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Anesth Analg 1999;89:932
© 1999 International Anesthesia Research Society

CRITICAL CARE AND TRAUMA

Inhaled Nitric Oxide and Nifedipine Have Similar Effects on Lung cGMP Levels in Rats

Damian J. Horstman, MS, David A. McCall, Deborah U. Frank, MD, PhD, and George F. Rich, MD, PhD

Departments of *Anesthesiology and {dagger}Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia

Address correspondence and reprint requests to George F. Rich, MD, PhD, Department of Anesthesiology, PO Box 10010, University of Virginia Health System, Charlottesville, VA 22906-0010. Address e-mail to gfr2f{at}virginia.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Inhaled nitric oxide (NO) may downregulate the endogenous NO/cyclic guanosine monophosphate (cGMP) pathway, potentially explaining clinical rebound pulmonary hypertension. We determined if inhaled NO decreases pulmonary cGMP levels, if the possible downregulation is the same as with nifedipine, and if regulation also occurs with the cyclic adenosine monophosphate (cAMP) pathway. Rats were exposed to 3 wk of normoxia, hypoxia (10% O2), or monocrotaline (MCT; single dose = 60 mg/kg) and treated with either nothing (control), inhaled NO (20 ppm), or nifedipine (10 mg · kg-1 · day-1). The lungs were then isolated and perfused with physiologic saline. Perfusate cGMP, prostacyclin, and cAMP levels were measured. Perfusate cGMP was not altered by inhaled NO or nifedipine in normoxic or MCT rats. Although hypoxia significantly increased cGMP by 128%, both inhaled NO and nifedipine equally prevented the hypoxic increase. Inhibition of the NO/cGMP pathway with NG-nitro-L-arginine methyl ester (L-NAME) decreased cGMP by 72% and 88% in normoxic and hypoxic lungs. Prostacyclin and cAMP levels were not altered by inhaled NO or nifedipine. L-NAME significantly decreased cGMP levels, whereas inhaled NO had no effect on cGMP in normoxic or MCT lungs, suggesting that inhaled NO does not inhibit the NO/cGMP pathway. Inhaled NO decreased cGMP in hypoxic lungs, however, nifedipine had the same effect, which indicates the decrease is not specific to inhaled NO.

Implications: High pulmonary pressure after discontinuation of inhaled nitric oxide (NO) may be secondary to a decrease in the natural endogenous NO vasodilator. This rat study suggests that inhaled NO either does not alter endogenous NO or that it has similar effects as nifedipine.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Endogenous nitric oxide (NO) is synthesized in the endothelium from L-arginine by the enzyme NO synthase (NOS). NO diffuses into the smooth muscle and activates soluble guanylate cyclase (GC) which stimulates the conversion of guanosine triphosphate to guanosine 3',5'-cyclic monophosphate (cGMP) resulting in smooth muscle vasodilation (1). Endothelial NOS (eNOS) plays an important role in regulation of vascular tone. Upregulation of eNOS and cGMP levels occurs with chronic hypoxia-induced increases in pulmonary arterial pressure and vascular remodeling (2–4). Although upregulation of endogenous NO during chronic hypoxia may be important in decreasing pulmonary vascular tone, exogenous sources of NO may downregulate the NO/cGMP pathway via feedback inhibition (5,6).

Inhaled NO is a selective pulmonary vasodilator that acts via the same mechanism as endogenous NO (7). Inhaled NO is used as therapy for pulmonary hypertension in a variety of diseases (8,9). The benefits of inhaled NO may be tempered by potential negative feedback on the endogenous NO/cGMP pathway (10). Rebound pulmonary hypertension has been reported whereby discontinuation of inhaled NO increases pulmonary arterial pressure (11,12). Although the mechanism is unclear, rebound pulmonary hypertension may result from downregulation of the endogenous NO/cGMP pathway. In vitro studies suggest that exogenous NO downregulates endogenous NO (6). Prolonged administration of inhaled NO has been shown to cause either no effect or a decrease in endothelium-dependent vasodilation (10,13,14). We have recently demonstrated that inhaled NO decreases pulmonary cGMP levels in chronically hypoxic rats (14).

