Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-5218
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ABSTRACT |
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Carbon monoxide (CO) has been proposed to attenuate the vasoconstrictor response to local hypoxia that contributes to pulmonary hypertension. However, the segmental response to CO, as well as its mechanism of action in the pulmonary circulation, has not been fully defined. To investigate the hemodynamic response to exogenous CO, lungs from male Sprague-Dawley rats were perfused with physiological saline solution. Measurements were made of pulmonary arterial, venous, and capillary pressures. Lungs were constricted with the thromboxane mimetic U-46619. To examine the vasodilatory response to CO, 500 µl of CO-equilibrated physiological saline solution or vehicle were injected into the arterial line. Additionally, CO and vehicle responses were examined in the presence of the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 µM) or the larger conductance calcium-activated K+ (BKCa) channel blockers tetraethylammonium chloride (10 mM) and iberiotoxin (100 nM). CO administration decreased vascular resistance to a similar degree in both vascular segments. This vasodilatory response was completely abolished in lungs pretreated with ODQ. Furthermore, CO administration increased whole lung cGMP content, which was prevented by ODQ. Neither tetraethylammonium chloride nor iberiotoxin affected the CO response. We conclude that exogenous CO administration causes vasodilation in the pulmonary vasculature via a soluble guanylyl cyclase-dependent mechanism that does not likely involve activation of KCa channels.
isolated rat lungs; pulmonary hypertension; vascular resistance; heme oxygenase
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INTRODUCTION |
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HEME OXYGENASE (HO) exists as three isoforms: constitutive (HO-1), inducible (HO-2), and a third not yet fully characterized form (HO-3). HO-1 and HO-2 have been found in both vascular smooth muscle and endothelial cells (6, 8). HO catalyzes the conversion of heme to biliverdin, with the release of carbon monoxide (CO) as a by-product. Several investigators (7, 9, 25, 33, 51, 52) have provided evidence that CO acts as an endogenously produced vasoactive molecule analogous to nitric oxide (NO). Functional evidence for a role of endogenous CO in regulating vascular tone has come from both whole animal (24, 27, 33, 34) and isolated vessel preparations (7, 10, 23, 25, 29, 49). For example, systemic administration of zinc protoporphyrin IX, a selective HO inhibitor, increases renal vascular resistance in chronically hypoxic rats (34). Furthermore, exogenous administration of CO or the HO substrate heme-L-lysinate produced concentration-dependent increases in vessel diameter (27). Taken together, these results suggest a potential role for endogenous CO in the regulation of vascular tone.
CO-induced vasodilation has been demonstrated in a number of vascular beds, including the skeletal, hepatic, renal, and cerebral circulations (25, 27, 34, 47). Although the mechanism of CO-induced vasodilation has been ardently investigated, there is considerable variability in the proposed mechanism between the vascular beds. It has been proposed that CO produces vasodilation by both soluble guanylyl cyclase (sGC)-dependent (7-9, 23, 32, 36, 40, 41, 45, 46, 49) and -independent (11, 43, 48-50) mechanisms. Indeed, CO-induced vasodilation has been shown to occur through a cGMP-dependent mechanism in rabbit aorta (23) and in the aorta (7) and tail artery (49) of the rat. In contrast, CO has been suggested to elicit cGMP-independent vasodilation in the lamb ductus arteriosus (10) as well as in the gracilis arterioles (25) and lungs of the rat (11, 43). In addition, vascular smooth muscle large-conductance calcium-activated K+ (BKCa) channels have been shown to play a role in CO-induced vasodilation in both rat tail artery (49) and porcine pial artery (27). However, whether activation of the vascular smooth muscle BKCa channel in response to CO occurs through a direct effect on the channel itself (48, 50) or through a cGMP-dependent mechanism is unclear. To date, the one study that investigated the mechanism of CO-induced vasodilation in the intact pulmonary circulation concluded that dilation was independent of sGC activation (43). However, CO was administered via the airway, and thus the results may not be representative of what occurs in response to CO produced within the vasculature.
Although CO appears to be a pulmonary vasodilator, the specific vascular segments within the lung that are affected have not been defined. NO donors cause dilation of both arteries and veins in the pulmonary circulation (15). This is likely indicative of even segmental distribution of sGC because NO-induced dilation appears to be cGMP dependent in the pulmonary vasculature (1). Thus if CO similarly acts solely via cGMP-dependent mechanisms, then an analogous uniform profile of dilation would be expected. In contrast, evidence exists that BKCa channels may be unevenly distributed within this bed (2), which would affect the sites of dilation if these channels are an integral part of pulmonary vascular CO signaling. Thus we examined the sites of CO-induced vasodilation in the isolated, perfused rat lung and further assessed the importance of the activation of sGC and of BKCa channels in these segmental responses. We hypothesized that CO produces vasodilation in the arterial and venous segments of the pulmonary vasculature in a cGMP-dependent manner involving activation of the vascular smooth muscle cell BKCa channel.
