Skip to main content
Erschienen in: Respiratory Research 1/2014

Open Access 01.12.2014 | Research

Pulmonary vasoreactivity in spontaneously hypertensive rats - Effects of endothelin-1 and leptin

verfasst von: Samantha Gomart, Cécile Damoiseaux, Pascale Jespers, Martine Makanga, Nathalie Labranche, Stéphanie Pochet, Charles Michaux, Guy Berkenboom, Robert Naeije, Kathleen McEntee, Laurence Dewachter

Erschienen in: Respiratory Research | Ausgabe 1/2014

Abstract

Background

Systemic hypertension may be associated with an increased pulmonary vascular resistance, which we hypothesized could be, at least in part, mediated by increased leptin.

Methods

Vascular reactivity to phenylephrine (1 μmol/L), endothelin-1 (10 nmol/L) and leptin (0.001–100 nmol/L) was evaluated in endothelium-intact and -denuded isolated thoracic aorta and pulmonary arteries from spontaneously hypertensive versus control Wistar rats. Arteries were sampled for pathobiological evaluation and lung tissue for morphometric evaluation.

Results

In control rats, endothelin-1 induced a higher level of contraction in the pulmonary artery than in the aorta. After phenylephrine or endothelin-1 precontraction, leptin relaxed intact pulmonary artery and aortic rings, while no response was observed in denuded arteries. Spontaneously hypertensive rats presented with increased reactivity to phenylephrine and endothelin-1 in endothelium-intact pulmonary arteries. After endothelin-1 precontraction, endothelium-dependent relaxation to leptin was impaired in pulmonary arteries from hypertensive rats. In both strains of rats, aortic segments were more responsive to leptin than pulmonary artery. In hypertensive rats, pulmonary arteries exhibited increased pulmonary artery medial thickness, associated with increased expressions of preproendothelin-1, endothelin-1 receptors type A and B, inducible nitric oxide synthase and decreased endothelial nitric oxide synthase, together with decreased leptin receptor and increased suppressor of cytokine signaling 3 expressions.

Conclusions

Altered pulmonary vascular reactivity in hypertension may be related to a loss of endothelial buffering of vasoconstriction and decreased leptin-induced vasodilation in conditions of increased endothelin-1.
Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1465-9921-15-12) contains supplementary material, which is available to authorized users.
Samantha Gomart, Cécile Damoiseaux contributed equally to this work.

Competing interests

The authors declare that they have no competing interest.

Authors’ contributions

Study conception and design: SG, CD, PJ, KM, LD - acquisition of data: SG, CD, PJ, MM - analysis and interpretation of data: SG, CD, PJ, MM, CM, KM, LD - drafting of manuscript: SG, RN, KM, LD - critical revision: SG, NL, SP, GB, RN, KM, LD. All authors read and approved the final manuscript.
Abkürzungen
ECE-1
Endothelin-converting enzyme 1
ETA
Endothelin receptor type A
ETB
Endothelin receptor type B
HPRT1
Hypoxanthine-guanine PhosphoRibosylTransferase
NO
Nitric oxide
eNOS
endothelial nitric oxide synthase
iNOS
inducible nitric oxide synthase
PA+
Pulmonary artery with Endothelium
PA-
Pulmonary Artery without Endothelium
PPET-1
Preproendothelin-1
PVR
Pulmonary vacsular resistance
RTQ-PCR
Real-time quantitative polymerase chain reaction
SEM
Standard error of the mean
SHR
Spontaneously hypertensive rat
SOCS3
Suppressor of cytokine signaling 3
TA+
Thoracic aorta with endothelium
TA-
Thoracic aorta without endothelium.

