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Anesth Analg 1999;89:152
© 1999 International Anesthesia Research Society

CRITICAL CARE AND TRAUMA

Combined Therapy with Inhaled Nitric Oxide and Intravenous Vasodilators During Acute and Chronic Experimental Pulmonary Hypertension

Margaret Aranda, MD*, Katherine Kilroy Bradford, MD{dagger}, and Ronald G. Pearl, MD, PhD*

Departments of *Anesthesia and {dagger}Pediatrics, Stanford University Medical Center, Stanford, California

Address correspondence and reprint requests to Ronald G. Pearl, MD, PhD, Department of Anesthesia, S274, Stanford University Medical Center, Stanford, CA 94305-5117. Address e-mail to RGP{at}leland.stanford.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Both inhaled nitric oxide (NO) and IV vasodilators decrease pulmonary hypertension, but the effects of combination therapy are unknown. We studied the response to inhaled NO (100 ppm) alone, IV vasodilator alone, and combined therapy during acute (U46619-induced) and chronic (monocrotaline-induced) pulmonary hypertension in the pentobarbital-anesthetized rat. Vasodilator doses were 1.0, 3.2, 10, and 32 µg · kg-1 · min-1 sodium nitroprusside (SNP); 50, 100, 150, 200, and 300 µg · kg-1 · min-1 adenosine; or 25, 50, 150, 200, and 300 ng · kg-1 · min-1 prostacyclin. In the absence of IV vasodilator therapy, inhaled NO decreased mean pulmonary artery pressure without decreasing mean systemic arterial pressure. In both acute and chronic pulmonary hypertension, the addition of inhaled NO to the largest dose of adenosine or prostacyclin, but not of SNP, decreased pulmonary artery pressure. Because inhaled NO and SNP activate guanylyl cyclase and adenosine and prostacyclin activate adenylyl cyclase, the results suggest that adding inhaled NO to a vasodilator not dependent on guanylyl cyclase may produce additional selective pulmonary vasodilation.

Implications: In therapy of pulmonary hypertension, inhaled nitric oxide should produce additional selective pulmonary vasodilation when combined with a vasodilator whose mechanism of action is not dependent on cyclic guanosine 3',5'-monophosphate.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Nitric oxide (NO) is a potent endogenous vasodilator (1). After its release from the endothelium, NO diffuses to the vascular smooth muscle cell, where it activates the enzyme guanylyl cyclase, increasing the conversion of cyclic guanosine 5'-triphosphate (cGTP) to cyclic guanosine 3',5'-monophosphate (cGMP). The increased levels of cGMP initiate a series of events and eventually activate a protein kinase that dephosphorylates myosin light chains, causing vasodilation.

IV nitrovasodilators similarly produce vasodilation and may therefore be beneficial in the treatment of pulmonary hypertension. However, these drugs produce vasodilation in both the pulmonary and systemic circulations, because of the direct release of NO (e.g., sodium nitroprusside [SNP]) or metabolism to NO (nitroglycerin, isosorbide dinitrate) (1). The systemic vasodilation may result in systemic hypotension, leading to right ventricular ischemia and heart failure.

Both endogenous and exogenous NO may modulate vascular tone. In some species, NO modulates baseline pulmonary tone, and in all species, pulmonary hypertension activates endogenous NO release and thereby modulates pulmonary hypertension (2,3). Inhaled NO decreases pulmonary hypertension and improves hypoxemia in animals (4,5) and humans (6–9). Selective pulmonary vasodilation occurs because inhaled NO is inactivated on binding to the iron moiety of oxyhemoglobin in the pulmonary circulation.

Many pulmonary vasodilators, such as prostacyclin (PGI2) and adenosine, act by increasing cyclic adenosine 3',5'-monophosphate (cAMP). PGI2 was discovered by Moncada and Vane (10) during their study of platelet interactions with vascular walls. Like NO, PGI2 is released secondary to physical stimuli, hormones, and platelet-derived substances. An arachidonic acid metabolite, PGI2 is synthesized and released from vascular endothelium and smooth muscle, leading to vascular relaxation and inhibition of platelet function. Its vasodilatory effects are mediated by activation of prostaglandin receptors coupled to the adenylyl cyclase system, which increases cAMP (11). Adenosine, a purine nucleoside, increases intracellular cAMP and produces vasodilation through activation of adenosine A2 receptors (12,13).