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METHODS |
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All protocols and surgical procedures employed in this study were reviewed and approved by the Institutional Animal Care and Use Committee of the University of New Mexico School of Medicine. Male Sprague-Dawley rats (200-250 g; Harlan Sprague Dawley) were used for all experiments.
Isolated Lung Preparation
The procedure for lung isolation has been described previously (1, 14, 21, 31). Briefly, animals were anesthetized with 25 mg of intraperitoneal pentobarbital sodium. The trachea was isolated and cannulated with a 17-gauge needle stub. A midsternal incision was made to expose the heart, and 100 U of heparin were injected directly into the right ventricle. The pulmonary artery was cannulated with a 13-gauge needle stub via an incision in the right ventricle. The left ventricle was cannulated with a 4-mm-diameter plastic tube, the preparation was quickly connected to a perfusion system containing a physiological saline solution [PSS; 290 mosmol/kgH2O; containing 126 mM NaCl, 5.4 mM KCl, 0.83 mM MgSO4, 19 mM NaHCO3, 1.8 mM CaCl2, 5.5 mM glucose, and 4% (wt/vol) albumin] and the heart and lungs were removed en bloc. For all protocols, meclofenamate (10 µg/ml) and NIsolated Lung Protocols
Characterization of the segmental response to exogenous CO in the pulmonary vasculature. The present protocol was designed to characterize the segmental profile of the vasodilatory response to exogenous CO in the pulmonary vasculature. Before each experiment, 10 ml of PSS stored on ice were vigorously bubbled for 15 min with 100% CO gas (Matheson Gas Products). Lungs (n = 5), prepared as described in Isolated Lung Preparations, were allowed to equilibrate for 30 min, at which time baseline capillary pressure (Ppc) was assessed by a double-occlusion procedure. The method of estimating microvascular pressure agrees with other methods (44) and has been described previously (15, 20). Briefly, the arterial inflow line and venous outflow line were simultaneously occluded. Ppa and Pv rapidly equilibrated to a new intermediate pressure representative of Ppc during the brief no-flow condition. The occlusion procedure was completed in <2 s. After baseline occlusion, the thromboxane mimetic U-46619 was added to the reservoir to elicit a pressor response of ~10 mmHg. U-46619 is known to constrict both the arterial and venous segments of the pulmonary circulation (15). Our laboratory (15) has previously shown roughly equal arterial and venous resistances in lungs treated in this fashion. Double occlusion was performed on establishment of a stable U-46619 pressor response and was followed by administration of a 500-µl bolus of CO-equilibrated PSS (4.2 ml CO/100 mol PSS) injected directly into the arterial pressure line. Double occlusion was repeated on achievement of a maximal response to CO. Occlusion was maintained until there was a plateau in both Ppa and Pv; this typically occurred in <2 s.
Effect of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one on
CO-induced dilation.
The following protocol was designed to examine the role of sGC in the
vasodilatory response to exogenous CO. Twenty lungs were prepared as
described in Isolated Lung Preparation. To examine the role
of sGC in the vasodilatory response to CO, the specific sGC inhibitor
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 µM) (17) or an equal volume of vehicle (75 µl of DMSO)
was added to the reservoir at the beginning of the 30-min equilibration period. Next, U-46619 was added to the reservoir to elicit a ~10 mmHg
pressor response. On establishment of a stable U-46619 pressor response, 500 µl of CO-equilibrated PSS (4.2 ml CO/100 ml PSS) were
administered via arterial injection. Once arterial pressure had
returned to baseline, a 500-µl bolus of the PSS vehicle was administered via arterial injection. To control for a potential order
effect, a second dose of CO-equilibrated PSS was given. Similar
responses were observed for the two CO injections (data not shown). In
separate experiments, the vasodilatory response when the
2-adrenergic receptor agonist isoproterenol (10 nM) was
added to the reservoir was assessed in U-46619-preconstricted lungs
(n = 6/group) treated with either ODQ or vehicle to
demonstrate that pretreatment with ODQ did not have nonspecific effects
on non-cGMP-dependent vasodilator responsiveness.
