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Ann Thorac Surg 2004;78:1433-1437
© 2004 The Society of Thoracic Surgeons

Original article: cardiovascular

Effects of a New Phosphodiesterase Enzyme Type V Inhibitor (UK 343-664) Versus Milrinone in a Porcine Model of Acute Pulmonary Hypertension

Felipe Urdaneta, MDa, Jessica L. Willert, MDa, Thomas Beaver, MDb, Bhiken Naik, MDa, David S. Kirby, BAc, Emilio B. Lobato, MDa,c,*

a Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida, USA
b Division of Thoracic and Cardiovascular Surgery, University of Florida College of MedicineGainesville, Florida, USA
c North Florida/South Georgia Veterans Health System, Malcolm B. Randall Veterans Affairs Medical Center, Gainesville, Florida, USA

Accepted for publication April 12, 2004.

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


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
BACKGROUND: Perioperative pulmonary hypertension remains a clinical challenge. The phosphodiesterase enzyme type III inhibitor milrinone produces pulmonary vasodilation but lacks selectivity. Sildenafil, a phosphodiesterase enzyme type V inhibitor, can also induce relaxation of the pulmonary vasculature; however, only the oral formulation is presently available. This study evaluated the effects of a new intravenous sildenafil analogue—UK 343-664—compared with milrinone during acute pulmonary hypertension in a porcine model of thromboxane-induced pulmonary hypertension.

METHODS: After acute pulmonary hypertension, 24 adult swine were randomized to 3 groups. Group 1 (n = 9) received an intravenous dose of 500 µg of UK 343-664, group 2 (n = 8) received milrinone 50 mg/kg, and group 3 (n = 7) received 10 mL of normal saline solution. All agents were administered for more than 5 minutes. Data were recorded continuously for 30 minutes.

RESULTS: Both milrinone and UK 343-664 partially reversed thromboxane-induced pulmonary hypertension, with a notable decrease in mean pulmonary artery pressure and pulmonary vascular resistance and a concomitant increase in cardiac output. In addition, milrinone improved right ventricular contractility but produced marked systemic vasodilatation. In contrast, the administration of UK 343-664 was associated with pulmonary vasodilatation, without appreciable changes in systemic arterial pressure or vascular resistance.

CONCLUSIONS: Milrinone and UK 343-664 were equally effective as pulmonary vasodilators; however, only UK 343-664 exhibited a high degree of pulmonary selectivity. Potential uses for this new phosphodiesterase enzyme type V inhibitor warrant further study.


   Introduction
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 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Acute intraoperative pulmonary hypertension can have an appreciable effect on right ventricular function, leading to hemodynamic decompensation and marked perioperative morbidity and mortality. With the exception of oxygen, the ability of most pharmacologic agents to vasodilate the pulmonary circulation depends on their capacity to increase the cyclic adenosine monophosphate (cAMP) of the pulmonary vascular smooth muscle (eg, ß-adrenergic agonists and prostaglandins) or cyclic guanosine monophosphate (cGMP) with either nitrovasodilators or inhaled nitric oxide [1–4]. The predominant pathway for the inactivation of these cyclic nucleotides in the pulmonary vasculature is by phosphodiesterase enzymes type III (PDEIII) and type V (PDEV) [5]. These enzymes have been shown to be upregulated and overexpressed in the smooth muscle cells of patients with chronic pulmonary vascular disease. Thus, a given dose of cAMP and cGMP agonists will produce a decreased response and a shorter duration of action, and this in turn necessitates larger doses, which can induce adverse effects [6]. Because of the importance of maintaining increased concentrations of cAMP and cGMP 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; systemic vasodilation, however, tends to occur because of the lack of pulmonary selectivity [7]. Experimentally, the inhibition of PDEV by drugs such as zaprinast, dipyridamole, or sildenafil is associated with pulmonary vasodilation [8–10]. The oral, intragastric, or nebulized administration of sildenafil has demonstrated appreciable effects on pulmonary vascular resistance (PVR) [11–13]. 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 assumed to be unpredictable. As a result, newer agents that can be administered intravenously are currently being developed. The purpose of this study was to compare the effects of a new intravenous sildenafil analogue, UK 343-664, with an established agent such as the PDEIII inhibitor milrinone during experimental pulmonary hypertension.


   Material and Methods
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 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
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 (Publication 85-23; revised 1985).

Twenty-four domestic swine weighing 50 to 55 kg were premedicated with intramuscular ketamine (35 mg/kg) and anesthetized with 1 minimum alveolar anesthetic concentration of isoflurane in 100% oxygen. A tracheostomy was then 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 Drager, Telford, PA). Pancuronium was used for muscle relaxation during the surgical preparation. A 7F 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 8F Cordis introducer (Arrow International, Reading, PA). A 7F triple-lumen central venous catheter was placed through the left internal jugular vein. The left carotid artery was exposed, and a 5F pressure-tipped catheter (Millar Instruments Inc) was placed and advanced into the ascending aorta for continuous arterial pressure monitoring.

