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Ann Thorac Surg 2004;77:238-242
© 2004 The Society of Thoracic Surgeons

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Original article: cardiovascular

Effects of sildenafil analogue UK 343-664 on a porcine model of acute pulmonary hypertension

^a Department of Surgery, Gainesville, Florida, USA
^b Department of Anesthesiology, University of Florida, College of Medicine, Gainesville, Florida, USA

^* Address reprint requests to Dr Lobato, Department of Anesthesiology, University of Florida College of Medicine, Box 100254, Gainesville, FL 32610-0254, USA.
e-mail: elobato{at}anest.ufl.edu

Presented at the Forty-ninth Annual Meeting of the Southern Thoracic Surgical Association, Miami Beach, FL, Nov 7–9, 2002.

	Abstract

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BACKGROUND: Sildenafil (Pfizer Pharmaceuticals, Sandwich, Kent, UK) has been associated with pulmonary vasorelaxation. A more potent Sildenafil analogue (UK 343-664 [Pfizer Pharmaceuticals]) has been developed, but its effects in vivo have not been studied. This study evaluated the effects of UK 343-664 (Pfizer) during acute pulmonary hypertension.

METHODS: Fourteen adult swine were anesthetized with 1 minimum alveolar concentration isoflurane and were mechanically ventilated with an FIO₂ of 50%. End tidal CO₂ was maintained between 32 and 36 mm Hg. Micromanometer tipped catheters were placed in the ascending aorta, pulmonary artery, and right ventricle. Pulmonary flow was measured with a perivascular probe using transit time ultrasound. Pulmonary hypertension was induced with a continuous infusion of the thromboxane analogue U46619. Animals were randomized into two groups. Group 1 (n = 9) received 500 µg of UK 343-664 (Pfizer) intravenously for more than 2 minutes. Group 2 (n = 5) served as the control group. Data were recorded continuously for 60 minutes. Statistical analyses were performed with the analysis of variance and t tests. A p less than 0.05 was considered significant.

RESULTS: Pulmonary hypertension was achieved in all animals. The administration of UK 343-664 (Pfizer) was associated with a significant decrease in pulmonary artery pressure (30.3%; p < 0.05) and pulmonary vascular resistance (42%; p < 0.05) with mild systemic vasodilatation. These effects were partially maintained at 30 minutes (a 17.3% and 39% decrease, respectively; p < 0.05).

CONCLUSIONS: The administration of UK 343-664 (Pfizer) was associated with predominant pulmonary vasodilatation without systemic hypotension. This may represent a significant advance in the treatment of acute pulmonary hypertension. Potential clinical implications for this new phosphodiesterase enzyme type V (PDEV) inhibitor merit further study.

	Introduction

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Acute pulmonary hypertension during cardiac surgery presents a formidable challenge for the clinician because of its association with high morbidity and mortality. The efficacy of pulmonary vasodilator therapy rests in the ability to increase vascular smooth muscle cyclic adenosine monophosphate with the use of ß-adrenergic agonists and prostaglandins, or cyclic guanosine monophosphate with either nitrosodilators or inhaled nitric oxide [1–4]. The pulmonary vasculature is rich in phosphodiesterase enzymes type III (PDEIII) and phosphodiesterase enzymes type V (PDEV), which inactivate cyclic adenosine monophosphate and cyclic guanosine monophosphate, respectively [5]. These enzymes are also over-expressed in patients with chronic pulmonary vascular disease, thus limiting the potency of agonist agents [6]. Because of the importance of maintaining increased concentrations of cyclic adenosine monophosphate and cyclic guanosine monophosphate to achieve pulmonary vasodilation, both PDEIII and PDEV have become targets for newer therapies.

Inhibition of PDEIII by drugs (such as amrinone and milrinone) is associated with pulmonary vasodilation and increased cardiac contractility; however, systemic vasodilation tends to occur due to the lack of pulmonary selectivity [7]. Experimentally, the inhibition of PDEV by drugs such as Zaprinast (A. G. Scientific Inc, San Diego, CA), Dipyridamole (Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT), or Sildenafil (Pfizer Pharmaceuticals) is associated with pulmonary vasodilation [8–10]. Anecdotal reports of intragastric administration of Sildenafil (Pfizer) have demonstrated significant effects on pulmonary vascular resistance [11–12]. A major limitation to its clinical use in the perioperative period is the lack of an intravenous preparation, because absorption through the gastrointestinal tract is presumed to be unpredictable. As a result, newer agents that can be administered intravenously are currently being developed. This pilot study examines the effects of a new intravenous Sildenafil analogue (UK 343-664 [Pfizer Pharmaceuticals]) during experimental pulmonary hypertension.

	Material and methods

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The protocol was approved by the University of Florida Institutional Animal Care and Use Committee. Animals were handled in accordance with guidelines established by the National Institutes of Health (National Institutes of Health, Publication No. 85-23, revised 1985).