Effect of dipyridamole on CO-induced dilation. To further demonstrate the significance of sGC in CO-induced pulmonary vasodilation, the vasodilatory response to CO was assessed in lungs pretreated with the specific phosphodiesterase 5 inhibitor dipyridamole (20 µM). Lungs were isolated, perfused, and studied as described in Isolated Lung Preparation. Because phosphodiesterase inhibition augmented the duration rather than the amplitude of the CO response, the effect of dipyridamole on CO-induced vasodilation was quantified by determining the duration of the nadir of the pulmonary vascular resistance response.
Effect of CO administration on cGMP whole lung cGMP content.
The experiments were designed to provide further support for the role
of sGC activation in CO-induced vasodilation. Lungs were isolated,
perfused, and studied as described in Isolated Lung
Preparation. Briefly, on establishment of a stable U-46619-induced pressor response, either CO or its vehicle was administered via arterial injection. Additional experiments were performed on lungs that
were pretreated with ODQ before administration of CO. All experiments
were performed in the presence of dipyridamole (20 µM). When the
CO-induced vasodilation was maximal, lungs were immediately frozen in
liquid N2 and stored at 80°C. Lungs that were given
vehicle or pretreated with ODQ were frozen at a time point similar to
the one for lungs that dilated to CO. cGMP content was measured in
whole lung homogenates via a radioimmunoassay kit (Amersham Pharmacia,
Piscataway, NJ).
Effect of BKCa channel inhibition on CO-induced vasodilation. To test the involvement of BKCa channel activation in CO-induced vasodilation, the vasodilatory response to CO was assessed in lungs pretreated with either the K+ channel inhibitor tetraethylammonium chloride (TEA; 10 mM; n = 4 lungs) or the highly specific BKCa channel inhibitor iberiotoxin (100 nM; n = 2). K+ channel inhibitors were added to the reservoir at the initiation of the equilibration period. Lungs were isolated, perfused, and studied as described in Isolated Lung Preparation.
Solutions
ODQ and dipyridamole (Sigma) were dissolved in DMSO and stored atCalculations and Statistical Analyses
Because flow through the pulmonary vascular bed was kept constant throughout the experiment, any changes in Ppa were reflective of changes in pulmonary vascular resistance. For the determination of segmental responses, pulmonary arterial resistance was calculated as the difference between Ppa and Ppc divided by flow. Similarly, pulmonary venous resistance was calculated as the difference between Ppc and Pv divided by flow. For all other experiments, changes in total vascular resistance were calculated as the difference between Ppa and Pv divided by flow. The vasodilatory responses to CO were calculated as percent reversal of the resistance response to U-46619 elicited in each segment. To meet the assumption of a normal distribution necessary for parametric statistics, percent changes in vascular resistance underwent arcsine transformation before analysis. Data were analyzed with a two-way repeated-measures ANOVA, one-way ANOVA, or an unpaired t-test as appropriate. Where significant main effects occurred, statistical differences between groups were assessed with the Student-Newman-Keuls post hoc test. A probability of P ![]() |
RESULTS |
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Characterization of the Segmental Response to Exogenous CO in the Pulmonary Vasculature
Baseline total vascular resistances for all experimental groups ranged from 0.10 to 0.12 mmHg · ml
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Effect of ODQ on CO-Induced Dilation
Pretreatment with ODQ did not alter baseline vascular resistance (Table 1). The total dose of U-46619 required to elicit an ~10 mmHg pressor response was similar between lungs treated with ODQ (2.0 ± 0.14 µg) and vehicle (2.17 ± 0.31 µg). Exogenous CO administration reduced total vascular resistance from 0.43 ± 0.08 to 0.33 ± 0.05 mmHg · ml
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Effect of Dipyridamole on CO-Induced Dilation
As shown in Fig. 4, the duration of the vasodilatory response to CO was prolonged in lungs pretreated with the phosphodiesterase 5 inhibitor dipyridamole. Although phosphodiesterase inhibition did not alter the magnitude of the vasodilatory response to CO (data not shown), pretreatment with dipyridamole resulted in an approximately twofold increase in the duration of the CO response.
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Effect of CO Administration on Whole Lung cGMP Content
Isolated lungs administered CO demonstrated greater cGMP content than lungs given vehicle. In addition, cGMP content in lungs pretreated with ODQ was lower than that in both CO- and vehicle-treated groups (Fig. 5).
