Ann Thorac Surg 2006;81:272-278
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Differential Effects of Phosphodiesterase-5 Inhibitors on Hypoxic Pulmonary Vasoconstriction and Pulmonary Artery Cytokine Expression
Ben M. Tsai, MD
a
,
Mark W. Turrentine, MD
a
,
Brett C. Sheridan, MD
b
,
Meijing Wang, MD
a
,
Andrew C. Fiore, MD
c
,
John W. Brown, MD
a
,
Daniel R. Meldrum, MD
a
,
*
a Section of Cardiothoracic Surgery, Indiana University School of Medicine, Indianapolis, Indiana
b Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
c Division of Cardiothoracic Surgery, Saint Louis University School of Medicine, St. Louis, Missouri
Accepted for publication June 10, 2005.
* Address correspondence to Dr Meldrum, Section of Cardiothoracic Surgery, Indiana University School of Medicine, 545 Barnhill Dr, EH 215, Indianapolis, IN 46202 (Email: dmeldrum{at}iupui.edu).
Presented at the Basic Science Forum of the Fifty-first Annual Meeting of the Southern Thoracic Surgical Association, Cancun, Mexico, Nov 2–4, 2004.
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Abstract
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BACKGROUND: Perioperative pulmonary hypertension is a challenging clinical problem with numerous etiologies including hypoxia, adrenergic stimulation, and local inflammation. New oral phosphodiesterase-5 (PDE-5) inhibitors used for the treatment of erectile dysfunction may have beneficial effects on the pulmonary vasculature owing to the abundance of PDE-5 receptors in the lung. The purpose of this study was to compare the efficacy of sildenafil, vardenafil, and tadalafil in preventing acute hypoxic pulmonary vasoconstriction and hypoxia-induced pulmonary artery tumor necrosis factor-alpha (TNF-
) and interleukin-1-beta (IL-1ß) expression.
METHODS: Isolated rat pulmonary arteries suspended in physiologic organ baths for measurement of isometric force transduction were treated with vehicle (dimethyl sulfoxide), sildenafil, vardenafil, or tadalafil to assess (1) pulmonary artery relaxation; (2) inhibition of phenylephrine-induced pulmonary artery contraction; (3) inhibition of hypoxic pulmonary vasoconstriction (pO2 = 30-35 mm Hg); and (4) hypoxia-induced pulmonary artery TNF- and IL-1ß expression (reverse transcriptase–polymerase chain reaction).
RESULTS: Sildenafil, vardenafil, and tadalafil resulted in dose-dependent pulmonary artery relaxation and inhibited phenylephrine-induced pulmonary artery contraction, but only tadalafil significantly inhibited hypoxic pulmonary vasoconstriction (52.08% ± 7.65% tadalafil versus 88.63% ± 8.96% vehicle; 98.61% ± 10.04% sildenafil; 68.46% ± 15.84% vardenafil). Hypoxia-induced upregulation of TNF- and IL-1ß mRNA in pulmonary artery was significantly decreased by tadalafil, but not sildenafil or vardenafil pretreatment.
CONCLUSIONS: We conclude that sildenafil, vardenafil, and tadalafil were equally efficacious in causing pulmonary artery relaxation, but only tadalafil inhibited hypoxic pulmonary vasoconstriction and attenuated hypoxia-induced pulmonary artery TNF- and IL-1ß expression.
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Introduction
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Perioperative pulmonary hypertension is a formidable problem with limited treatment options. The challenge lies in identifying a therapeutic agent that is efficacious, selective for the pulmonary vasculature, has minimal systemic effects, and can be easily administered. Although phosphodiesterase inhibitors (eg, milrinone) have been used for the short-term treatment of perioperative pulmonary hypertension, there is increasing interest in the utilization of newer phosphodiesterase-5 (PDE-5) inhibitors [1–4]. There are at least seven isoforms of the PDE family, each having different tissue distributions and substrate specificity [5]. Recent studies have demonstrated abundant PDE-5 expression and activity in the pulmonary vasculature [2, 6, 7], which suggests that selective inhibition of the type 5 isoform may be advantageous in treating pulmonary hypertension.
