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CARDIOVASCULAR
Klinik für Kinder und Jugendliche (M.A.K., K.v.d.H., S.M., M.C., E.S., W.R., J.D.), Pathologisch-Anatomisches Institut (T.P.) der Friedrich-Alexander-Universität, Erlangen-Nuernberg, Germany
Received January 30, 2003; accepted May 8, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionConclusionReferences |
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-MPAP -13.5 ± 1.4 versus -6.2 ± 2.4 mm Hg).
PaO2 significantly increased in the ADM (PaO2
243.3 mm Hg) and the ADM + L-NAME group (PaO2
217.4 mm Hg) compared with the control group (PaO2 82.9 mm
Hg; p < 0.001). Aerosolized ADM did not influence mean systemic
arterial pressure (baseline 63.2 ± 2.7 versus end of the study 66.3
± 6.5 mm Hg; not significant). NO synthases gene expressions were 20 to
30% lower with ADM compared with control. ET-1 gene expression was
significantly reduced (>50%) after ADM aerosol therapy (p <
0.001). Aerosolized adrenomedullin significantly reduced MPAP without lowering
the systemic arterial pressure and improved profoundly the arterial oxygen
tension. This effect seems to be mediated at least in part by the reduction of
ET-1.
).
Pulmonary hypertension is associated with increased expression of endothelin-1
(ET-1), a potent constrictor, in pulmonary vascular endothelial cells. The
local production of endothelin-1 is assumed to contribute to the vascular
abnormalities associated with this disorder
(Giaid et al., 1993).
Adrenomedullin (ADM) is a potent vasodilator peptide. In the lung, ADM was
shown to be present in several cells, such as endothelial and smooth muscle
cells, alveolar macrophages and the columnar epithelium
(Jougasaki and Burnett, 2000).
ADM receptors are highly expressed in lung and heart tissue. Analysis of the
ADM binding sites suggests a regulatory role of the peptide for the pulmonary
circulation and cell differentiation
(Kapas et al., 1995;
Owji et al., 1995). ADM
preferentially reduces pulmonary artery pressure through a decrease of
pulmonary vascular resistance (Cheng et
al., 1994; Lippton et al.,
1994; Heaton et al.,
1995). The marked elevation of ADM plasma levels in patients with
pulmonary hypertension may represent a compensatory mechanism
(Kakishita et al., 1999).
Intravenous infusion of ADM in adult patients with precapillary pulmonary
hypertension reduces the pulmonary vascular resistance significantly. However,
systemic vascular resistance is simultaneously decreased
(Nagaya et al., 2000). Similar
systemic effects are seen with the application of ADM into the pulmonary
artery of fetal sheep (Takahashi et al.,
1999). Although pulmonary hypertension may respond to systemic
vasodilator therapy, the treatment frequently fails because intravenous
administration of vasodilators may increase blood flow in nonventilated lung
areas, increasing the ventilation/perfusion mismatch. In addition, adverse
effects on the systemic blood pressure are common
(Agusti and Rodriguez-Roisin,
1993). Administration of therapeutic drugs via inhalation is
supposed to be more selective for the pulmonary vascular bed. This has been
shown for inhaled nitric oxide (Demirakca
et al., 1996; Nagamine et al.,
2000) and for inhaled prostacyclin
(Olschewski et al., 1999). To
date, no studies on the efficacy and pulmonary selectivity of aerosolized ADM
in pulmonary hypertension have been performed. We therefore examined the
impact of aerosolized ADM on pulmonary artery pressure, systemic arterial
pressure, and oxygenation in neonatal piglets with acute respiratory distress
syndrome and pulmonary hypertension.
Intravenous infusion of ADM (50 ng/kg/min) showed significant effects after
15 min (Nagaya et al., 2000).
Hence, in the present intervention 30-min inhalation intervals with
incremental doses of ADM, followed by 30-min observation were used.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionConclusionReferences |
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After a venous catheter had been placed into an ear vein, anesthesia was
induced with midazolam (1 mg/kg), fentanyl (2.5 µg/kg), and ketamine (5
mg/kg) followed by continuous infusion of midazolam (1.5 mg/kg/h), fentanyl
(0.01 mg/kg/h), and ketamine (15 mg/kg/h)
(Kandler et al., 2001;
von der Hardt et al., 2002b).
Piglets generally require high doses of anesthetics for narcosis. Therefore,
the combination of three anesthetics was used. It was the intention to prevent
adverse effects such as hyperthermia that occurs, e.g., in inadequate
sedation.
After tracheotomy, paralysis was induced with vecuronium 0.2 mg/kg i.v. and maintained with vecuronium (0.2 mg/kg/h), to avoid any interference due to spontaneous breathing that is thought to influence the efficacy of mechanical ventilation.