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Effect of TEA and Iberiotoxin on CO-Induced Vasodilation
Figure 6 depicts the CO response in lungs pretreated with K+ channel inhibitors. The vasodilatory response to exogenous CO was unaltered in the presence of either TEA (n = 4 lungs) or iberiotoxin (n = 2 lungs). Pretreatment with these K+ channel inhibitors had no effect on baseline vascular resistance. Close injection of 500 µl of CO solution into the arterial line decreased pulmonary vascular resistance by 0.21 ± 0.02 and 0.16 ± 0.03 mmHg · ml
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DISCUSSION |
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The major findings of the present study are that 1) exogenous CO produces vasodilation in the pulmonary circulation, 2) CO alters vascular resistance by acting equally on both the arterial and venous segments, 3) CO-induced vasodilation is dependent on the activation of sGC, 4) CO administration increases lung cGMP content, and 5) exogenous CO-induced vasodilation does not appear to involve activation of the BKCa channel. These findings suggest that the mechanism of CO-induced vasodilation in the pulmonary circulation depends on the activation of sGC through a signal transduction cascade that is independent of K+ channel activation.
Several lines of evidence have suggested a role for HO-1-derived CO in the altered vascular reactivity that occurs after chronic hypoxia (7, 9, 33-35, 43, 51). Indeed, chronic hypoxia has been shown to increase HO-1 mRNA, protein, and enzyme activity both in endothelial and vascular smooth muscle cells (6, 9, 32). Moreover, transcriptional activation of the HO-1 gene in response to hypoxia has been shown to be mediated by the transcription factor hypoxia-inducible factor-1 in rat aortic vascular smooth muscle cells (26). Additionally, a recent study by Christou et al. (9) provided support for CO as a protective agent in animals chronically exposed to a hypoxic environment. These investigators demonstrated that enhancement of endogenous CO production attenuated hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy in response to 1 wk of hypoxia in Sprague-Dawley rats (9). Moreover, hypoxic exposure increases right ventricular dilation in HO-1-knockout mice compared with dilation in control animals (51). Taken together, these results suggest that the induction of HO-1 by prolonged exposure to a hypoxic environment may play a protective role in ameliorating some of the pathophysiological adaptations that occur in response to hypoxia.
In the present study, exogenous administration of CO to the pulmonary vasculature reversed the vasoconstriction induced by U-46619 in both the arterial and venous segments to a similar degree. Previous work from our laboratory (15, 37) has demonstrated that the vasodilatory response to NO donors in the pulmonary vasculature is similar to that observed in response to CO in U-46619-preconstricted lungs. For example, although NO appears to be a more potent vasodilator than CO, administration of S-nitroso-N-acetylpenicillamine (1 µM) to isolated perfused rat lungs reversed U-46619-induced constriction by ~50 and ~45% in pulmonary arterial and venous segments, respectively (38). In contrast to the present results, Villamor et al. (46) observed that the maximal vasodilatory response to CO was greater in porcine pulmonary veins than in arteries. The apparent discrepancy between these results and those of the present study could be attributed to either species differences or differences in the size of the vessels studied. Indeed, the vasoconstrictor responses to U-46619 occur preferentially in small pulmonary arteries and veins (15). Hence CO-induced vasodilation would be confined to those vessels in our experimental preparation. In contrast, Villamor et al. (46) studied larger arteries and veins. Thus differences in the observed segmental profile may be a function of the size of the vessels examined. Finally, because HO has been shown to be expressed in both pulmonary arteries and veins (30), endogenously produced CO could potentially cause dilation in both vascular segments as observed in the present study, which employed exogenous CO. Moreover, it would be anticipated that CO would act locally in the intact circulation because CO produced within the arterial segment would bind avidly to hemoglobin before transit to downstream sites.
We have demonstrated that CO produces vasodilation in both segments of the pulmonary vasculature through sGC activation. This is consistent with evidence suggesting that sGC is expressed in both arterial and venous smooth muscle cells (3, 13, 28). Indeed, CO-induced vasodilation was abolished by sGC inhibition and prolonged by inhibition of phosphodiesterase 5. Furthermore, CO increased whole lung cGMP content. Numerous studies with different vascular beds and varied experimental approaches have provided support for a role of sGC in CO-induced vasodilation. For example, HO-derived CO has been shown to increase cGMP levels in cultured rat aortic smooth muscle cells (32). In addition, treatment of isolated rat tail artery with the membrane permeable cGMP-dependent protein kinase inhibitor Rp-8-bromo-cGMPS partially inhibited CO-induced relaxation (49). Moreover, in rabbit and rat aortic rings, the vasodilatory response to exogenous CO was blocked in the presence of the sGC inhibitor ODQ (7, 23). However, Kozma et al. (25) proposed that activation of sGC is not involved in the regulation of vascular tone by CO, but these experiments were performed in the presence of ODQ, NG-nitro-L-arginine methyl ester, and the HO inhibitor chromium mesoporphyrin. Thus it is unlikely that ODQ would have an additional effect when both the production of NO and CO were inhibited.
