Anesth Analg 2003;97:1497-1500
© 2003 International Anesthesia Research Society
CRITICAL CARE AND TRAUMA
Intermittent Nitric Oxide Combined with Intravenous Dipyridamole in a Piglet Model of Acute Pulmonary Hypertension
Luc Foubert, MD PhD*,
Daniël De Wolf, MD PhD
,
Koen Reyntjens, MD*,
Yves Van Belleghem, MD DSc
,
Filip De Somer, CCP PhD,
Guido Van Nooten, MD PhD, and
Eric Mortier, MD DSc*
*Department of Anesthesia, Division of Cardiac Anesthesia;
Department of Pediatrics, Division of Pediatric Cardiology; and
Department of Cardiac Surgery, University Hospital Ghent, and Laboratory for Experimental Cardiac Surgery, Ghent University, Ghent, Belgium
Address correspondence to Luc Foubert, MD, PhD, Department of Anesthesia and Intensive Care, OLV Hospital Aalst, Moorselbaan 164, Aalst, Belgium. Address e-mail to Luc.Foubert{at}olvz-aalst.be Reprints will not be available.
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Abstract
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Continuous administration of inhaled nitric oxide is now widely used as a potent and selective pulmonary vasodilator. We have evaluated the effects of IV dipyridamole, a cyclic guanosine monophosphate (cGMP) phosphodiesterase inhibitor, on the magnitude and duration of action of inhaled nitric oxide (NO)-mediated pulmonary vasodilation. We hypothesized that inhibition of cGMP degradation could augment and prolong the pulmonary vasodilating effects of NO and allow for intermittent NO inhalation. In eight anesthetized and mechanically ventilated piglets, IV U-46619, a thromboxane A2 analog, was used to induce pulmonary hypertension. The effects of 2, 5, and 10 ppm of NO, delivered during 4 min for each concentration and followed by a 10-min NO-free interval after each NO concentration, were evaluated without and with dipyridamole. Pulmonary vascular resistance decreased from 825 ± 49 dynes · s · cm-5 (U-46619) to 533 ± 48 dynes · s · cm-5 (10 ppm NO) (P < 0.05 versus U-46619) and 396 ± 42 dynes · s · cm-5 (dipyridamole 10 µg · kg-1 · min-1 and 10 ppm NO) (P <0.05 versus NO), and cardiac output increased from 1.93 ± 0.09 L/min to 2.03 ± 0.13 L/min and 2.60 ± 0.30 L/min (P < 0.05 versus NO). Mean arterial blood pressure decreased from 90 ± 5 mm Hg (10 ppm NO) to 75 ± 3 mm Hg (dipyridamole plus 10 ppm NO) (P < 0.01). The pulmonary vasodilation obtained with NO alone could be prolonged from 12 to 42 min when inhaled NO was combined with IV dipyridamole, accounting for a time-weighted reduction in NO exposure by 72%. We conclude that dipyridamole augments the effects of NO on right ventricular afterload, allows for intermittent NO inhalation, and can significantly reduce exposure to NO.
IMPLICATIONS: IV dipyridamole prolongs the action of inhaled nitric oxide (NO) in a piglet model of acute pulmonary hypertension. Intermittent NO inhalation combined with IV dipyridamole decreases pulmonary artery pressure for a prolonged period of time and reduces exposure to NO.
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Introduction
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Nitric oxide (NO) diffuses into vascular smooth muscle cells and mediates vasorelaxation through stimulation of guanylyl cyclase and production of cyclic guanosine monophosphate (cGMP), which is inactivated by cGMP-specific phosphodiesterases (1). Dipyridamole inhibits cGMP phosphodiesterase (PDE 5) activity in vascular rings and induces pulmonary vasodilation in the ovine fetus and in pediatric patients with pulmonary hypertension (2–4). Although inhaled NO is used in pulmonary hypertension, toxicity remains a concern (5,6), and it should be administered at the smallest effective concentration and for short periods of time. However, the pulmonary vasodilator effect of inhaled NO disappears after only 1–2 min, but it can theoretically be prolonged by inhibiting the breakdown of its second messenger cGMP. We investigated whether IV dipyridamole can prolong pulmonary vasodilation in anesthetized piglets and evaluated the hemodynamic effects of dipyridamole alone and in combination with inhaled NO.