The three commercially available PDE-5 inhibitors (sildenafil, vardenafil, and tadalafil) are currently approved for the treatment of erectile dysfunction [8]. These inhibitors are now receiving attention for their activity in the pulmonary vasculature [9]. There are several small reports of sildenafil demonstrating beneficial effects in the treatment of pulmonary hypertension [10–12]. However, there are few reports regarding the use of vardenafil or tadalafil on the pulmonary vasculature. Although sildenafil, vardenafil, and tadalafil act on the same enzyme, these drugs exhibit different pharmacokinetics and selectivity [8], and therefore may not be equally efficacious in the pulmonary vascular bed. Indeed, Ghofrani and colleagues [9] recently reported differences between the three PDE-5 inhibitors in the responses of patients with pulmonary arterial hypertension.
The purpose of this study was to compare the efficacy of sildenafil, vardenafil, and tadalafil on pulmonary hypertension using a well-established model of acute hypoxic pulmonary vasoconstriction in isolated rat pulmonary arteries [13–15]. We have previously shown that hypoxia alone upregulates the expression of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-) and interleukin-1-beta (IL-1ß) in pulmonary artery tissue [13]. Phosphodiesterase inhibitors may also have anti-inflammatory effects [16–18]. Therefore, we hypothesized that PDE-5 inhibitors may inhibit hypoxic pulmonary vasoconstriction and attenuate hypoxia-induced upregulation of TNF- and IL-1ß in pulmonary artery tissue.
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Material and Methods
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Animals
All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" (NIH publication No. 85-23, revised 1985). All animal protocols are approved by the Institutional Animal Care and Use Committee of the Indiana University School of Medicine. Male Sprague-Dawley rats (Harlan, Indianapolis, Indiana) weighing 250 to 350 g were allowed ad libitum access to food and water up to the time of experimentation.
Isolated Pulmonary Artery Ring Preparation
Rats were anesthetized with pentobarbital (150 mg/kg intraperitoneally). Median sternotomy was performed, and the heart and lungs were removed en bloc and placed in modified Krebs-Henseleit solution at 4°C. Under a dissecting microscope, extralobar pulmonary artery (PA) branches were dissected and cleared of surrounding tissue. Right and left main branch PA were cut into 2 to 3 mm wide rings (4 per animal) and suspended on steel hooks connected to force transducers (ADInstruments, Colorado Springs, Colorado) for measurement of isometric force displacement. Care was taken during this process to minimize endothelial injury by avoiding contact with the luminal surface of the arteries. Pulmonary artery rings were immersed in individual water-jacketed organ chambers containing modified Krebs-Henseleit solution bubbled with 95% O2/5% CO2 at 37°C. Krebs-Henseleit solution is a physiologic balanced salt solution containing (in mmol/L): NaCl 127, KCl 4.7, NaHCO3 17, MgSO4 1.17, KH2PO4 1.18, CaCl2 2.5, and D-glucose 5.5. Force displacement was recorded using a PowerLab (ADInstruments) eight-channel data recorder on an Apple iMac PowerPC G4 computer (Apple Computer, Cupertino, California).
Experimental Protocol and Groups
Before starting experimental protocols, PA rings were stretched to a predetermined [19] optimal passive tension of 750 mg and allowed to equilibrate for 60 minutes, during which time Krebs-Henseleit solution was changed every 15 minutes. Viability of each PA ring was then checked by measuring contractile response to 80 mmol/L KCl. This dosage was determined to produce maximal contractile response to KCl in previous experiments [19]. After washout of KCl, endothelial integrity of each PA ring was assessed with relaxation to acetylcholine (1 µmol/L) after phenylephrine (1 µmol/L) precontraction. These concentrations were derived from preliminary experiments to produce optimal contraction and relaxation. Rings demonstrating less than 50% vasorelaxation to acetylcholine were discarded (9 out of 92 total PA rings). Dose response curves (0.001 to 10 µmol/L) to vehicle (dimethyl sulfoxide), sildenafil, vardenafil, and tadalafil were generated in PA rings (n = 5 to 9 in each group) precontracted with phenylephrine (1 µmol/L). In separate experiments, PA rings (n = 5 or 6 in each group) were incubated with vehicle, sildenafil, vardenafil, or tadalafil (1 µmol/L) for 20 minutes before generation of dose response curves to phenylephrine (0.01 to 10 µmol/L). In another set of experiments, hypoxia was induced for 60 minutes by changing the organ bath gas to 95% N2/5% CO2 in PA rings (n = 8 to 10 in each group) pretreated with vehicle, sildenafil, vardenafil, or tadalafil for 20 minutes before hypoxia. After hypoxia, PA rings were snap frozen in liquid nitrogen for subsequent mRNA analysis.