Although sGC activation has been shown to be important in CO-induced vasodilation in a number of vascular beds (7-9, 23, 32, 45, 49), results from studies investigating the mechanism of CO-induced vasodilation in the pulmonary circulation have been inconsistent. For example, induction of HO with NiCl2 increased cGMP levels in rat lung under normoxic conditions and reduced systolic right ventricular pressure and medial wall thickness after chronic hypoxia (9). However, others (43) have shown that pretreating isolated rat lungs with methylene blue did not alter the ability of CO administered through the airway to blunt the vasoconstrictor response to hypoxia (2% O2). The cause of the disparity in these results is not apparent, especially in view of the present study of isolated perfused rat lungs. One possibility may be a result of differences in the type of perfusate (e.g., blood vs. PSS) used in these studies (39). Indeed, because hemoglobin has a high affinity for CO, the effectiveness of CO to produce vasodilation in the presence of red cells may be reduced. In addition, it is possible that this discrepancy may be due to differences in the method of CO administration. The vascular administration of CO used in the present study was chosen to more closely mimic the likely source of endogenous CO within the circulation. For example, there is evidence that CO produced within the vasculature is of endothelial origin (7). Furthermore, administration of CO directly into the vasculature would likely reduce the diffusional distance for CO to reach its target within the vascular smooth muscle cell. Results of studies that used inhaled CO to elicit pulmonary vasodilation have been inconsistent. Indeed, the studies of Cantrell and Tucker (5) and of Grover et al. (19) failed to demonstrate vasodilation to CO when administered through the airway, although Tamayo et al. (43) observed marked inhibition of hypoxic vasoconstriction with higher concentrations of CO in the inspired gas mixture. Thus the ability of CO to dilate the pulmonary vasculature may be concentration dependent. The necessity of using higher concentrations of inspired CO to elicit vasodilation may be due to the lower diffusibility of CO compared with NO (22) and the lower affinity of sGC for CO compared with that for NO (42).
The activation of vascular smooth muscle BKCa channels has been implicated in the vasodilatory response to CO (27, 49). Evidence for an involvement of K+ channel activation in CO-induced vasodilation has arisen from studies employing both isolated vessel and patch-clamp techniques. For example, CO administration produced dose-dependent increases in pial vessel diameter that were abolished in the presence of TEA, iberiotoxin, or charybdotoxin (27). Furthermore, CO has been shown to reduce the open probability of the BKCa channel in vascular smooth muscle cells (48, 50). Interestingly, these studies suggest that CO may have a direct effect on the vascular smooth muscle BKCa channel (48, 50). To date, the present study is the first to examine the effects of K+ channel inhibition on CO-induced vasodilation in the intact pulmonary vasculature. However, our data do not support an involvement of the K+ channel activation in CO-induced vasodilation in the pulmonary vasculature. Although not directly tested, it is unlikely that the failure of K+ channel inhibition to alter the vasodilatory response to CO observed in the present study is due to an incomplete block of vascular smooth muscle K+ channels. Indeed, the concentrations of K+ channel inhibitors used in this study have been shown to effectively block K+ channel activity both in vivo (12) and in vitro (4, 16, 18). Thus inconsistencies between the present study and previous investigations demonstrating a role for K+ channels in CO-induced vasodilation are most likely due to differences in mechanisms of action between vascular beds.
In summary, the current study provides evidence that CO administered directly into the pulmonary circulation of the isolated perfused rat lung causes vasodilation in both the arterial and venous segments of the vasculature through a sGC-dependent pathway that is independent of K+ channel activation. Further studies are needed to elucidate the targets downstream of cGMP production and cGMP-dependent protein kinase activation that are involved in CO-induced vasodilation.
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ACKNOWLEDGEMENTS |
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We thank Minerva Murphy, Anna Holmes, and Nikki Jernigan for technical assistance.
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FOOTNOTES |
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This work was supported by National Heart Lung, and Blood Institute Grants HL-58124, HL-63207 (to B. R. Walker), and F32-HL-08456 (to J. S. Naik).
Address for reprint requests and other correspondence: B. R. Walker, Dept. of Cell Biology and Physiology, Univ. of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, NM 87131-5218 (E-mail: bwalker{at}salud.unm.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 12 March 2001; accepted in final form 9 August 2001.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Archer, SL,
Rist LK,
Nelson DP,
DeMaster EG,
Cowan N,
and
Weir EK.