In this study, we determined if 3 wk of inhaled NO (20 ppm) alters pulmonary cGMP levels in normoxic conditions and after induced pulmonary hypertension caused by hypoxia or monocrotaline (MCT)-mediated chemical inflammation (15). Second, we determined if possible downregulation with inhaled NO also occurs with nifedipine (Ni), a vasodilator that acts independently of NO. We hypothesized that similar results with Ni may suggest that vasodilation, rather than specific effects of NO, are responsible for decreasing cGMP levels. Finally, we determined if inhaled NO alters other endogenous vasodilating pathways or if the effects of inhaled NO are limited to the NO/cGMP pathway. Previous studies have indicated that prostacyclin (PGI2) and cyclic adenosine monophosphate (cAMP) are regulated by hypoxia and pressure (16,17). Therefore, we measured perfusate PGI2 as determined by 6-keto-PGF1a and cAMP levels in MCT and hypoxic rats exposed to either inhaled NO or Ni.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This study was approved by the animal research committee at the University of Virginia. Male Sprague-Dawley rats (n = 5–7 per group), weighing 250–290 g, were subjected to one of nine treatment regimes. Rats were exposed to 3 wk of normoxia, hypoxia (10% O2), or MCT and treated with either inhaled NO (20 ppm), Ni, or nothing (control). MCT groups were given a single 60 mg/kg intraperitoneal injection at the start of the 3-week period. MCT was prepared by dissolving 100 mg MCT in 2 mL 1N HCl, adjusting to 7.0 pH with 1N NaOH and diluting to a final volume of 5 mL. Ni groups were injected with Ni (10 mg/kg) intraperitoneally daily. Ni was prepared by dissolving 10 mg Ni in 1 mL of dimethyl sulfoxide. To determine the effects of NOS inhibition on perfusate cGMP levels, NG-nitro-L-arginine methyl ester (L-NAME, 100 µM) was added to the perfusate in additional rats exposed to normoxia, normoxia plus NO, hypoxia, and hypoxia plus NO (n = 6 for each group).

All groups were enclosed in their environment for 3 wk. Oxygen levels were regulated with a Pro:Ox Model 350 U (Reming Bioinstrument Co., Redfield, NY) by infusion of N2 for the hypoxic groups or by infusion of O2 for normoxic groups. A pump (Willinger Bros. Inc., Oakland, NJ) circulated the gaseous environment through anhydrous calcium sulfate (W.A. Hammond Drierite Company, Xenia, OH), barium hydroxide lime (Chereton Medical Division, Allied Healthcare Products Inc., St. Louis, MO), and activated carbon (Fisher Scientific, Newark, DE) to remove water vapor, CO2, NO2, and ammonia, respectively.

NO was delivered at a constant flow rate from a compressed gas cylinder containing 400 ppm NO in N2. Environmental NO was monitored by chemiluminescence with a Nitric Oxide Analyzer (Sievers, Boulder, CO), and flow rate was adjusted to achieve 20 ppm NO. Nitrogen dioxide (NO2) levels were monitored daily by electrochemical sensors. NO2 levels were always <2.0 ppm.

After 3 wk of environmental exposure, rats were anesthetized with 0.4 g urethane and 30 mg {alpha}-chloralose. A 17-gauge cannula was inserted into the trachea via a tracheotomy. The lungs were ventilated with warmed gas (5% CO2, balance air) using a small animal ventilator (Harvard, South Natick, MA) with a tidal volume of 1 mL/100g body weight and a frequency of 60 breaths/min. A sternotomy was performed to expose the heart and lungs, and the rat was heparinized (100 U) via the right ventricle. Pulmonary artery pressure was measured by inserting a 22-gauge catheter into the right ventricle and advancing it into the pulmonary artery. The systolic and diastolic pressures were read on a Datascope 2001A monitor (Paramus, NJ) and the mean pressure (Pa) was calculated.

The lungs were isolated and perfused with a blood-free perfusate. A 13-gauge cannula, connected to the primed perfusion system, was inserted through the pulmonic valve into the pulmonary artery. A suture was tied around the pulmonary artery and aorta to secure the cannula and prevent systemic blood flow. A 3.5-mm OD cannula was inserted into the apex of the left ventricle and secured with umbilical tape. Perfusate drained from the left ventricle to a glass reservoir and returned to the pulmonary artery by a roller pump (Cole Parmer, Barrington, IL). A circumferential water jacket warmed the perfusate in the reservoir to 37°C. The lungs remained in situ, and once the pulmonary circulation was isolated, the perfusate flow rate was increased to 16 mL/min. The initial drainage from the circulation was discarded to ensure a cell free perfusate.