Fourteen domestic swine weighing 50 to 55 kg were pre-medicated with intramuscular ketamine (35 mg/kg) and anesthetized with isoflurane in 50% oxygen. Then a tracheostomy was performed, and the animals were mechanically ventilated at 12 breaths per minute with tidal volumes of 12 mL/kg to maintain an end-tidal CO₂ between 32 and 36 mm Hg. Anesthesia and mechanical ventilation were maintained with the use of a Narkomed 4 anesthesia machine (North American Dräger, Telford, PA). Pancuronium was used for muscle relaxation during the surgical preparation. A 7 French pressure-tipped flotation pulmonary artery catheter (Millar Instruments Inc, Houston, TX) was inserted through the right internal jugular vein into the main pulmonary artery through an 8 French Cordis introducer (Arrow Intl, Reading, PA). A 7 French triple lumen central venous catheter was placed through the left internal jugular vein. The left carotid artery was exposed, and a 5 French pressure-tipped catheter (Millar Instruments Inc, Houston, TX) was placed and advanced into the ascending aorta for continuous arterial pressure monitoring. Then a median sternotomy was performed, and the heart placed in a pericardial cradle. A 5 French pressure-tipped catheter (Millar Instruments Inc) was inserted through a small stab wound into the right ventricular cavity for measurement of right ventricular pressure. Cardiac output was measured with a 10-mm perivascular ultrasound probe placed in the main pulmonary artery. All transducers were connected to a biomedical amplifier (Grass, model 7D [Grass Instruments Co, Quincy, MA]). The signals were digitized and continuously recorded at 200 Hz on a personal computer for later analysis (Sonometrics Corp, London, Ontario, Canada).

Maintenance of intravascular volume was accomplished with lactated Ringer's solution administered by continuous infusion through a peripheral vein at a rate of 10 mL/kg/h. Normothermia (pulmonary artery temperature of 37°C) was maintained by the application of a warming blanket. All animals were allowed to stabilize for one hour after the surgical preparation before data collection

Hemodynamic measurements
Hemodynamic measurements included systemic arterial pressure, pulmonary artery pressure, right ventricular pressure, central venous pressure, cardiac output, right ventricular dp/dt. Pulmonary and systemic vascular resistances were calculated using standard formulas (pulmonary vascular resistance = mean pulmonary artery pressure-pulmonary artery occlusion/cardiac output; systemic vascular resistance = mean arterial pressure-central venous pressure divided by cardiac output).

Drug preparation
Lyophilized UK 343-664 (Pfizer Pharmaceuticals) was mixed with 0.1 N-dimethyl-sulfoxide. This solution was diluted in normal saline to render a final concentration of 10 mg/mL). Before the study, 1 mg of the thromboxane A2 analogue U46619 was diluted in 20 mL of lactated Ringer's solution (Biomol Inc, St. Louis, MO).

After baseline measurements, a continuous intravenous infusion of the thromboxane analogue U46610 (Biomol Inc, St. Louis, MO), was administered and was slowly titrated (rate: 0.5 to 2.5 µg/kg/min) to achieve a two-fold elevation in mean pulmonary artery pressure. When the target mean pulmonary artery pressure was achieved, the infusion of U46610 remained constant. Sustained pulmonary hypertension was maintained for 30 minutes. The animals were then randomized to receive a dose of 500 µg/kg UK 343-664 (Pfizer) for more than 2 minutes (n = 9), or a placebo (normal saline solution) in equal volume (equivalent to the total dose of UK 343-664 [in ccs] [Pfizer]) through the central venous catheter. The second group (n = 5) received normal saline in equal volume. Measurements were performed before and 5 and 30 minutes after the administration of UK 343-664 (Pfizer).

	Results

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Table 1 shows the measured hemodynamic data in both groups of animals. Both groups had comparable hemodynamics before the induction of pulmonary hypertension.

During U46619-induced pulmonary hypertension, the administration of UK 343-664 (Pfizer) decreased mean PAP from 38.2 ± 6.4 mm Hg to 26.5 ± 5.8 mm Hg at 5 minutes (32%; p < 0.05) and at 30 minutes (16%) from 38.2 mm Hg to 31.7 mm Hg, whereas mean PAP in the controls was maintained through the duration of the experiment (Fig 1). There were no significant changes in systemic vascular resistance from baseline in either group. Pulmonary vascular resistance increased significantly in both groups with U46619, but returned to near baseline levels in the UK 343-664 group (Pfizer), whereas in the control group it remained significantly elevated (Fig 2). Cardiac output, although higher in the UK 343-664 group (Pfizer) was not significantly different than the control group. Right ventricular contractility, as measured by dp/dt, was significantly depressed during pulmonary hypertension in both groups and was not improved by the administration of UK 343-664 (Pfizer).

View larger version (22K): [in this window] [in a new window]   Fig 1. Mean pulmonary arterial pressure in mm Hg in both groups. *p less than 0.05 compared with other sampling sites. p less than 0.05 compared with U46619. (Dashed line = UK343-664; straight line = control.)