Reverse Transcription–Polymerase Chain Reaction
Semiquantitative reverse transcription–polymerase chain reaction (RT-PCR) was used to assess TNF- and IL-1ß gene expression in PA rings. After tissue homogenization, total RNA was extracted from each pulmonary artery segment using RNA STAT-60 (TEL-TEST, Friendswood, Texas). Total RNA, 0.1 µg, was then subjected to cDNA synthesis using a cloned Avian Myeloblastosis Virus first-strand cDNA synthesis kit (Maxim Biotech, South San Francisco, California). The cDNA from each sample was used for PCR of cytokines using message screen rat PCR kits (Maxim Biotech). The PCR products were separated by electrophoresis on 2% agarose gel stained with ethidium bromide. Gels were digitally photographed under ultraviolet illumination with a FotoAnalyst Luminary cooled camera electronic documentation system (Fotodyne, Hartland, Wisconsin). Gel densitometries were quantified using ImageJ software (National Institutes of Health).
Chemicals and Reagents
All chemical reagents were obtained from Sigma (St. Louis, Missouri), unless otherwise specified. Sildenafil (Pfizer, New York, New York), vardenafil (Bayer Pharmaceuticals, West Haven, Connecticut), and tadalafil (Eli Lilly, Indianapolis, Indiana) were dissolved in dimethyl sulfoxide (DMSO) to make stock solutions (10 mM), which were then serially diluted in deionized distilled water. All drug concentrations were expressed as final molar concentration in the organ bath. Final pH of all solutions was 7.35 to 7.45. All reagents were dissolved in deionized distilled water unless otherwise specified.
Statistical Analysis
Vasodilation was expressed as the percentage difference from the force caused by phenylephrine precontraction. Force displacement during hypoxia was expressed as percentage change from the amount of phenylephrine-precontraction. All reported values were mean ± SEM. Experimental groups were compared using two-way analysis of variance (ANOVA) with post-hoc Bonferroni test or unpaired Student's t test (Prism 4; Graphpad Software, San Diego,California). A p value less than 0.05 was considered statistically significant.
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Results
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Pulmonary Artery Vasodilation
To assess the direct vasodilatory properties, sildenafil, vardenafil, and tadalafil (0.001 to 10 µmol/L) were added separately to PA rings precontracted with phenylephrine. All three PDE-5 inhibitors caused a dose-dependent vasorelaxation (Fig 1A). Although the maximum dose tested (10 µmol/L) resulted in the greatest amount of relaxation, there was some vasodilation caused by the corresponding concentration of vehicle (0.1% DMSO). Thus, the 1 µmol/L dose of PDE-5 inhibitor was used in the remaining experiments. The 1 µmol/L dose of sildenafil, vardenafil, or tadalafil resulted in equivalent PA vasorelaxation (Fig 1B).
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Fig 1. Phosphodiesterase-5 (PDE-5) inhibitors cause pulmonary artery vasodilation. (A) In phenylephrine-precontracted pulmonary artery rings, sildenafil (squares), vardenafil (diamonds), and tadalafil (circles) caused dose-dependent vasorelaxation. (B) The remaining experiments utilized the 1 µmol/L dose of PDE-5 inhibitor, which resulted in equivalent amounts of vasodilation (mean ± SEM, n = 5 to 9 per group).  p < 0.01 sildenafil, vardenafil, or tadalafil versus vehicle (triangles).
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Inhibition of Phenylephrine-Induced Contraction
Since pulmonary artery contracts in response to circulating catecholamines, we examined the effect of PDE-5 inhibitor treatment before phenylephrine-induced contraction. Sildenafil, vardenafil, tadalafil (1 µmol/L), or vehicle were added to resting PA rings 20 minutes before the addition of escalating doses of phenylephrine (0.01 to 10 µmol/L). Pretreatment with sildenafil and vardenafil significantly attenuated phenylephrine-induced PA contraction compared with vehicle pretreatment (Fig 2A, B). Tadalafil pretreatment also inhibited contraction to phenylephrine, but this was only statistically significant at the highest dose of phenylephrine (Fig 2C).