A median sternotomy was then performed, and the heart was placed in a pericardial cradle. A 5F 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, ONT, Canada).

Maintenance of intravascular volume was accomplished with lactated Ringer's solution administered by continuous infusion through a peripheral vein at 10 mL · kg–1 · h–1. Normothermia (pulmonary artery temperature of 37°C) was maintained by the application of a warming blanket. All animals were allowed to stabilize for 1 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, and right ventricular dP/dT (maximum rate of rise of systolic pressure during isovolumic contraction). PVR and systemic vascular resistance (SVR) were calculated with standard formulas (PVR = 80 x MPAP – PAOP/CO and SVR = 80 x MAP – CVP/CO, where MPAP is mean pulmonary artery pressure, PAOP is pulmonary artery occlusion pressure, MAP is mean arterial blood pressure, and CO is cardiac output).

Drug Preparation
Lyophilized UK 343-664 (a gift from Pfizer Pharmaceuticals, Sandwich, Kent, UK) was mixed with sterile water. This solution was diluted in normal saline to render a final concentration of 10 mg/mL. Undiluted injectable milrinone acetate at a concentration of 1 mg/mL (a gift from Sanofi-Synthelabo, New York, NY) was administered. Before the study was initiated, 1 mg of the thromboxane A2 analogue U46619 (Biomol Inc, St. Louis, MO) was diluted in 20 mL of lactated Ringer's solution.

After base line measurements, a continuous intravenous infusion of the thromboxane analogue U46619 was administered and slowly titrated (0.5 to 2.5 µg · kg–1 · min–1) to achieve a twofold increase in MPAP. Once the target MPAP was achieved, the infusion of U46619 remained constant and sustained pulmonary hypertension, which was maintained for 30 minutes. The animals were then randomized into 3 groups. Group 1 (n = 9) received UK 343-664 500 µg/kg; group 2 (n = 8) received milrinone 50 mg/kg; and group 3 (n = 7) received placebo (5 mL of normal saline solution). All agents were administered through the central venous catheter for more than 5 minutes with an infusion pump (Medfusion 2010; Medex Inc, Duluth, GA). Measurements were performed before and 5 and 30 minutes after the administration of UK 343-664, milrinone, or placebo.

Statistical Analysis
Data are expressed as mean ± standard deviation. A 2-way analysis of variance was used, followed by a Student-Newman-Keuls test for multiple comparisons. One-way analysis of variance was used for base line measurements to determine whether the 3 groups were comparable before the interventions. A p less than 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Table 1 shows the measured hemodynamic data in all 3 groups. There were no significant differences among the 3 groups at base line. The infusion of U46619 produced a marked increase in MPAP and central venous pressure, with a concomitant reduction in cardiac output and right ventricular dP/dT. During pulmonary hypertension, the administration of UK 343-664 was associated with a 32% and 16% reduction in MPAP at 5 and 30 minutes, respectively, whereas milrinone decreased MPAP by 20% and 14% at 5 and 30 minutes, respectively. Both milrinone and UK 343-664 markedly increased cardiac output. Systemic vasodilatation occurred with milrinone (a trend of reduction in MAP of 17% and 11% at 5 and 30 minutes, respectively), but not with UK 343-664. There were no considerable hemodynamic changes in the placebo group.


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  		Table 1. Hemodynamic Data

 
Figures 1 and 2 show the calculated values of PVR and SVR in all 3 groups. UK 343-664 and milrinone markedly decreased PVR at 5 and 30 minutes. SVR was relatively preserved with UK 343-664. In contrast, the administration of milrinone was associated with a marked reduction in SVR after pulmonary hypertension was induced. The effects on right ventricular contractility (dP/dT) are shown in Figure 3. Milrinone increased right ventricular dP/dT by 38% and 25% at 5 and 30 minutes, respectively, but it remained unchanged after UK 343-664.



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  		Fig 1. Changes in pulmonary vascular resistance (PVR) in all 3 groups. PVR markedly increased during the infusion of the thromboxane analogue U46619. The administration of UK 343-664 was associated with a 42% and 33% reduction in PVR at 5 and 30 minutes, respectively. Milrinone also decreased PVR by 39% and 30%. Pulmonary hypertension was maintained in the control group. ---- = UK 343-664; --{blacksquare}-- = milrinone; --{blacktriangleup}-- = placebo. *p < 0.05 to sampling time. {dagger}p < 0.05 to 46619.

 


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  		Fig 2. Changes in systemic vascular resistance (SVR) in all groups. The systemic vasodilatory effect of milrinone was evident by a 40% and 31% reduction in SVR at 5 and 30 minutes, respectively. SVR remained unchanged in both the UK 343-664 and placebo groups. ---- = UK 343-664; --{blacksquare}-- = milrinone; --{blacktriangleup}-- = placebo. *p < 0.05 to sampling time. {dagger}p < 0.05 to 46619.