Comparison of the hemodynamic effects of nitric oxide and endothelium-dependent vasodilators in intact lung.
J Appl Physiol
68:
735-747,
1990
2.
Barman, SA.
Potassium channels modulate hypoxic pulmonary vasoconstriction.
Am J Physiol Lung Cell Mol Physiol
275:
L64-L70,
1998
3.
Bloch, KD,
Filippov G,
Sanchez LS,
Nakane M,
and
De La Monte A.
Pulmonary soluble guanylate cyclase, a nitric oxide receptor, is increased during the perinatal period.
Am J Physiol Lung Cell Mol Physiol
272:
L400-L406,
1997
4.
Brayden, JE,
and
Nelson MT.
Regulation of arterial tone by activation of calcium-dependent potassium channels.
Science
256:
532-535,
1992[ISI][Medline].
5.
Cantrell, JM,
and
Tucker A.
Low-dose carbon monoxide does not reduce vasoconstriction in isolated rat lungs.
Exp Lung Res
22:
21-32,
1996[ISI][Medline].
6.
Carraway, MS,
Ghio AJ,
Carter JD,
and
Piantadosi CA.
Expression of heme oxygenase-1 in the lung in chronic hypoxia.
Am J Physiol Lung Cell Mol Physiol
278:
L806-L812,
2000
7.
Caudill, TK,
Resta TL,
Kanagy NL,
and
Walker BR.
Role of endothelial carbon monoxide in attenuated vasoreactivity following chronic hypoxia.
Am J Physiol Regulatory Integrative Comp Physiol
275:
R1025-R1030,
1998
8.
Christodoulides, N,
Durante W,
Kroll MH,
and
Schafer AI.
Vascular smooth muscle cell heme oxygenase generate guanylyl cyclase-stimulatory carbon monoxide.
Circulation
91:
2306-2309,
1995
9.
Christou, H,
Morita T,
Hsieh CM,
Koike H,
Arkonac B,
Perrella MA,
and
Korembanas S.
Prevention of hypoxia-induced pulmonary hypertension by enhancement of endogenous heme oxygenase-1 in the rat.
Circ Res
86:
1224-1229,
2000
10.
Coceani, F,
Kelsey L,
and
Seidlitz E.
Carbon monoxide formation in the ductus arteriosus in the lamb: implications for the regulation of muscle tone.
Br J Pharmacol
120:
599-608,
1997[Abstract].
11.
Coceani, F,
Kelsey L,
and
Seidlitz E.
Carbon monoxide-induced relaxation of the ductus arteriosus in the lamb: evidence against a prime role of guanylyl cyclase.
Br J Pharmacol
118:
1689-1696,
1996[Abstract].
12.
Cook, DI,
Wegman EA,
Ishikawa T,
Poronnik P,
Allen DG,
and
Toung JA.
Tetraethylammonium blocks muscarinically evoked secretion in the sheep parotid gland by a mechanism additional to its blockade of BK channels.
Pflügers Arch
420:
167-171,
1992[ISI][Medline].
13.
D'Angelo, C,
Nickerson P,
Steinhorn R,
and
Morin F.
Heterogenous distribution of soluble guanylate cyclase in the pulmonary vasculature in fetal lamb.
Anat Rec
251:
62-69,
1998.
14.
Doyle, MP,
Galey WR,
and
Walker BR.
Reduced erythrocyte deformability alters pulmonary hemodynamics.
J Appl Physiol
67:
2593-2599,
1989
15.
Eichinger, MR,
and
Walker BR.
Segmental heterogeneity of NO-mediated pulmonary vasodilation in the rat.
Am J Physiol Heart Circ Physiol
267:
H494-H499,
1994
16.
Galvez, A,
Gimenez-Gallego G,
Reuben JP,
Roy-Contancin L,
Feigenbaum P,
Koczorowski GJ,
and
Garcia ML.
Purification and characterization of a unique, potent, peptidyl probe for the high conductance calcium-activated potassium channel from venom of the scorpion Buthus tamulus.
J Biol Chem
265:
11083-11090,
1990
17.
Garthwaite, J,
Southern E,
Boulten CL,
Nielsen B,
Schmidt K,
and
Mayer B.
Potent and selective inhibition of nitric oxide-sensitive guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one.
Mol Pharmacol
48:
184-188,
1995[Abstract].
18.
Giangiacomo, KM,
Garcia ML,
and
McManus OB.
Mechanisms of iberiotoxin block of the large-conductance calcium activated potassium channel from bovine aortic smooth muscle.