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Fig 2. Phosphodiesterase-5 (PDE-5) inhibition attenuates phenylephrine-induced pulmonary artery contraction. (A) Sildenafil (squares) pretreatment and (B) vardenafil (diamonds) pretreatment attenuated phenylephrine (PE)-induced pulmonary artery contraction; (C) tadalafil (circles) pretreatment significantly decreased contraction only at the highest concentration of phenylephrine (mean ± SEM, n = 5 to 6 per group). *p < 0.05. p < 0.01 versus vehicle (triangles).
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Effect of PDE-5 Inhibition on Acute Hypoxic Pulmonary Vasoconstriction
The effect of PDE-5 inhibition on acute hypoxic pulmonary vasoconstriction was examined by pretreating PA rings with sildenafil, vardenafil, or tadalafil 20 minutes before the onset of hypoxia. Bubbling the organ baths with 95% N2/5% CO2 produced a pO2 of 30 to 35 mm Hg. Acute hypoxia resulted in a biphasic PA contraction: an initial transient contraction followed by a delayed sustained contraction. There was no difference between the groups in the magnitude of the early transient contraction (data not shown). Sildenafil and vardenafil pretreatment had no effect on the delayed contraction (sildenafil 98.61% ± 10.04%, vardenafil 68.46% ± 15.84% versus vehicle 88.63% ± 8.96%; Fig 3A, B), but tadalafil pretreatment significantly inhibited delayed contraction (52.08% ± 7.65% versus 88.63% ± 8.96%; Fig 3C).
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Fig 3. Effect of phosphodiesterase-5 (PDE-5) inhibition on hypoxic pulmonary vasoconstriction. Pulmonary artery rings subjected to 60 minutes of hypoxia (pO2 = 30 to 35 mm Hg) resulted in a delayed sustained contraction that occurred 15 to 20 minutes after the onset of hypoxia. Delayed contraction began at time 0. Pretreatment with (A) sildenafil (squares) or (B) vardenafil (diamonds) had no effect on hypoxic pulmonary vasoconstriction. Pretreatment with (C) tadalafil (circles) decreased hypoxic contraction (mean ± SEM, n = 8 to 10 per group). p < 0.01 versus vehicle (triangles).
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Expression of TNF- and IL-1ß by Pulmonary Artery Tissue During Hypoxia
Pulmonary artery rings exposed to hypoxia were homogenized and subjected to RT-PCR for measurement of TNF- and IL-1ß mRNA expression. Hypoxia resulted in increased TNF- and IL-1ß expression compared with normoxic controls (Figs 4 and 5).
Sildenafil and vardenafil pretreatment had no effect on hypoxia-induced upregulation of TNF- and IL-1ß mRNA. However, tadalafil pretreatment significantly decreased both TNF- and IL-1ß expression in PA tissue during hypoxia (Figs 4 and 5).
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Fig 5. Interleukin-1ß (IL-1ß) expression in pulmonary artery (PA) tissue after hypoxia. (A) Representative gel photographs of IL-1ß mRNA from PA exposed to 60 minutes of hypoxia. Positive control (PC) was provided by the polymerase chain reaction (PCR) assay manufacturer (Maxim Biotech). The GAPDH housekeeping gene was used as an internal standard. Control PA rings were given dimethyl sulfoxide vehicle and subjected to 60 minutes of normoxia. (B) Gel densitometry software (Image J) was used to quantify the amplified PCR products (n = 4 to 6 per group). Values are expressed as ratio of IL-1ß to GAPDH. Hypoxia increased IL-1ß expression in vehicle-treated PA rings. Hypoxia-induced upregulation of IL-1ß was decreased by tadalafil, but not by sildenafil or vardenafil pretreatment (mean ± SEM). *p < 0.05 versus control.  p < 0.001 versus vehicle.