Both IV vasodilators and inhaled NO have been used to treat pulmonary hypertension. In theory, combination therapy with inhaled NO and IV vasodilators may have additive or synergistic effects on pulmonary hypertension without producing excessive systemic hypotension. Because there are few studies of this strategy, we evaluated the use of combined therapy in acute and chronic pulmonary hypertension in the rat. Acute pulmonary hypertension was produced by the vasoconstrictor thromboxane mimetic U46619. Chronic pulmonary hypertension was produced by the administration of monocrotaline, a cytotoxic pyrrolizidine alkaloid extracted from the plant Crotolaria spectabilis.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The protocol was approved by the Stanford Administrative Panel on Laboratory Animal Care.

Male Sprague-Dawley rats (n = 24, 425–475 g; Simonsen Labs, Inc., Gilroy, CA) were maintained in a temperature-controlled setting with normal day/night cycles and were allowed to eat and drink ad libitum before study. Anesthesia was induced with 80 mg/kg pentobarbital sodium subcutaneously (SC), 40 mg/kg ketamine IM, and 0.28 mg/kg atropine intraperitoneally (IP). Anesthesia was maintained with 2.5–5.0 mg of pentobarbital SC every 30–60 min as needed. Blood temperature was maintained at 38–39°C with a Deltaphase pad. During surgery, 60% oxygen was delivered via flow-by mask. A bilateral carotid artery and three internal jugular vein catheters were inserted. Hetastarch 6% (Hespan; Dupont Pharm, Wilmington, DE) 5–10 mL/kg IV was given for a mean arterial pressure <100 mm Hg. A pulmonary artery (PA) catheter was inserted via the internal jugular vein (14) under pressure waveform guidance until the catheter wedged in the PA. The catheter was then withdrawn until it displayed PA pressure. A 2.5F aortic thermodilution catheter (Model 94–030-2.5F; Baxter Healthcare Corporation, Irvine, CA) for measurement of cardiac output (CO) was inserted via the carotid artery. Mean systemic arterial pressure (SAP) and mean pulmonary arterial pressure (PAP) were monitored continuously by an oscilloscope (Model 78534C; Hewlett-Packard, Palo Alto, CA) and strip-chart recorder (Model 78576A/78339A; Hewlett-Packard). CO was measured in triplicate by thermodilution with 0.3 mL iced isotonic sodium chloride solution.

After catheter insertion, the rat was enclosed in a polycarbonate sealed container with a scavenging system. The fraction of inspired oxygen was decreased to 30%, and baseline measurements of SAP, PAP, and CO were obtained. After baseline measurements, inhaled NO was added to the inspiratory limb of the circuit to produce an inspired concentration of 100 ppm, a concentration that produces maximal effects in this model (see Discussion). Inhaled NO was administered using a tank of 800 ppm in nitrogen, and inhaled NO and NO2 concentrations were continuously monitored by chemiluminesence. NO2 concentrations were always <1 ppm. Hemodynamic measurements were obtained after at least 5 min of inhaled NO administration. Inhaled NO was then discontinued. Acute pulmonary hypertension was then produced by a continuous IV infusion of U46619 at 830-1125 ng · kg-1 · min-1. The infusion rate was adjusted to a PAP of 25–30 mm Hg, with stabilization for at least 30 min.

Chronic pulmonary hypertension was produced in 26 rats by a monocrotaline injection (60 mg/kg SC) 3–4 wk before surgery. On the day of surgery, rats were treated identically to the acute pulmonary hypertension rats, but U46619 was not infused.

For both acute and chronic pulmonary hypertension, the effects of inhaled NO were studied before vasodilator therapy and with increasing doses of one of three vasodilators in each rat. After baseline measurements during pulmonary hypertension, inhaled NO (100 ppm) was administered. Measurements were obtained after at least 5 min of NO, and at least 10 min was allowed for recovery after NO discontinuation. Rats were then assigned to one of three vasodilator groups. The following increasing doses were used: SNP at 1, 3.2, 10, and 32 µg · kg-1 · min-1; adenosine at 50, 100, 150, 200, and 300 µg · kg-1 · min-1; and prostacyclin at 25, 50, 150, 200, and 300 ng · kg-1 · min-1. At each vasodilator dose, data were recorded after 20–30 min stabilization with and without inhaled NO (order randomized). At study conclusion, rats were killed and PA catheter placement was confirmed.

U46619 (Upjohn Laboratories, Kalamazoo, MI) was prepared in 95% ethanol at 5 mg/mL and diluted to 10 µg/mL before infusion. SNP (Elkins-Sinn, Inc., Cherry Hill, NJ) was infused at a concentration of 200 µg/mL. Adenosine (Sigma Chemical Company, St. Louis, MO) was infused at a concentration of 2 mg/mL isotonic sodium chloride solution. PGI2 (Glaxo Wellcome, Research Triangle Park, NC) was mixed with Tris buffer for a final concentration of 1125 ng/mL.

