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.

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.

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.

Sexual dimorphism in regional blood flow responses to vasopressin in conscious rats

1997 ◽  
Vol 273 (3) ◽  
pp. R1126-R1131 ◽  
Author(s):  
Y. X. Wang ◽  
J. T. Crofton ◽  
S. L. Bealer ◽  
L. Share
Keyword(s):  
Blood Flow ◽  
Vascular Resistance ◽  
Regional Blood Flow ◽  
Pressor Response ◽  
Peripheral Resistance ◽  
Female Rats ◽  
Sexually Dimorphic ◽  
Arterial Blood ◽  
Vasoconstrictor Response ◽  
Renal Vascular

The greater pressor response to vasopressin in male than in nonestrous female rats results from a greater increase in total peripheral resistance in males. The present study was performed to identify the vascular beds that contribute to this difference. Mean arterial blood pressure (MABP) and changes in blood flow in the mesenteric and renal arteries and terminal aorta were measured in conscious male and nonestrous female rats 3 h after surgery. Graded intravenous infusions of vasopressin induced greater increases in MABP and mesenteric vascular resistance and a greater decrease in mesenteric blood flow in males. Vasopressin also increased renal vascular resistance to a greater extent in males. Because renal blood flow remained unchanged, this difference may be due to autoregulation. The vasopressin-induced reduction in blood flow and increased resistance in the hindquarters were moderate and did not differ between sexes. Thus the greater vasoconstrictor response to vasopressin in the mesenteric vascular bed of male than nonestrous females contributed importantly to the sexually dimorphic pressor response to vasopressin in these experiments.

scholarly journals Aging augments renal vasoconstrictor response to orthostatic stress in humans

2015 ◽  
Vol 309 (12) ◽  
pp. R1474-R1478 ◽  
Author(s):  
Christine M. Clark ◽  
Kevin D. Monahan ◽  
Rachel C. Drew
Keyword(s):  
Blood Flow ◽  
Healthy Aging ◽  
Lower Body Negative Pressure ◽  
Systemic Circulation ◽  
Young Group ◽  
Orthostatic Stress ◽  
Renal Vasoconstriction ◽  
Arterial Blood ◽  
Vasoconstrictor Response ◽  
Renal Vascular

The ability of the human body to maintain arterial blood pressure (BP) during orthostatic stress is determined by several reflex neural mechanisms. Renal vasoconstriction progressively increases during graded elevations in lower body negative pressure (LBNP). This sympathetically mediated response redistributes blood flow to the systemic circulation to maintain BP. However, how healthy aging affects the renal vasoconstrictor response to LBNP is unknown. Therefore, 10 young (25 ± 1 yr; means ± SE) and 10 older (66 ± 2 yr) subjects underwent graded LBNP (−15 and −30 mmHg) while beat-to-beat renal blood flow velocity (RBFV; Doppler ultrasound), arterial BP (Finometer), and heart rate (HR; electrocardiogram) were recorded. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as mean BP/RBFV. All baseline cardiovascular variables were similar between groups, except diastolic BP was higher in older subjects ( P < 0.05). Increases in RVR during LBNP were greater in the older group compared with the young group (older: −15 mmHg Δ10 ± 3%, −30 mmHg Δ20 ± 5%; young: −15 mmHg Δ2 ± 2%, −30 mmHg Δ6 ± 2%; P < 0.05). RBFV tended to decrease more ( P = 0.10) and mean BP tended to decrease less ( P = 0.09) during LBNP in the older group compared with the young group. Systolic and diastolic BP, pulse pressure, and HR responses to LBNP were similar between groups. These findings suggest that aging augments the renal vasoconstrictor response to orthostatic stress in humans.

scholarly journals Role of endothelial carbon monoxide in attenuated vasoreactivity following chronic hypoxia