Biochemistry
31:
6719-6727,
1992[ISI][Medline].
19.
Grover, TR,
Rairigh RL,
Zenge JP,
Abman ST,
and
Kinsella JP.
Inhaled carbon monoxide does not cause pulmonary vasodilation in the late-gestation fetal lamb.
Am J Physiol Lung Cell Mol Physiol
278:
L779-L784,
2000
20.
Hakim, TS.
Identification of constriction in large versus small vessels using the arterial-venous and the double-occlusion techniques in isolated canine lungs.
Respiration
54:
61-69,
1988[ISI][Medline].
21.
Hauge, A.
Role of histamine in hypoxic pulmonary hypertension in the rat. I. Blockade of potentiation of endogenous amines, kinins, and ATP.
Circ Res
22:
371-383,
1968[ISI][Medline].
22.
Heller, H,
Fuchs G,
and
Klaus-Dieter S.
Single-breath diffusing capacities for NO, CO, and C18O2 in rabbits.
Pflügers Arch
435:
254-258,
1998[ISI][Medline].
23.
Hussain, AS,
Marks GS,
Brien JF,
and
Nakatsu K.
The soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) inhibits relaxation of rabbit aortic rings induced by carbon monoxide, nitric oxide, and glyceryl trinitrate.
Can J Physiol Pharmacol
75:
1034-1037,
1997[ISI][Medline].
24.
Johnson, RA,
Lavesa M,
Askari B,
Abraham NG,
and
Nasjletti A.
A heme oxygenase product, presumably carbon monoxide, mediates a vasodepressor function in rats.
Hypertension
25:
166-169,
1995
25.
Kozma, F,
Johnson RA,
Zhang F,
Yu C,
Tong X,
and
Nasjletti A.
Contribution of endogenous carbon monoxide to regulation of diameter in resistance vessels.
Am J Physiol Regulatory Integrative Comp Physiol
276:
R1087-R1094,
1999
26.
Lee, PJ,
Jiang BH,
Chin BY,
Iyer NV,
Alam J,
Semenza GL,
and
Choi AM.
Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia.
J Biol Chem
272:
5375-5381,
1997
27.
Leffler, CW,
Nasjletti A,
Yu C,
Johnson RA,
Fedinec AL,
and
Walker N.
Carbon monoxide and cerebral microvascular tone in newborn pigs.
Am J Physiol Heart Circ Physiol
276:
H1641-H1646,
1999
28.
Li, D,
Zhou N,
and
Johns RA.
Soluble guanylate cyclase gene expression and localization in rat lung after exposure to hypoxia.
Am J Physiol Lung Cell Mol Physiol
277:
L841-L847,
1999
29.
Lin, H,
and
McGrath JJ.
Carbon monoxide effects on calcium levels in vascular smooth muscle.
Life Sci
43:
1813-1816,
1988[ISI][Medline].
30.
Marks, GS,
McLaughlin BE,
Vreman HJ,
Stevenson DK,
Nakatsu K,
Brien JF,
and
Pang SL.
Heme oxygenase activity and immunohistochemical co-localization in bovine pulmonary artery and vein.
J Cardiovasc Pharmacol
30:
1-6,
1997[ISI][Medline].
31.
McMurtry, IF,
Davidson AB,
Reeves JT,
and
Grover RF.
Inhibition of hypoxic pulmonary vasoconstriction by calcium agonists in isolated lungs.
Circ Res
38:
99-104,
1976[Abstract].
32.
Morita, T,
Perrella MA,
Lee ME,
and
Kourembanas S.
Smooth muscle cell-derived carbon monoxide is a regulator of vascular cGMP.
Proc Natl Acad Sci USA
92:
1475-1479,
1995[Abstract].
33.
Motterlini, R,
Gonzales A,
Foresti R,
Clark JE,
Green CJ,
and
Winslow RM.
Heme oxygenase-1-derived carbon monoxide contributes to the suppression of acute hypertension in vivo.
Circ Res
83:
568-577,
1998
34.
O'Donaughy, TL,
and
Walker BR.
Renal vasodilatory influence of endogenous carbon monoxide in chronically hypoxic rats.
Am J Physiol Heart Circ Physiol
279:
H2908-H2915,
2000
35.
Otterbein, LE,
Kolls JK,
Mantell LL,
Cook JL,
Alam J,
and
Choi AM.
Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury.
J Clin Invest
103:
1047-1054,
1999
36.
Ramos, KS,
Lin H,
and
McGrath JJ.
Modulation of cyclic guanosine monophosphate levels in cultured aortic smooth muscle cells by carbon monoxide.