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Methods
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All procedures were approved by the hospital ethics committee for animal research. After premedication (azaperone 8 mg/kg IM), eight piglets (10–12 kg) were anesthetized with IV sodium thiopental (10 mg/kg), intubated, and mechanically ventilated (fraction of inspired oxygen, 0.40). Normocapnia was achieved by adjusting respiratory rate, and anesthesia and paralysis were maintained with sufentanil (0.03 µg · kg-1 · min-1), propofol (160–200 µg · kg-1 · min-1), and pancuronium (0.15 mg/kg and 7 µg · kg-1 · min-1). The carotid artery (20 G; Vygon, Ecouen, France), the pulmonary artery (5F thermodilution catheter; Baxter Healthcare, McGaw Park, IL), and the external jugular vein (5F triple lumen; Cook, Bjaeverskov, Denmark) were cannulated for blood sampling, hemodynamic measurements, and drug administration. Invasive blood pressures and electrocardiogram were continuously monitored (HP 78304 A; Hewlett-Packard, Palo Alto, CA). Inhaled NO and nitrogen dioxide (NO2) concentrations were monitored with a chemiluminescence analyzer (NOX 4000; Seres, Aix-en-Provence, France).
After stabilization, mean pulmonary artery pressure (MPAP) was increased to 170%–180% of baseline values with U-46619, a stable thromboxane A2 analog (0.03–0.05 µg · kg-1 · min-1) and pulmonary vasoconstrictor. NO 2 ppm was delivered during 4 min and was then stopped for 10 min. The same procedure was repeated with 5 and 10 ppm of NO. Hemodynamic measurements were performed during NO administration and at 2, 4, 6, 8, and 10 min after cessation of each NO concentration. After the last NO-free period, the infusion of U-46619 was stopped for 30 min to allow recovery of the right ventricle. U-46619 was restarted to obtain similar MPAP as before, a continuous infusion of dipyridamole (10 µg · kg-1 · min-1) was started, and 20 min later, the NO dosing scheme was repeated (Fig. 1). The t1/2 was defined as the time from discontinuation of each NO inhalation to the time when mean MPAP returned to the value halfway between the MPAP during each NO inhalation and the pulmonary hypertension value during infusion of U-46619 (7). Data are presented as mean ± SD. Comparisons between two discrete variables were made with a paired Student’s t-test. For comparison between data on NO versus NO plus dipyridamole, a two-way analysis of variance for repeated measures was used.
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Figure 1. Schematic representation of the study protocol. Each nitric oxide (NO) (ppm) dose was administered during 4 min followed by a 10-min NO-free period. Hemodynamic measurements were performed at baseline, during U-46619, at the end of each NO dosing period, and every 2 min during each NO-free interval. The same measurements were performed during dipyridamole infusion.
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Results
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Infusion of U-46619 increased MPAP from 14 ± 1 mm Hg to 25 ± 2 mm Hg (P < 0.001) and increased mean arterial blood pressure (MAP) from 82 ± 14 mm Hg to 90 ± 11 mm Hg (P < 0.01). Inhaled NO decreased MPAP without changes in systemic hemodynamic variables. The second infusion of U-46619 increased MPAP to 25 ± 2 mm Hg. Dipyridamole decreased MPAP to 21 ± 2 mm Hg (P < 0.001) and decreased MAP to 72 ± 8 mm Hg (P < 0.01), and it increased cardiac output (CO) (P < 0.05). The addition of inhaled NO to dipyridamole further increased CO without changes in MAP (Table 1). The t1/2 for MPAP increased from 1.3 ± 0.5 min, 1.1 ± 0.3 min, and 1.1 ± 0.3 min (2, 5, and 10 ppm NO) to 6.1 ± 3.0 min, 5.5 ± 3.0 min, and 6.7 ± 3.3 min, respectively, during dipyridamole infusion (Fig. 2). For all NO concentrations studied, MPAP returned to pretreatment values within 2 min after NO was discontinued (Fig. 3). Combined with dipyridamole, NO-induced vasodilation is prolonged over 42 min for 12 min of NO inhalation. This accounts for a time-weighted reduction in NO exposure by 72%.