Data are reported as mean ± SEM. Data were analyzed by using analysis of variance, followed by Newman-Keuls' test when appropriate. Statistical significance occurred at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Acute Pulmonary Hypertension
In the acute pulmonary hypertension studies (n = 24 rats), baseline PAP was 12.4 ± 0.5 mm Hg, and inhaled NO produced a small but significant decrease in PAP to 11.3 ± 2.9 mm Hg (P < 0.01). Inhaled NO did not significantly affect SAP (126 ± 3 vs 122 ± 3 mm Hg) or CO (152 ± 5 vs 156 ± 7 mL · kg-1 · min-1). U46619 increased PAP by 15.9 ± 0.9 mm Hg (P < 0.01) without affecting SAP or CO. Inhaled NO during U46619-induced pulmonary hypertension decreased PAP by 5.7 ± 0.9 mm Hg (P < 0.01) without affecting SAP or CO (Tables 1–3).


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  		Table 1. Effects of SNP and Inhaled NO in Rats with Acute Pulmonary Hypertension due to U46619 Administration
 

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  		Table 2. Effects of Adenosine and Inhaled NO in Rats with Acute Pulmonary Hypertension due to U46619 Administration
 

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  		Table 3. Effects of Prostacyclin and Inhaled NO in Rats with Acute Pulmonary Hypertension due to U46619 Administration
 
SNP (n = 8 rats) produced dose-related decreases in PAP and SAP, without any effect on CO (Table 1). Adding inhaled NO to the smaller doses of SNP (1 and 3.2 µg · kg-1 · min-1) caused significant decreases in PAP without affecting SAP or CO. At larger doses of SNP, the addition of inhaled NO did not affect PAP, SAP, or CO.

Adenosine (n = 8 rats) produced dose-related decreases in PAP and SAP with no change in CO (Table 2). Inhaled NO decreased PAP at all adenosine doses. Inhaled NO did not affect SAP or CO at any adenosine dose.

PGI2 (n = 8 rats) produced dose-related decreases in PAP without any effect on CO (Table 3); changes in SAP did not reach statistical significance. Inhaled NO decreased PAP at all PGI2 doses without changes in SAP or CO.

Chronic Pulmonary Hypertension
In the chronic pulmonary hypertension studies (n = 26 rats), baseline PAP was 25.0 ± 1.4 mm Hg (all three groups combined) (Tables 4–6). Inhaled NO decreased PAP by 4.1 ± 1.4 mm Hg (P < 0.01) and did not affect SAP or CO.


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  		Table 4. Effects of SNP and Inhaled NO in Rats with Monocrotaline (MCT)-Induced Chronic Pulmonary Hypertension (PHTN)
 

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  		Table 5. Effects of Adenosine and Inhaled NO in Rats with Monocrotaline (MCT)-Induced Chronic Pulmonary Hypertension (PHTN)
 

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  		Table 6. Effects of Prostacyclin and Inhaled NO in Monocrotaline (MCT)-Treated Rats
 
SNP (n = 10 rats) produced dose-related decreases in PAP and SAP, with no change in CO (Table 4). Adding inhaled NO to the smaller doses of SNP decreased PAP, but adding inhaled NO to the larger doses of SNP did not decrease PAP. Inhaled NO did not affect SAP or CO.

Adenosine (n = 8 rats) produced dose-dependent decreases in SAP with no effect on PAP or CO (Table 5). Inhaled NO decreased PAP at all adenosine doses, with no change in SAP and CO.

PGI2 (n = 8 rats) produced dose-related decreases in SAP and increases in CO (Table 6). Decreases in PAP did not reach statistical significance. Inhaled NO further decreased PAP at all prostacyclin doses, without any effect on SAP or CO.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In treating pulmonary hypertension, the achievement of pulmonary vasodilation with minimal systemic effects is desirable. Current therapy includes the use of oral, IV, and inhaled drugs. IV and oral therapy is frequently limited by systemic hypotension. Therapeutic strategies to provide selective pulmonary vasodilation without systemic hypotension include drugs delivered via inhalation. Inhaled NO selectively decreases PAP in patients with pulmonary hypertension (6,15). The vasodilator effects are limited to the pulmonary circulation because NO is rapidly inactivated by binding to hemoglobin.