 


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  		Fig 3. Changes in right ventricular (RV) contractility (dP/dT) over time. The induction of acute pulmonary hypertension was associated with a marked decrease in dP/dT in all groups. Only milrinone had an appreciable inotropic effect on the RV (increase in RV dP/dT of 39% and 24% at 5 and 30 minutes, respectively). In both the UK 343-664 and placebo groups, RV contractility remained markedly depressed. ---- = UK 343-664; --{blacksquare}-- = milrinone; --{blacktriangleup}-- = placebo. *p < 0.05 to sampling time. {dagger}p < 0.05 to 46619.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
The results of this study demonstrate that the administration of the PDEV inhibitor UK 343-664 was associated with appreciable pulmonary vasodilation, as evidenced by a decrease in MPAP and PVR. In addition, there seems to be a certain degree of pulmonary selectivity at the dose studied, because the slight decrease in mean systemic arterial pressure and SVR was not significant. In contrast, the inodilator milrinone predictably induced pulmonary vasodilation and improved right ventricular dP/dT, but at the expense of a greater decrease in MAP and SVR because of its systemic vasodilatory properties [7].

The perioperative treatment of acute pulmonary hypertension with traditional agents such as nitrovasodilators, ß-adrenergic agonists, and PDEIII inhibitors is limited by the risk of hypotension as a result of their systemic vasodilatory effects [14, 15]. Patients with preexisting pulmonary hypertension seem to be at an increased risk because they require higher doses of these agents [16].

Inhaled nitric oxide is a potent selective pulmonary vasodilator that exerts its effects through stimulation of guanylyl cyclase, leading to increased intracellular cGMP [17]. Several trials have demonstrated its efficacy in patients during heart transplantation and congenital heart disease repair [8, 18]. Its main limitation, however, is that it requires delivery through a closed system; thus, patients require an endotracheal tube or a sealed mask. In addition, rebound pulmonary hypertension occurs upon withdrawal of nitric oxide, and, thus, monitoring for toxicity is required [19, 20].

The ability of sildenafil and other PDEV inhibitors, such as zaprinast and dipyridamole, to decrease MPAP and PVR in experimental models of pulmonary hypertension has consistently been demonstrated [9, 10, 13]. These effects seem to correlate with the degree of PDEV inhibition and the increase in intracellular cGMP in pulmonary vascular smooth muscle [21].

Anecdotal reports describing the use of PDEV inhibitors as pulmonary vasodilators after cardiac surgery are encouraging. Intravenous dipyridamole was used successfully in a group of postoperative pediatric heart surgery patients [7]. The effects on platelet aggregation and hemostasis limit any potential use for dipyridamole in the immediate postoperative period or in the presence of coagulopathy.

Clinicians have recently described the use of oral sildenafil in patients with pulmonary hypertension to facilitate withdrawal of nitric oxide during placement of ventricular assist devices or in the postoperative period in adults and pediatric patients [22, 23]. A notable limitation is the lack of a widely available intravenous formulation.

UK 343-664 is a recently developed analogue of sildenafil with PDEV-inhibiting properties. Preliminary data suggest that UK 343-664 is approximately 2 to 3 times more potent than sildenafil (Pfizer, data on file). Unlike its parent compound, UK 343-664 is easily reconstituted for intravenous use. The results of this study suggest that UK 343-664 produces marked pulmonary vasodilation with relatively high selectivity.

The decrease in PVR seen after UK 343-664 was not associated with improvement in right ventricular dP/dT, as demonstrated by the persistent depression of right ventricular dP/dT. In contrast, the inotropic effects of milrinone on right ventricular function were clearly demonstrated by a marked improvement in dP/dT, but at the expense of considerable systemic vasodilation. The hemodynamic effects of both UK 343-664 and milrinone were at least partially preserved after 30 minutes.

In conclusion, this preliminary study showed that intravenous UK 343-664 is an effective pulmonary vasodilator. Future studies will better define the pharmacokinetic behavior of this new PDEV inhibitor and its potential role in the treatment of acute pulmonary hypertension.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

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  8. Ziegler JW, Ivy DD, Wiggins JW, Kinsella JP, Clarke WR, Abman SH. Effects of dipyridamole and inhaled nitric oxide in pediatric patients with pulmonary hypertension. Am J Respir Crit Care Med. 1998;158:1388–1395[Abstract/Free Full Text]
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 Br J AnaesthHome page
E. B. Lobato, T. Beaver, J. Muehlschlegel, D. S. Kirby, C. Klodell, and A. Sidi
Treatment with phosphodiesterase inhibitors type III and V: milrinone and sildenafil is an effective combination during thromboxane-induced acute pulmonary hypertension
Br. J. Anaesth., March 1, 2006; 96(3): 317 - 322.
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