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Comment
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The PDE-5 isoform is abundantly expressed in the pulmonary vascular bed [2, 6, 7], which has generated interest in the use of PDE-5 inhibitors for pulmonary hypertension and other vascular pathology [20]. In this study, sildenafil, vardenafil, and tadalafil caused pulmonary artery relaxation in a dose-dependent fashion. There was no significant difference in the magnitude of PA relaxation between the three inhibitors. When pretreated with sildenafil, vardenafil, or tadalafil, phenylephrine-induced PA contraction was attenuated. Because the three PDE-5 inhibitors had similar effects on PA relaxation, we expected similar effects on inhibition of hypoxic pulmonary vasoconstriction. Interestingly, only tadalafil inhibited hypoxic pulmonary vasoconstriction and pulmonary artery TNF- and IL-1ß expression after hypoxia.
Hypoxia is a potent stimulus for pulmonary vasoconstriction [13, 15], and this may be a response to shunt blood to well-oxygenated areas of the lung. However, sustained hypoxic pulmonary vasoconstriction may result in pulmonary hypertension and right heart failure. Phosphodiesterases remain active in the lung during hypoxia [21, 22] and are also expressed during hypoxia-induced vascular remodeling [23]. Phosphodiesterase-5 inhibitors act by preventing metabolism of cGMP, which may contribute to inhibition of hypoxic pulmonary vasoconstriction. Indeed, McIntyre and coworkers [24] reported that cyclic adenosine monophosphate (cAMP)–mediated vasodilation was impaired in pulmonary arteries exposed to hypoxia, whereas cyclic guanosine monophosphate (cGMP)–mediated vasodilation was unaffected by hypoxia. Furthermore, cGMP causes vascular relaxation by activating cGMP-dependent protein kinases leading to a decrease in intracellular calcium. Cytosolic calcium appears to be an important mediator in hypoxic pulmonary vasoconstriction. Investigators have shown that blocking calcium channels [25, 26], depletion of intracellular calcium stores [27], and removing extracellular calcium [25] inhibited hypoxic contraction. Thus, inhibition of PDE-5 may attenuate hypoxic contraction by decreasing intracellular calcium stores via cGMP-dependent protein kinases. Surprisingly, of the three inhibitors tested, only tadalafil significantly inhibited hypoxic pulmonary vasoconstriction. This effect can not be explained by differences in drug potency because at the dosage tested (1 µmol/L), all three inhibitors caused equal amounts of PA relaxation (Fig 1B). Moreover, both sildenafil and vardenafil appeared to be more potent than tadalafil in attenuating phenylephrine-induced contraction (Fig 2). Instead, we postulated that the effects of tadalafil on hypoxic pulmonary vasoconstriction were related to inflammatory signaling.
Previous studies have demonstrated an inverse relationship between local inflammatory cytokine production and tissue function. For example, cardiomyocytes generated an intense inflammatory response after acute ischemia-reperfusion injury and these local mediators contributed to myocardial dysfunction [28]. Hypoxia can induce an inflammatory response in the lung [29]. Ziesche and colleagues [30] demonstrated that hypoxia increased the expression of proinflammatory cytokines in pulmonary artery tissue and downregulated the expression of constitutive nitric oxide synthase. They further showed that TNF- and IL-1ß augmented the effects of hypoxia on PA tissue [30]. We have previously shown that PA tissue upregulated TNF- and IL-1ß expression during acute hypoxia, and this process was mediated by protein kinase C [13]. Thus, there may be a correlation between PA inflammatory cytokine production and hypoxic pulmonary vasoconstriction. In this regard, PA pretreated with tadalafil had lower TNF- and IL-1ß expression compared with vehicle-treated PA. Neither sildenafil nor vardenafil pretreatment had a significant effect on PA cytokine expression. Thus, tadalafil-mediated inhibition of hypoxic pulmonary vasoconstriction correlated with attenuation of hypoxia-induced pulmonary artery TNF- and IL-1ß expression. This is the first study to demonstrate an anti-inflammatory effect of tadalafil on the pulmonary vasculature.