Perfusate was a physiologic salt solution containing (in mM) 119.0 NaCl, 4.7 KCl, 1.2 MgSO4 · 7H2O, 22.6 NaHCO3, and 1.2 KH2PO4. Dextrose (0.1g/100 mL), Ficoll (4g/100 mL), and insulin (100mU/mL) were also added. The perfusate pH was maintained between 7.35 and 7.45 by addition of HCl or NaHCO3, as necessary. A total perfusate volume of 50 mL was recirculated.

After 90 min, a 1-mL sample of perfusate was collected for analysis. The 1-mL sample was divided into aliquots of: 1) 250 µL diluted with 250 µL of 0.2 N HCl for measurement of cAMP, 2) 250 µL diluted with 25 µL of IBMX (5 x 10-4 M) and 225 µL of 0.2 N HCl for measurement of cGMP, and 3) 500 µL diluted with 50 µL indomethacin in EDTA for measurement of prostacyclin. The samples were stored at -20°C. cGMP and cAMP levels were determined using radioimmunoassay. PGI2 levels were determined by measuring 6-keto-PGF1a, a stable PGI2 metabolite, with an RIA kit (Amersham Corp., Arlington Heights, IL).

To determine the extent of right ventricular hypertrophy, the ventricles were separated from the vessels and the atria. The right ventricular free wall (RV) was cut from the left ventricle and septum (LV + S), and each were weighed separately. The ventricular weight ratio was determined from RV/(LV + S). Dry lung weights were determined by removing the lungs from the body and excising all vessels and connective tissue. The lungs were then baked overnight until all fluid was removed.

Results are expressed as mean ± SEM. Statistical comparisons of pulmonary arterial pressures, right ventricular hypertrophy, cAMP, cGMP, and 6-keto-PGF1a concentrations were performed using a one-way analysis of variance with a Dunnett test for multiple comparisons. Differences were reported as significant at P < 0.05.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Hemodynamics and Morphology
All rats survived the 3 wk of environmental exposure and treatment. Inhaled NO and Ni did not significantly alter Pa in the normoxic group (Table 1). Hypoxia significantly increased Pa compared with normoxic controls, while inhaled NO and Ni equally attenuated the increase in Pa secondary to hypoxia (as measured in normoxic conditions in the absence of NO). MCT significantly increased Pa compared with normoxic controls, although neither inhaled NO nor Ni attenuated this increase. Inhaled NO and Ni had no effect on right ventricular hypertrophy in the normoxic group. RV hypertrophy was significantly increased by hypoxia and MCT compared with normoxic controls. Inhaled NO and Ni equally attenuated the increase in the hypoxic and MCT groups.


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  		Table 1. Hemodynamics and Morphology
 
Hypoxic and MCT groups gained significantly less weight than the normoxic group (Table 1). NO and Ni significantly decreased the weight gains in normoxic, hypoxic, and MCT groups, with the effect of Ni being greater than that of NO. Hypoxia and MCT significantly increased dry lung to body weight ratio. Inhaled NO and Ni significantly increased dry lung to body weight ratio in MCT rats, but had no effect in hypoxic or normoxic rats.

Perfusate cGMP Concentration
Perfusate cGMP concentration was not altered by inhaled NO or Ni in the normoxic group (Figure 1). The cGMP levels were significantly increased in the untreated hypoxic lungs compared with the normoxic controls. Inhaled NO and Ni prevented the increase in the hypoxic groups equally. Perfusate cGMP concentration was not affected by MCT compared with normoxic controls. Inhaled NO and Ni had no significant effect on cGMP in the MCT group.



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  		Figure 1. The effect of inhaled nitric oxide and nifedipine on perfusate cGMP levels in rats exposed to 3 wk of normoxic, monocrotaline, or hypoxic conditions. * indicates that hypoxia significantly (P < 0.05) increased cGMP compared with normoxic controls. # indicates that inhaled nitric oxide and nifedipine significantly decreased (P < 0.05) cGMP compared with hypoxia alone. Data are mean ± SEM.