Because of its activation of A2 receptors, adenosine is an effective pulmonary vasodilator (11,13). It has been used as a screening drug and as a therapeutic drug in patients with pulmonary hypertension (11,15). In vivo feline responses to U46619-induced pulmonary hypertension show that adenosine causes vasoconstriction (A1 receptor effects) at low baseline pulmonary vascular tone and vasodilation (A2 receptor effects) at high pulmonary vascular tone (12). IV adenosine has been successfully used for treating refractory pulmonary hypertension (11,16) and postcardiac surgical pulmonary hypertension (17).

PGI2 is a potent pulmonary vasodilator. In patients with primary pulmonary hypertension, acute treatment with IV PGI2 and its synthetic analogs may produce pulmonary vasodilation (18,19), and long-term IV PGI2 is effective in reducing pulmonary vascular resistance (18,20) and may result in improved long-term survival (21).

In the present study, we investigated whether the combination of an IV vasodilator and inhaled NO would have additive effects in decreasing experimental pulmonary hypertension. We used established models of acute and chronic pulmonary hypertension. U46619 activates thromboxane receptors, producing pulmonary vasoconstriction that is primarily precapillary (22). Monocrotaline produces pathologic changes, including increased collagen formation and muscularization of small pulmonary arteries (23), similar to primary pulmonary hypertension. Inhaled NO and IV vasodilators decrease PAP during U46619-induced acute pulmonary hypertension (24,25) and monocrotaline-induced chronic pulmonary hypertension (26,27).

We delivered inhaled NO at 100 ppm. Dose-dependent pulmonary vasodilator effects have been reported to occur in monocrotaline-treated rats at 20–60 ppm (27) and in U46619-treated pigs at 5–40 ppm (24). In studies of acute pulmonary hypertension due to U46619 administration in rats, inhaled NO at 1, 20, and 100 ppm produced identical decreases in PAP (n = 7) (Hill LL, Pearl RG, unpublished observations). Similarly, in pilot studies (n = 4) in chronic monocrotaline-induced pulmonary hypertension in rats, we found that inhaled NO doses of 10–100 ppm equivalently decreased PAP. Our dose of 100 ppm should have produced a maximal effect.

The combination of inhaled NO and either adenosine or PGI2 produced an additive effect in decreasing PAP. Adenosine and PGI2 produce vasodilation via increases in cAMP; inhaled NO produces vasodilation via increases in cGMP. Combination therapy with inhaled NO and a vasodilator that activates adenylyl cyclase, rather than guanylyl cyclase, may be responsible for the additive pulmonary vasodilator effects (28). The results from this study are consistent with the limited reports available, which show additive decreases in PAP when two drugs with different mechanisms of action are used to treat pulmonary hypertension (24,29,30). During U46619-induced pulmonary hypertension in pigs, additive decreases in PAP occurred when inhaled NO was used in combination with the IV PGI2 analog ciloprost (24). In a case report, combined therapy with inhaled NO and IV PGI2 was beneficial in refractory pulmonary hypertension in an infant (30). In humans, preferential reductions in PAP with combined therapy have been shown with inhaled NO and an oral PGI2 analog, beraprost sodium (29).

Therapy with inhaled drugs other than NO has been studied. U46619-treated perfused rabbit lungs receiving both IV and inhalation therapy with PGI2 and prostaglandin E1 had reduced shunt flow only with inhaled therapy (25). In humans, inhaled PGI2 may be more beneficial than IV PGI2 or inhaled NO alone in reducing PAP (31). Combined therapy with inhaled NO and inhaled PGI2 in experimental acute pulmonary hypertension (28) and in monocrotaline-treated rats results in additive decreases in PAP (32).

In the current study, the addition of inhaled NO to large doses of IV SNP did not further decrease PAP. These results differ from those of Rich et al. (9), who noted that inhaled NO did produce pulmonary vasodilation in patients receiving IV nitrates after cardiopulmonary bypass. It is possible that Rich et al. (9) did not use maximally effective pulmonary vasodilator doses of nitrates, thereby corresponding to the small dose of SNP used in the current study. Our results are consistent with those of Obbergh et al. (24), who showed that the addition of inhaled NO to IV nitroglycerin did not decrease pulmonary hypertension in pigs.

In summary, we studied combination therapy with inhaled and IV drugs in acute and chronic pulmonary hypertension. Inhaled NO, in combination with adenosine or PGI2, but not with SNP, produced additional selective pulmonary vasodilation. Further studies are required to assess whether combined therapy is effective in the clinical setting.


   Footnotes
 
Presented in part at the 1997 annual meeting of the American Society of Anesthesiologists, San Diego, CA.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 6, 1999.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press