Although sildenafil, vardenafil, and tadalafil are classified as PDE-5 inhibitors, they differ slightly in their selectivity, pharmacokinetics, and side effects profile. The main difference among the three inhibitors is in their half lives: approximately 4 hours for sildenafil and vardenafil and 18 hours for tadalafil. Ghofrani and colleagues [9] recently reported differences between sildenafil, vardenafil, and tadalafil in their effects on pulmonary hypertension. These authors noted pulmonary vasorelaxation with all three inhibitors, but only sildenafil caused a significant improvement in arterial oxygenation. In addition, sildenafil and tadalafil caused a reduction in the pulmonary to systemic vascular resistance ratio, whereas vardenafil did not. The current study demonstrated that tadalafil, but not sildenafil or vardenafil, inhibited hypoxic pulmonary vasoconstriction and attenuated hypoxia-induced PA cytokine expression. The etiology of these differences is not known, but one possibility is the different selectivities of the three PDE-5 inhibitors with respect to other PDE isoforms. These agents may also differ in their binding capacity to PDE-5 during hypoxia. Thus, it is important for future studies to differentiate sildenafil, vardenafil, and tadalafil in terms of relative efficacy and selectivity on the pulmonary vasculature.
The precise etiology of pulmonary hypertension is unknown. As a result, current treatment options are directed at vascular relaxation rather than targeting the cause of pulmonary vasoconstriction. Identifying a therapeutic agent that is efficacious, selective for the pulmonary vasculature, has minimal systemic effects, and can be easily administered has been a difficult task. Current treatment options include inhaled nitric oxide, intravenous prostacyclin, inhaled iloprost, and intravenous milrinone. With the exception of inhaled preparations (which are costly and difficult to administer), most vasodilators lack specificity for the pulmonary vasculature and can cause concomitant systemic effects during their use. Since PDE-5 is highly expressed in the lung, it is an appealing target for treating pulmonary vascular contraction. However, as suggested by these results and others [9], sildenafil, vardenafil, and tadalafil are not equally efficacious in the treatment of pulmonary hypertension despite their classification as PDE-5 inhibitors. Further studies are needed to differentiate the effects of these agents on the pulmonary vasculature before successful clinical application can occur.
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Acknowledgments
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This work was supported by National Institutes of Health Grant R01GM070628, the Cryptic Masons Medical Research Foundation, a Clarian Values Grant, and a Showalter Grant (all grants to D.R.M.).
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References
|
|---|
- Sheridan BC, McIntyre RC, Meldrum DR, Fullerton DA. Phosphodiesterase inhibition overcomes pulmonary vasomotor dysfunction in acute lung injury J Surg Res 1997;71:145-149.[Medline]
- Cohen AH, Hanson K, Morris K, et al. Inhibition of cyclic 3'-5'-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxic rats J Clin Invest 1996;97:172-179.[Medline]
- Ghofrani HA, Pepke-Zaba J, Barbera JA, et al. Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension J Am Coll Cardiol 2004;43:68S-72S.[Abstract/Free Full Text]
- Matot I, Gozal Y. Pulmonary responses to selective phosphodiesterase-5 and phosphodiesterase-3 inhibitors Chest 2004;125:644-651.[Abstract/Free Full Text]
- Beavo JA. Cyclic nucleotide phosphodiesterasesfunctional implications of multiple isoforms. Physiol Rev 1995;75:725-748.[Abstract/Free Full Text]
- Rabe KF, Tenor H, Dent G, Schudt C, Nakashima M, Magnussen H. Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors Am J Physiol 1994;266:L536-L543.