A sheath (4.5 French; Cook, Mönchengladbach, Germany) was placed into the right jugular vein and a pulmonary artery catheter (4.0 French; Arrow, Erding, Germany) was introduced into the pulmonary artery. After preparation of the left femoral artery, an arterial catheter (20 gauge; Arrow) was placed and a sensor for online blood gas monitoring (Paratrend 7; Philips, Böblingen, Germany) was inserted for online registration of blood gases. The pulmonary artery and the femoral artery catheter were continuously rinsed, each by 2 ml of normal saline containing 2.0 IU heparin/h. The piglets received a transcutaneous urinary catheter (Cystofix mini-paed; Braun, Melsungen, Germany). Heart rate, oxygen saturation, body temperature, central venous, pulmonary artery, and systemic arterial pressure were continuously recorded (CMS 2001; Philips). Arterial blood gas analysis was performed from arterial blood samples in 30-min intervals (ABL 330; Radiometer Copenhagen, Copenhagen, Denmark). Intermittent mandatory ventilation was performed with a neonatal respirator (Infant Star 950; Mallinckrodt, Hennef, Germany). Breath rate was 50 breaths/min, peak inspiratory pressure was 32 cm H2O, positive end expiratory pressure was 8 cm H2O, and the inspiratory fractional oxygen concentration was 1.0 (100%).
Study Protocol. Lung injury with pulmonary hypertension was induced
by surfactant depletion [repeated saline lung lavage (NaCl 0.9%, temperature
39°C)] using 30 ml/kg/side (Lachmann
et al., 1980; Kandler et al.,
2001). Piglets were included if lung injury was considered to be
stable, defined as PaO2 constantly remaining below 80 mm Hg for a
period of 60 min. If inclusion criteria failed, repeated lung lavages were
performed until criteria had been met.
During instrumentation and for the duration of the experiment, animals were
in supine position. The animals were randomly assigned to three different
therapy groups (adrenomedullin, ADM + L-NAME, and control). In all
animals, respiratory support was maintained constant at identical respiratory
settings (positive end expiratory pressure 8 cm of H2O; peak
inspiratory pressure 32 cm H2O; and fractional oxygen concentration
1.0, 50 breaths/min). Before onset of treatment, baseline recordings of
pulmonary and circulatory parameters were performed. Adrenomedullin (Bachem,
Heidelberg, Germany) was applied in saline solution as aerosol (aerosol
generator; Trudell Medical Inc., London, Canada;
MacIntyre et al., 1996;
Kandler et al., 2001;
MacIntyre, 2001). Five dose
levels (6.25, 12.5, 25, 50, and 100 ng/kg/min) each for 30 min were applied,
followed by 30-min inhalation-free intervals over a total period of 5 h
(volume rate of 4 ml/h). The observation was continued for 3 h after the
inhalation procedure. To investigate the role of NO formation in the mechanism
of ADM effects, NO synthases were inhibited in the ADM + L-NAME
group. Piglets additionally received the inhibitor of the nitric-oxide
synthases L-NAME (Sigma-Aldrich, Steinheim, Germany) at a dose of
25 mg/kg/h intravenously 30 min before and continuously during the 8 h of the
experiment. Piglets in the control group received aerosolized saline solution
(4 ml/h). After an additional observation period of 3 h, animals were
sacrificed by intravenous injection of 50 mg/kg methohexital and 20 ml of
potassium chloride (7.46%). Lungs and heart were removed en bloc.
Tissue Processing. The left lung was perfused with 5% buffered
paraformaldehyde. For histological examinations from standardized sites,
samples were taken from the peripheral upper and lower lobe. Sections (5
µm) of paraffin-embedded tissue sections were stained with
hematoxylin-eosin for routine histopathological evaluation. Chloracetate
esterase histochemical reaction was performed to visualize neutrophil
granulocytes. One blinded expert pathologist examined the sections for the
items hyaline membranes, hyperemia, interstitial edema, intra-alveolar
hemorrhage, and neutrophil accumulation and attributed each item to a 4-point
score: 0, none; 1, mild; 2, moderate; and 3, severe. Lung injury score was
calculated including all sites and items
(Quintel et al., 1998). For
each site, the score of all items was summarized. Data are presented as mean
± S.E.M. of this summary score, including all the sites.
Reverse Transcription-PCR. Standardized specimens [four from the inferior lobe (central and basal), two from the superior, and two from the middle lobe] were taken from the native peripheral right lung and stored at -80°C until mRNA extraction was performed using guanidine-thiocyanate acid phenol (RNAzol; WAK Chemie, Medical GmbH, Bad Homburg, Germany). One microgram of RNA per tissue sample was reversely transcribed in a volume of 20 µl at 39°C for 60 min (all chemicals were obtained from Boehringer Mannheim, Mannheim, Germany). The cDNA samples were stored at -20°C.