Biochem Pharmacol
38:
1368-1370,
1989[ISI][Medline].
37.
Resta, TL,
Chicoine LG,
Omdahl JL,
and
Walker BR.
Maintained upregulation of pulmonary eNOS and protein expression during recovery from chronic hypoxia.
Am J Physiol Heart Circ Physiol
276:
H699-H708,
1999
38.
Resta, TC,
and
Walker BR.
Chronic hypoxia selectively augments endothelium-dependent pulmonary arterial vasodilation.
Am J Physiol Heart Circ Physiol
270:
H888-H896,
1996
39.
Rodman, DM,
Stelzner TJ,
Zamora MR,
Bonvallet ST,
Oka M,
Sato K,
O'Brien RF,
and
McMurtry IF.
Endothelin-1 increases the pulmonary microvascular pressure and causes pulmonary edema in salt solution but not blood-perfused rats lungs.
J Cardiovasc Pharmacol
20:
658-663,
1992[ISI][Medline].
40.
Schmidt, H.
NO, CO, OH. Endogenous soluble guanylyl cyclase-activating factors.
FEBS Lett
307:
102-107,
1992[ISI][Medline].
41.
Steiner, AA,
and
Branco LG.
Carbon monoxide is the heme oxygenase product with a pyretic action: evidence for a cGMP signaling pathway.
Am J Physiol Regulatory Integrative Comp Physiol
280:
R448-R457,
2001
42.
Stone, JR,
and
Marletta MA.
Soluble guanylate cyclase from bovine lung: activation with nitric oxide and carbon monoxide and spectral characterization of the ferrous and ferric states.
Biochemistry
33:
5636-5640,
1994[ISI][Medline].
43.
Tamayo, L,
Lopez-Lopez JR,
Castaneda J,
and
Gonzalez C.
Carbon monoxide inhibits hypoxic pulmonary vasoconstriction in rats by a cGMP-independent mechanism.
Pflügers Arch
434:
698-704,
1997[ISI][Medline].
44.
Townsley, MI,
Korthuis RJ,
Rippe B,
Parker JC,
and
Taylor AE.
Validation of double occlusion method for Pc,i in lung and skeletal muscle.
J Appl Physiol
61:
127-132,
1986
45.
Utz, J,
and
Ullrich V.
Carbon monoxide relaxes ileal smooth muscle through activation of guanylate cyclase.
Biochem Pharmacol
41:
1195-1201,
1991[ISI][Medline].
46.
Villamor, E,
Perez-Vizcaino F,
Cogolludo AL,
Conde-Oviedo J,
Zaragoza-Arnaez F,
Lopez-Lopez JG,
and
Tomargo J.
Relaxant effects of carbon monoxide compared with nitric oxide in pulmonary and systemic vessels of newborn piglets.
Pediatr Res
48:
546-553,
2000
47.
Wakabayashi, Y,
Takamiya R,
Mizuki A,
Kyokane T,
Goda N,
Yamaguchi T,
Takeoka S,
Tsuchida E,
Suematsu M,
and
Ishimura Y.
Carbon monoxide overproduced by heme oxygenase-1 causes a reduction of vascular resistance in perfused rat liver.
Am J Physiol Gastrointest Liver Physiol
277:
G1088-G1096,
1999
48.
Wang, R,
Lingyun W,
and
Wang Z.
The direct effect of carbon monoxide on Kca channel in vascular smooth muscle.
Pflügers Arch
434:
285-291,
1997[ISI][Medline].
49.
Wang, R,
Wang Z,
and
Wu L.
Carbon monoxide-induced vasorelaxation and the underlying mechanisms.
Br J Pharmacol
121:
927-934,
1997[Abstract].
50.
Wang, R,
and
Wu L.
The chemical modification of Kca channels by carbon monoxide in vascular smooth muscle cells.
J Biol Chem
272:
8222-8226,
1997
51.
Yet, SF,
Perrella MA,
Layne MD,
Hsieh C,
Maemura K,
Kobzik L,
Wiesel P,
Christou H,
Kourembanas S,
and
Lee M.
Hypoxia induces severe right ventricular dilation and infarction in heme oxygenase-1 null mice.
J Clin Invest
103:
R23-R29,
1999
52.
Zhang, F,
Kaide J,
Wei Y,
Jiang H,
Yu C,
Balazy M,
Abraham NG,
Wang W,
and
Nasjletti A.
Carbon monoxide produced by isolated arterioles attenuates pressure-induced vasoconstriction.
Am J Physiol Heart Circ Physiol
281:
H350-H358,
2001