoked by sevoflurane anesthesia in vivo. Methods Rats, pretreated with or without hemin, were anesthetized with sevoflurane in 100% O2, and lungs were mechanically ventilated. Platelets labeled with carboxyfluorescein diacetate succinimidyl ester and leukocyte behavior in mesenteric venules were visualized during sevoflurane anesthesia at 1,000 frames/s using intravital ultrahigh-speed intensified fluorescence videomicroscopy. To examine the mechanisms for the effects of HO-1 on leukocyte and platelet behavior, these studies were repeated with superfusion of either CO, bilirubin, or Nomega-nitro-L-arginine methyl ester (L-NAME). Results As reported previously, the elevation of sevoflurane concentration evoked adhesive responses of leukocytes, concurrent with platelet margination and rolling. Pretreatment with hemin, a HO-1 inducer, prevented such sevoflurane-elicited changes in the microvessels. These changes were restored by zinc protoporphyrin IX, a HO inhibitor, and repressed by CO but not by bilirubin. During sevoflurane anesthesia, however, nitric oxide suppression by L-NAME deteriorated microvascular flows irrespective of the presence or absence of the HO-1 induction. Conclusions These results indicate that endogenous CO via HO-1 induction attenuates sevoflurane-induced microvascular endothelial interactions with leukocytes and platelets, although local nitric oxide levels appear to dominate microvascular flow in situ.

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