Quantitative TaqMan Real-Time PCR. Efficiency and reliability of
this method have been shown previously
(Heid et al., 1996;
Dötsch et al., 1999;
Schoof et al., 2002). The use
of TaqMan real-time PCR in this animal model was recently published
(von der Hardt et al., 2002b;
von der Hardt et al., 2003).
Primers and TaqMan probes were elected for the porcine model
(Table 1). This approach is
based upon the 5' exonuclease activity of the Taq polymerase.
Briefly, within the amplicon defined by a gene specific oligonucleotide primer
pair an oligonucleotide probe labeled with two fluorescent dyes is designed.
As long as the probe is intact, the emission of a reporter dye (i.e.,
6-carboxy-fluorescein) at the 5' end is quenched by the second
fluorescence dye (6-carboxy-tetramethyl-rhodamine) at the 3' end. During
the extension phase of the PCR, the Taq polymerase cleaves the probe
releasing the reporter dye. An automated photo-metric detector combined with a
special software (ABI Prism 7700 sequence detection system, PerkinElmer Life
Sciences, Foster City, CA) monitors the increasing reporter dye emission. The
algorithm normalizes the signal to an internal reference (Rn) and
calculates the threshold cycle number (CT), when the
Rn reaches 10 times the standard deviation of the baseline. Commercial
reagents (TaqMan PCR reagent kit; PerkinElmer Life Sciences) and conditions
according to the manufacturer's protocol were used. cDNA (2.5 µl, reverse
transcription mixture) and oligonucleotides with a final concentration of 300
nM of primers and 200 nM of TaqMan hybridization probe were added to 25 µl
of reaction mix. The thermocycler parameters were 50°C for 2 min, 95°C
for 10 min followed by 40 cycles of 95°C for 15 s and 60°C for 1 min.
A serial dilution of known copy numbers of a PCR product served as reference
providing a relative quantification of the unknown samples. Gene expression
was related to the housekeeping genes 
-actin (A) and
hypoxanthine-guanine-phosphoribosyl-transferase (HPRT). Real-time PCR
fragments of the measured porcine genes are shown in
Fig. 1.
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Data Analysis and Statistics. Values are expressed as mean ± S.E.M. After testing for Gaussian distribution, two-way ANOVA with Bonferroni's post hoc test was used. To evaluate the data compared with the baseline one-way ANOVA with Dunnett's multiple comparison test was applied. A p value of less than 0.05 was considered significant. For PCR data, depending on the presence of Gaussian distribution, either the ANOVA or Kruskal-Wallis test was used for comparison of the groups. In case of significance, Bonferroni's and Dunn's post hoc tests were applied. Comparing two groups, t test or Mann-Whitney test was used, respectively.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionConclusionReferences |
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Mean Arterial Pressure (MAP). During administration of aerosolized ADM and throughout the observation period, systemic MAP was not influenced compared with baseline (Figs. 3 and 4). There was no significant difference in MAP between the ADM and the control group (Fig. 4). In contrast, L-NAME increased MAP significantly and maintained higher levels throughout the course of the experiment (p < 0.001; Fig. 4).
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Arterial Oxygen Tension. Compared with the baselines (after establishment of pulmonary hypertension), PaO2 significantly increased in the ADM group (p < 0.01) and in the ADM + L-NAME group (p < 0.01; Fig. 5). The arterial oxygen tension in both groups was significantly higher than in the control group (p < 0.001). There was no significant difference in PaO2 between the ADM and the ADM + L-NAME group during the treatment and the post-treatment observation period (Fig. 5).
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NO Synthases. Inducible nitric-oxide synthase (iNOS) mRNA expression
was slightly but significantly lower in the ADM and the ADM +
L-NAME group compared with the control group (p <
0.05). These results were obtained irrespectively of whether gene expression
was normalized to the housekeeping genes -actin or HPRT
(Fig. 6). Endothelial
nitric-oxide synthase (eNOS) mRNA expression was significantly lower in the
ADM group than in the control group only when normalized to -actin
(p < 0.01; Fig. 6).
eNOS mRNA expression was significantly lower in the ADM + L-NAME
group than in the control group when normalized to both -actin and HPRT
(p < 0.01; Fig.
6).
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Endothelin-1. ET-1 mRNA gene expression was significantly reduced after treatment with aerosolized ADM compared with the control group (reduction: ET-1/A, 62.4%; ET-1/HPRT, 51.0%; p < 0.001; Fig. 7).