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Table 1. Hemodynamic Changes (Mean ± sd) During Nitric Oxide (NO) Inhalation Alone and with Infused Dipyridamole (Dip)
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Figure 2. Effect of IV dipyridamole (10 µg · kg-1 · min-1) on the half-times of the vasodilating response to nitric oxide (NO) inhalation during U-46619-induced pulmonary hypertension. Values are mean ± SD; n = 8. *P < 0.05 versus control.
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Figure 3. Effect of intermittent nitric oxide (NO) inhalation (2, 5, and 10 ppm) on mean pulmonary artery pressure (MPAP) during infusion of U-46619 without and with IV dipyridamole infusion. Each NO concentration was inhaled during 4 min and followed by a 10-min NO-free interval. Values are mean ± SD; n = 8.
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Discussion
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The vasodilator response to inhaled NO is short lived and variable, which may be related to increased PDE activity or inhibition of guanylate cyclase (8–10). Despite the lack of prospective trials on long-term NO and NO2 toxicity in humans, potential toxicity remains a concern (11–13).
As previously reported in pediatric patients (4), our data confirm that dipyridamole is a nonselective pulmonary vasodilator. In our study, addition of inhaled NO to an infusion of dipyridamole further increased CO by >20% without changes in MAP (Table 1). This suggests augmentation of the effects obtained with NO plus dipyridamole, because inhaled NO alone does not increase CO. The t1/2 for NO increased almost fivefold during dipyridamole infusion, and this reflects dipyridamole’s potential to prolong the clinical effects of NO inhalation (Fig. 2). During the infusion of dipyridamole, the pulmonary vasodilation resulting from 4 minutes of NO inhalation persisted 10 minutes after the cessation of NO (Fig. 3). The clinical relevance of this finding may be that intermittent NO inhalation combined with IV dipyridamole may attenuate pulmonary hypertension for prolonged periods. This would result in less exposure to NO and NO2 and might consequently reduce potential toxicity.
Zaprinast, a selective PDE 5 inhibitor, has been reported to prolong the effect of inhaled NO (7,9), probably via an increase of cGMP in the pulmonary vascular smooth muscle cell (7). We have recently shown (14) that IV dipyridamole increases plasma cGMP levels, which remain increased even 20 minutes after discontinuation of both dipyridamole and inhaled NO. Furthermore, dipyridamole could prevent rebound pulmonary hypertension on withdrawal of inhaled NO. Instead of zaprinast (7,9), we studied dipyridamole, because it is a commercially available drug with a known safety profile in humans. Because of its long half-life, further study is warranted to investigate whether a submaximal dose of dipyridamole (two or three times a day) prolongs the effects of NO inhalation, without the risk for accumulation in systemic blood vessels and systemic hypotension. However, new selective PDE 5 inhibitors such as sildenafil seem to have selective pulmonary vasodilator activity devoid of systemic effects (15), although the conflicting results as to whether these drugs augment and prolong the effects of inhaled NO have to be clarified (16).
We conclude that intermittent NO inhalation attenuates pulmonary hypertension for a prolonged period of time when combined with IV dipyridamole. In clinical practice, a combination of intermittent NO inhalation with appropriate dosing of IV dipyridamole may be useful for decreasing NO and NO2 exposure in children who need prolonged NO inhalation, with clinically acceptable effects on the systemic circulation.
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References
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Accepted for publication June 3, 2003.
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Abstract
Introduction