- Ahn HS, Foster M, Cable M, Pitts BJ, Sybertz EJ. Ca/CaM-stimulated and cGMP-specific phosphodiesterases in vascular and non-vascular tissues Adv Exp Med Biol 1991;308:191-197.[Medline]
- Rosen RC, Kostis JB. Overview of phosphodiesterase 5 inhibition in erectile dysfunction Am J Cardiol 2003;92:9M-18M.[Medline]
- Ghofrani HA, Voswinckel R, Reichenberger F, et al. Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension. A randomized prospective study J Am Coll Cardiol 2004;44:1488-1496.[Abstract/Free Full Text]
- Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertensiona randomised controlled trial. Lancet 2002;360:895-900.[Medline]
- Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertensioncomparison with inhaled nitric oxide. Circulation 2002;105:2398-2403.[Abstract/Free Full Text]
- Wilkens H, Guth A, Konig J, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension Circulation 2001;104:1218-1222.[Abstract/Free Full Text]
- Tsai BM, Wang M, Pitcher JM, Meldrum KK, Meldrum DR. Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C Am J Physiol Lung Cell Mol Physiol 2004;287:L1215-L1219.[Abstract/Free Full Text]
- Tsai BM, Wang M, Clauss M, Sun P, Meldrum DR. Endothelial monocyte-activating polypeptide II causes NOS-dependent pulmonary artery vasodilationa novel effect for a proinflammatory cytokine. Am J Physiol Regul Integr Comp Physiol 2004;287:R767-R771.[Abstract/Free Full Text]
- Tsai BM, Wang M, Turrentine MW, Mahomed Y, Brown JW, Meldrum DR. Hypoxic pulmonary vasoconstriction in cardiothoracic surgerybasic mechanisms to potential therapies. Ann Thorac Surg 2004;78:360-368.[Abstract/Free Full Text]
- Chanani NK, Cowan DB, Takeuchi K, et al. Differential effects of amrinone and milrinone upon myocardial inflammatory signaling Circulation 2002;106:I284-I289.
- Takeuchi K, del Nido PJ, Ibrahim AE, et al. Vesnarinone and amrinone reduce the systemic inflammatory response syndrome J Thorac Cardiovasc Surg 1999;117:375-382.[Abstract/Free Full Text]
- Matsui S, Matsumori A, Matoba Y, Uchida A, Sasayama S. Treatment of virus-induced myocardial injury with a novel immunomodulating agent, vesnarinone. Suppression of natural killer cell activity and tumor necrosis factor-alpha production J Clin Invest 1994;94:1212-1217.[Medline]
- Fullerton DA, McIntyre Jr RC, Hahn AR, et al. Dysfunction of cGMP-mediated pulmonary vasorelaxation in endotoxin-induced acute lung injury Am J Physiol 1995;268:L1029-L1035.
- Raja SG, Nayak SH. Sildenafilemerging cardiovascular indications. Ann Thorac Surg 2004;78:1496-1506.[Abstract/Free Full Text]
- Wagner RS, Smith CJ, Taylor AM, Rhoades RA. Phosphodiesterase inhibition improves agonist-induced relaxation of hypertensive pulmonary arteries J Pharmacol Exp Ther 1997;282:1650-1657.[Abstract/Free Full Text]
- Phillips PG, Long L, Wilkins MR, Morrell NW. Cyclic AMP phosphodiesterase inhibitors potentiate effects of prostacyclin analogues in hypoxic pulmonary vascular remodeling Am J Physiol Lung Cell Mol Physiol 2005;288:L103-L115.[Abstract/Free Full Text]
- Sebkhi A, Strange JW, Phillips SC, Wharton J, Wilkins MR. Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension Circulation 2003;107:3230-3235.[Abstract/Free Full Text]
- McIntyre Jr RC, Banerjee A, Hahn AR, Agrafojo J, Fullerton DA. Selective inhibition of cyclic adenosine monophosphate-mediated pulmonary vasodilation by acute hypoxia Surgery 1995;117:314-318.[Medline]
- Jin N, Packer CS, Rhoades RA. Pulmonary arterial hypoxic contractionsignal transduction. Am J Physiol 1992;263:L73-L78.
- Barman SA. Potassium channels modulate hypoxic pulmonary vasoconstriction Am J Physiol 1998;275:L64-L70.
- Gelband CH, Gelband H. Ca2+ release from intracellular stores is an initial step in hypoxic pulmonary vasoconstriction of rat pulmonary artery resistance vessels Circulation 1997;96:3647-3654.[Abstract/Free Full Text]
- Meldrum DR. Tumor necrosis factor in the heart Am J Physiol 1998;274:R577-R595.
- Minamino T, Christou H, Hsieh CM, et al. Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia Proc Natl Acad Sci USA 2001;98:8798-8803.[Abstract/Free Full Text]
- Ziesche R, Petkov V, Williams J, et al. Lipopolysaccharide and interleukin 1 augment the effects of hypoxia and inflammation in human pulmonary arterial tissue Proc Natl Acad Sci USA 1996;93:12478-12483.[Abstract/Free Full Text]
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Abstract
Introduction