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Histology. The lung injury score (mean ± S.E.M.) was not significantly different between the ADM and the control group (6.5 ± 0.6 versus 5.3 ± 0.4).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionConclusionReferences |
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). Similar effects were observed after inhalation of various
vasodilators such as nitric oxide, iloprost, and sodium nitroprusside
(Demirakca et al., 1996;
Olschewski et al., 1999;
Schutte et al., 2001). The
positive effect of ADM on pulmonary vascular resistance might be even enhanced
or perpetuated by the improvement of oxygenation. Because histology of
representative pulmonary specimens did not show significant differences
between the groups, it seems unlikely that changes in lung injury led to
consecutive reduction of vascular resistance. As far as safety issues are
concerned, there were no expected or unexpected side effects of the therapy.
In particular, none of the animals died during the use of inhaled ADM.
Instead, an anti-inflammatory effect of inhaled ADM could be demonstrated by
reduction of transforming growth factor-1 and interleukin-1 gene
expression (von der Hardt et al.,
2002a). In prior studies, the vasodilating effect of ADM has been
shown to be, at least in part, mediated by activation of nitric-oxide
synthases and enhancement of iNOS expression
(Feng et al., 1994). Under
physiological conditions, the ADM effect on pulmonary vascular resistance can
be attenuated by NOS inhibitor administration to fetal sheep
(Takahashi et al., 1999). The
close interaction of ADM and nitric oxide in vascular cells also becomes
obvious by an increase of ADM gene expression and peptide synthesis after
incubation of human umbilical venous cells with different NO donors
(Dötsch et al., 2002). In
our present series of experiments, L-NAME did not attenuate the
beneficial effect of inhaled ADM on pulmonary vasodilation and oxygenation. In
addition, ADM did not increase iNOS gene expression. The reduced gene
expression of iNOS and eNOS does not necessarily reflect enzyme activity.
Nonetheless, it can be concluded from the L-NAME experiment that
ADM does not work exclusively via NO synthase activation or expression. The
fact that L-NAME does not influence ADM induced vasodilatation in
this study implies that ADM might predominantly act via other pathways. For
future experiments, it might be useful to assess the effect of
L-NAME on pulmonary arterial resistance in comparison with
L-NAME + ADM. The effect of ADM might be mediated via the
transmembrane ADM receptor by an increase in intracellular cyclic AMP
concentration (Ishizaka et al.,
1994; Shimekake et al.,
1995), which is vasorelaxant itself
(Maurice and Haslam, 1990).
Furthermore, cAMP might impede the function of phosphodiesterase IIIa, which
is responsible for the decay of cyclic GMP, the most important mediator of
nitric oxide-induced vasodilation (Shah
and Kadowitz, 2002), this mechanism mimics NO-mediated
vasodilatation. To prove the specific intrapulmonary ADM effect manipulation
of ADM receptor function, e.g., by the infusion or inhalation of a specific
antagonist such as ADM 22-52 might be included in future studies.
The reduction of ET-1 mRNA expression after treatment with aerosolized ADM
might be mediated by the suppressive effect of cAMP on ET-1 synthesis
(Magnusson et al., 1994).
Therefore, the vasorelaxant effect of ADM might be potentiated by the
reduction of ET-1 synthesis. It seems unlikely that the mechanism of ADM
action is via an increased activity of prostaglandins or is exerted by
activation of calcitonin gene-related peptide receptor
(Takahashi et al., 1999).
Recently, a number of publications have addressed the systemic use of ADM
in humans for the correction of various hemodynamic disorders. Apart from the
improvement of pulmonary hypertension
(Nagaya et al., 2000), cardiac
afterload could be reduced (Del Bene et
al., 2000). Interestingly the vascular effects of ADM are
significantly attenuated in patients with chronic heart failure, in part
because of impaired production of nitric oxide
(Nakamura et al., 1997). In
our model, animals have experienced serious pulmonary damage before the onset
of ADM inhalation with probably severe impairment of NO synthases. Therefore,
the effect of ADM on pulmonary artery pressure of newborn piglets might be
even more pronounced if NO synthases function was maintained at a normal
level. Nonetheless, the studies in humans are encouraging toward a potential
use of inhaled ADM in humans.
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Conclusion |
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TopAbstractMaterials and MethodsResultsDiscussionConclusionReferences |
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: ET-1, endothelin-1; ADM, adrenomedullin; L-NAME, NG-nitro-L-arginine methylester; NO, nitric oxide; PCR, polymerase chain reaction; HPRT, hypoxanthine-guanine-phosphoribosyl-transferase; ANOVA, analysis of variance; MPAP mean pulmonary artery pressure; MAP, mean arterial pressure; iNOS, inducible nitric-oxide synthase; eNOS, endothelial nitric-oxide synthase; bp, base pairs.
1 These authors contributed equally to this work. 
Address correspondence to: Dr. M. A. Kandler, Universitätsklinik für Kinder und Jugendliche, Loschgestrasse 15, 91054 Erlangen/Germany. E-mail: michael.kandler{at}web.de
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