View larger version (20K): [in this window] [in a new window]   Fig 2. Derived hemodynamic measurements of systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) in Wood units in both groups. *p less than 0.05 compared with other sampling sites. (Line 1 = SVR control; line 2 = SVR UK343-664; line 3 = PVR control; line 4 = PVR UK343-664.)

	Comment

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The treatment of acute pulmonary hypertension in the perioperative period is limited by several factors. The use of traditional intravenous agents to induce pulmonary vasodilation is limited by the risk of hypotension as a result of their systemic vasodilatory effects [13]. Patients with chronic pulmonary hypertension appear to be at higher risk because they require higher doses of these agents [14].

Inhaled nitric oxide is a potent selective pulmonary vasodilator that exerts its effects through the augmentation of cyclic guanosine monophosphate [15]. Several trials have demonstrated its efficacy in patients during heart transplantation and congenital heart disease repair [16–17]. However, its main drawback is that it requires delivery through a closed system; patients require the presence of an endotracheal tube or a sealed mask. In addition, rebound pulmonary hypertension occurs when withdrawing the nitric oxide, and monitoring for toxicity is required [18, 19].

The pulmonary vasodilatory properties of the PDEV inhibitor, Sildenafil (Pfizer), have been recently described [20]. In experimental models of pulmonary hypertension, both the intragastric administration and nebulized Sildenafil (Pfizer) produced a significant decrease in pulmonary vascular resistance in the absence of significant hypotension [20, 21]. These effects seem to correlate with the degree of PDEV inhibition and the increase in intracellular cyclic guanosine monophosphate in pulmonary vascular smooth muscle [22].

Clinicians have recently reported the use of oral Sildenafil (Pfizer) in patients with pulmonary hypertension to facilitate withdrawal of nitric oxide during placement of ventricular assist devices or in the postoperative period [23, 24]. Despite its advantages and initial enthusiasm, a significant drawback is the lack of an intravenous formulation to ensure absorption and titration.

UK 343-664(Pfizer) is a recently developed analogue of Sildenafil (Pfizer) with PDEV-inhibiting properties. Preliminary data suggest that UK 343-664 (Pfizer) is approximately three times more potent than Sildenafil (Pfizer). Unlike its parent compound, UK 343-664 (Pfizer) is easily reconstituted for intravenous use. The results of this preliminary study demonstrate that UK 343-664 (Pfizer) produces significant pulmonary vasodilation with a minor concomitant reduction in systemic vascular resistance, thus suggesting relative pulmonary selectivity. Future work will define its role and that of other second-generation Sildenafil (Pfizer) analogues in the treatment of acute pulmonary hypertension.

Statistical analysis
Data were expressed as mean ± standard deviations. A two-way analysis of variance was used, followed by the Student Newman-Keuls test for multiple comparisons. A p less than 0.05 was considered significant. A Student's t test was performed to determine whether the two groups were comparable at baseline.

	Acknowledgments

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Support was provided from institutional or departmental funds, or a combination of these, Department of Anesthesiology, University of Florida, College of Medicine, Gainesville, FL.

	Discussion

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DR CONSTANTINE MAVROUDIS (Chicago, IL): I question this model in terms of here you are giving a drug to cause pulmonary hypertension, then simply reversing this effect with another.

DR BONNELL: I agree, this model seems overly simple and far removed from a true clinical scenario. It is, however, a well-described and widely used model from the literature and seemed like a good place to start. Thromboxane is implicated as an important mediator of pulmonary hypertension in humans coming off pump, so this may have some correlation to clinical events. We have moved on to test this in a more complex model, these results are still pending.

DR MAVROUDIS: What is the halflife and time of onset?

DR BONNELL: Truthfully, I don't know. The pharmacokinetics are not yet known or released. The onset of action in our experience was very rapid, within a couple minutes. It also seems relatively short-lived, as in less than an hour. Oral sildenafil has a halflife of 4 hours, is shortened by other p-450 drugs, and is prolonged in renal failure. I imagine this drug may have similar, albeit shorter kinetics.

DR MAVROUDIS: Have you thought of comparing this drug with NO, milrinone, or Flolan (GlaxoSmithKline, Research Triangle Park, NC)?

DR BONNELL: Yes, though I may not discuss the results here; we have compared this drug with milrinone. We have not compared it with Flolan or nitric oxide. There are some reports in the literature using oral sildenafil either instead of, or as an adjunct to NO in the clinical management of pulmonary hypertension with promising results.

DR MAVROUDIS: How do you see this as being clinically applicable?

DR BONNELL: There is certainly a subset of patients, that is, those with severe mitral disease that have significant pulmonary hypertension and subsequent right ventricular dysfunction coming off pump. In addition, transplant candidates with elevated RV and pulmonary pressures may not be candidates, as placing a new heart with a conditioned RV results in immediate RV failure. A highly selective and effective pulmonary vasodilator may make such patients transplantable.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Thomas M. Beaver Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bonnell, M. R. Articles by Lobato, E. B. Search for Related Content PubMed PubMed Citation Articles by Bonnell, M. R. Articles by Lobato, E. B. Related Collections Cardiac - pharmacology