 
L-NAME significantly decreased the cGMP level in normoxic rats with and without inhaled NO by 72% ± 15% and 54% ± 8%. Likewise, L-NAME decreased the cGMP levels by 88% ± 10% and 40% ± 8% in the hypoxic and hypoxic plus NO groups.

Perfusate cAMP and 6-keto-PGF1a Concentrations
Perfusate cAMP and 6-keto-PGF1a concentrations (Figures 2 and 3) were not altered by inhaled NO or Ni in the normoxic or hypoxic groups. The hypoxic group was not significantly different from the normoxic group. Perfusate cAMP and 6-keto-PGF1a concentrations were significantly decreased in the MCT group compared with normoxic controls. Inhaled NO and Ni did not alter cAMP levels in the MCT group.



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  		Figure 2. The effect of inhaled nitric oxide and nifedipine on perfusate cAMP levels in rats exposed to 3 wk of normoxic, monocrotaline, or hypoxic conditions. * indicates that MCT significantly (P < 0.05) decreased cAMP compared with normoxic controls. Data are mean ± SEM.

 


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  		Figure 3. The effect of inhaled NO and nifedipine on perfusate 6-keto-PGF1a levels in rats exposed to 3 wk of normoxic, monocrotaline, or hypoxic conditions. * indicates that MCT significantly (P < 0.05) decreased 6-keto-PGF1a compared with normoxic controls. Data are mean ± SEM.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Previous studies have suggested that endogenous and exogenous NO may inhibit the NO/cGMP pathway because of negative feedback inhibition (5,6). We investigated the effect of inhaled NO on the NO/cGMP pathway by measuring perfusate cGMP levels in isolated lungs of normoxic rats and hypoxia- and MCT-induced pulmonary hypertensive rats. Our results suggest that inhaled NO does not alter cGMP levels in normoxic or MCT rats, but attenuates the increase in cGMP levels associated with three weeks of hypoxia. The attenuation with inhaled NO, however, was no different than that of rats treated with Ni, suggesting that the decrease in cGMP is not specific to NO.

There was no difference in isolated lung perfusate cGMP levels between normoxic controls and those exposed to three weeks of inhaled NO. This suggests that the NO/cGMP pathway is unaffected by inhaled NO. Although controversial, other groups have suggested that inhaled NO downregulates the endogenous NO pathway under normoxic conditions (10,13). Combes et al. (10) and Oka et al. (13) independently showed that 48 hours of inhaled NO resulted in a decrease in endothelium NO-dependent vasodilation. In their studies, NO inhalation during normoxic conditions also resulted in an increased pressor response to angiotensin II and thromboxane analog U-46619. These in vivo studies are supported by in vitro reports that suggest NO or NO-donors inhibit eNOS activity by directly interacting with the NO synthase (6,18). NO has also been reported to inhibit NO synthesis in response to bradykinin and increased fluid shear or flow (19). In contrast, our previous studies indicate that endothelium NO-dependent vasodilation, eNOS protein levels, and NOS activity are not altered by three weeks of inhaled NO (14). The present study also suggests that inhaled NO does not downregulate the NO/cGMP pathway, as measured by perfusate cGMP levels.

Chronic hypoxia markedly increased perfusate cGMP levels. This is consistent with Muramatsu et al. (20), who showed that isolated lung cGMP perfusate levels are increased with exposure to chronic hypoxia. Previous studies also indicate that lung tissue cGMP levels from hypoxic rats are increased by Day 3 of hypoxia and continue to increase with prolonged exposure (3). Upregulation of eNOS and iNOS genes and protein expression in the pulmonary vasculature of chronically hypoxic rats have been reported, and it is likely that increased cGMP levels are the direct result of increased NOS (2).

Inhibition of the endogenous NO/cGMP pathway, with the NOS inhibitor L-NAME, decreased perfusate cGMP levels by 72% in normoxic rats and by 88% in hypoxic rats. This indicates that inhibition of NOS results in a decrease in perfusate cGMP and that the majority of cGMP measured in the perfusate is a product of the NO/soluble GC pathway. This finding is consistent with results by Kurrek et al. (21), however, others have suggested that particulate GC may also contribute significantly to perfusate cGMP (20).