1998 ◽  
Vol 275 (4) ◽  
pp. R1025-R1030 ◽  
Author(s):  
Timothy K. Caudill ◽  
Thomas C. Resta ◽  
Nancy L. Kanagy ◽  
Benjimen R. Walker
Keyword(s):  
Chronic Hypoxia ◽  
Soluble Guanylyl Cyclase ◽  
Hypoxic Exposure ◽  
Zinc Protoporphyrin ◽  
Response Curves ◽  
No Donor ◽  
Enhanced Production ◽  
Synthase Inhibitor

Chronic hypoxic exposure has been previously demonstrated to attenuate systemic vasoconstrictor activity to a variety of agents. This attenuated responsiveness is observed not only in conscious animals but in isolated vascular preparations as well. Because hypoxia has been documented to increase heme oxygenase (HO) levels and the subsequent production of the vasodilator CO in vitro, we hypothesized that the blunted reactivity observed with chronic hypoxia (CH) may be in part due to increased HO activity. In thoracic aortic rings from CH rats, cumulative dose-response curves to phenylephrine (PE) in the presence of the nitric oxide (NO) synthase inhibitor N ω-nitro-l-arginine (l-NNA) and the HO inhibitor zinc protoporphyrin 9 (ZnPPIX) elicited increased contractility compared with CH rings treated with onlyl-NNA. Similar results were observed in rings incubated overnight with the HO-inducing agent sodium m-arsenite. In contrast, contractile responses in rings from control rats were unaffected by the HO inhibitor. Furthermore, endothelium-denuded rings from either control or CH rats did not exhibit an increase in reactivity to PE following ZnPPIX incubation. ZnPPIX had no effect on relaxant responses to the NO donor S-nitroso- N-penicillamine, suggesting that its actions were specific to HO inhibition. Finally, aortic rings exhibited dose-dependent relaxant responses to exogenous CO that were endothelium independent and blocked by an inhibitor of soluble guanylyl cyclase. The other products of HO enzyme activity, iron and biliverdin, were without effect on vasoreactivity. Thus we conclude that the attenuated vasoreactivity to PE following CH is likely to involve the induction of endothelial HO and the subsequent enhanced production of CO.

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.

scholarly journals Hemin and Zinc Protoporphyrin IX Affect Granisetron Constipating Effects In Vitro and In Vivo

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Addolorata Zigrino ◽  
Valentina Leo ◽  
Giuseppe Renna ◽  
Monica Montagnani ◽  
Maria Antonietta De Salvia
Keyword(s):  
Protoporphyrin Ix ◽  
Electrical Field Stimulation ◽  
Zinc Protoporphyrin ◽  
Electrical Field ◽  
Anticancer Chemotherapy ◽  
Protein Levels ◽  
Basal Activity ◽  
Per Se

Granisetron is a 5-HT3 receptors antagonist used in the management of emesis associated with anticancer chemotherapy. It affects intestinal motility with constipating effect. Since the pathway heme oxygenase/carbon monoxide (HO/CO) is involved in gastrointestinal motility, we evaluated the possible interplay between granisetron and agents affecting HO/CO pathways such as zinc protoporphyrin IX (ZnPPIX), an HO inhibitor, or hemin, an HO-1 inducer. ZnPPIX (10 µM) or hemin (10 µM), but not granisetron (0.1, 0.3, 1 µM), affected spontaneous basal activity recorded in rat duodenal strips, in noncholinergic nonadrenergic conditions. Granisetron restored spontaneous basal activity after ZnPPIX, but not after hemin. ZnPPIX decreased and hemin increased the inhibition of activity after electrical field stimulation (EFS), but they did not affect the contraction that follows the relaxation induced by EFS called off contraction. Granisetron did not alter the response to EFS per se but abolished both ZnPPIX and hemin effect when coadministered. In vivo study showed constipating effect of granisetron (25, 50, 75 µg/kg/sc) but no effect of either ZnPPIX (50 µg/kg/i.p.) or hemin (50 µM/kg/i.p.). When coadministered, granisetron effect was abolished by ZnPPIX and increased by hemin. Specimens from rats treated in vivo with hemin (50 µM/kg/i.p.) showed increased HO-1 protein levels. In conclusion, granisetron seems to interact with agents affecting HO/CO pathway both in vitro and in vivo.

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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