Inhaled NO and Ni decreased cGMP levels equally in hypoxic rats. While inhaled NO may inhibit NOS by a direct feedback mechanism, Ni, a calcium channel antagonist, acts independently of NO and is unlikely to have any direct effects on the NOS enzyme. The observation that inhaled NO and Ni decrease cGMP equally suggests the etiology may be pulmonary vasodilation, rather than specific effects of the NO molecule. Furthermore, the decrease in perfusate cGMP levels caused by L-NAME-induced NOS inhibition was greater than the reduction in cGMP caused by inhaled NO or Ni in hypoxic rats. L-NAME also significantly decreased cGMP in hypoxic rats exposed to inhaled NO. Despite these results, we cannot rule out that the effects of inhaled NO may be decreased, because NO was discontinued at the time of lung isolation, whereas the effects of L-NAME and Ni persist after isolation. Additionally, Ni may increase cGMP because Ni has been shown to inhibit phosphodiesterase in porcine smooth muscle cell cultures (22). Nevertheless, these results suggest that the effects of inhaled NO and Ni on cGMP are not the same as inhibiting NOS. More importantly, in normoxic rats inhaled NO and Ni had no effect on cGMP levels. This is despite the observation that inhibition of the NO/cGMP pathway with L-NAME significantly decreased cGMP levels in normoxic lungs.

Although both Ni and inhaled NO attenuate pulmonary vascular remodeling (23,24), it is unlikely that the quantity of vascular smooth muscle is a significant determinant of the cGMP level. First, in hypoxic rats, the cGMP levels were decreased to normoxic levels by inhaled NO and Ni despite limited attenuation of hypoxic-induced pulmonary hypertension and right ventricular hypertrophy. Second, both inhaled NO and Ni attenuated vascular remodeling as suggested by RV hypertrophy in MCT rats, yet there was no effect on cGMP levels.

Perfusate cGMP levels were increased after hypoxia, but unaffected in MCT-induced pulmonary hypertension. While eNOS and cGMP are upregulated by hypoxia, the mechanisms are unclear. LeCras et al. (2) suggested that increased NOS expression is unlikely to be a result of shear stress alone. Everett et al. (25) recently demonstrated that, unlike chronic hypoxia-induced vascular remodeling, pulmonary vascular remodeling resulting from increased pulmonary blood flow is not associated with changes in eNOS. MCT and hypoxia result in vascular remodeling and increased Pa, however, previous studies have shown that arterial PO2 values from MCT rats remain unaltered throughout a three-week exposure (15). The observation in our study that hypoxia, but not MCT, increases cGMP levels, suggests that lower PO2 is required for NO/cGMP upregulation. The effect of MCT on the NO/cGMP pathway is not well documented. While MCT-induced endothelial injury may decrease NO (26), others have reported that NO production is increased 7 and 14 days after MCT administration (27).

We also investigated the effect of inhaled NO and Ni on the PGI2/cAMP pathway to determine if endogenous vasodilating pathways, other than NO/cGMP, are altered. Neither inhaled NO nor Ni had an effect on cAMP or PGI2 levels in normoxic, hypoxic, or MCT rats. The effect of hypoxia and MCT-induced pulmonary hypertension on the production of the PGI2 and cAMP is not well known, although Yamaguchi et al. (27) suggested that PGI2 production is increased in rats two weeks after MCT. In our study, MCT significantly decreased production of cAMP and 6-keto-PGF1a, although hypoxia had no effect. Acute hypoxia has been reported to stimulate PGI2 synthesis in cultured neonatal lung cells (16) and bovine aortic endothelial cells (28). In contrast, PGI2 levels are decreased in the lungs of chronically hypoxic animals (17) and are significantly lower in resistance in mesenteric arteries of spontaneously hypertensive rats (29). Previous studies have suggested that PGI2 and cAMP production levels are related to hemodynamics and shear stress (17,30). Yet, in our study, hypoxia and subsequent treatment with inhaled NO or Ni did not affect cAMP or the PGI2 metabolite, 6-keto-PGF1a.

In conclusion, this rat study suggests that inhaled NO may not downregulate the endogenous NO/cGMP pathway as measured by perfusate cGMP levels under normoxic conditions or in a MCT pulmonary hypertensive model. Under hypoxic conditions, inhaled NO decreases lung perfusate cGMP levels, but this decrease is the same as with Ni, suggesting that the decrease in cGMP is not specific to inhaled NO.


   Footnotes
 
Funded by a grant from Ohmeda Pharmaceutical.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication June 2, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press