Background

It has long been known that pulmonary vascular resistance (PVR) may be increased in patients with systemic hypertension, even when left ventricular filling pressures are within the limits of normal [1]. Guazzi et al. hypothesized that this would be related to shared abnormal smooth muscle calcium handling mechanisms in the systemic and pulmonary resistive vessels [2]. In support of this notion, these authors reported an enhanced pulmonary vascular reactivity to hypoxia in patients with uncomplicated systemic hypertension [3]. However, additional factors could also be implicated such as decreased expression of nitric oxide (NO) and increased expression of endothelin-1 [4, 5] related to latent left heart failure at rest, but increased left ventricular diastolic pressures at exercise, as a cause of intermittent upstream transmission of mechanical stress with endothelial damage to the pulmonary circulation. Another factor involved could be leptin, a peptide hormone secreted by adipocytes, which has been shown to be increased in hypertensive patients even after adjustment for major confounders, including obesity [6, 7]. Leptin is currently thought to contribute to systemic hypertension by a combination of mechanisms including sympathetic nervous system activation [8, 9], overproduction of endothelin-1 [10, 11] and decreased release of NO [12]. In patients with pulmonary arterial hypertension, there is an increase in circulating leptin which may contribute to inflammatory changes in the pulmonary circulation and thereby increase PVR [13].
We, therefore, explored and compared the vascular reactivity to endothelin-1 and leptin in isolated systemic and pulmonary arteries from spontaneously hypertensive (SHR) compared to control Wistar rats. The results are compatible with the notion of abnormal pulmonary endothelial function involving leptin and endothelin-1 control in systemic hypertension.

Methods

The present study was approved by the Institutional Animal Care and Use Committee of the Faculty of Medicine of the Université Libre de Bruxelles (Brussels, Belgium) and was conducted in accordance with the “Guide for the Care and Use of Laboratory Animals” published by the US National Institutes of Health (NIH publication no. 85 – 23, revised 1996).

Animals and sample preparation

Experiments were conducted in 18-week-old male spontaneously hypertensive (SHR) and control Wistar rats (Janvier, Le Genest Saint-Isle, France), weighing respectively 340 ± 4 and 441 ± 10 g. During a one-week acclimatization period, the rats were housed in a temperature (21°C)- and relative humidity (60%)-controlled room and exposed to a 12-hour light and dark cycle. Standard rat chow and tap water were given ad libitum.
After euthanasia of the animals with carbon dioxide, thoracic aorta and pulmonary artery (taken after the first branch point of the common pulmonary trunk) were carefully excised and cleaned of blood. Adhesive fat and connective tissue were removed. Sampled artery sections were immediately snap-frozen and stored at −80°C for biological evaluation, or placed in Krebs-Henseleit solution (118.1 mmol/L NaCl; 4.7 mmol/L KCl; 1.2 mmol/L MgSO4; 1.2 mmol/L KH2PO4; 2.5 mmol/L CaCl2; 25 mmol/L NaHCO3; 5.1 mmol/L glucose) for vasoreactivity experiments.
Thoracic aortic and pulmonary artery segments were harvested, snap-frozen in liquid nitrogen and stored at −80°C for biological experiments. Pulmonary tissue samples were immediately harvested and embedded in paraffin for morphometric evaluation.

Vascular reactivity

Under a dissecting microscope, thoracic aorta and pulmonary artery were cut into segments of ~3 mm-length and 2.3 ± 0.1 and 1.8 ± 0.2 mm internal diameter respectively. During dissection, care was taken to protect the endothelial lining in endothelium-intact rings. In half of the rings, the endothelium was removed by rubbing the inner intimal surface of the vascular lumen with a surgical steel rod to obtain endothelium-denuded rings.
Thoracic aortic and pulmonary artery rings were mounted on stainless steel hooks in 5 mL-organ baths filled with Krebs-Henseleit solution bubbled with 95% O2 and 5% CO2 and maintained at 37°C. One of the steel hooks was anchored in the chamber; the other was connected to a force transducer for continuous recording of isometric tension by a personal computer and a chart recorder (EMKA Technologies, Paris, France). The rings were placed under a resting tension of 1000 mg and 600 mg for thoracic aortic and pulmonary artery rings respectively and were allowed to equilibrate for 60 minutes. Krebs solution was changed every 20 minutes.
Thoracic aortic and pulmonary artery rings were contracted with 80 mmol/L KCl (Sigma-Aldrich, Bornem, Belgium) to assess their contractility. Subsequently, segments were contracted with phenylephrine hydrochloride (1 μmol/L; Sigma-Aldrich, Bornem, Belgium) and acetylcholine chloride (0.001 to 10 μmol/L; Sigma-Aldrich) was added to functionally confirm the presence of the endothelium. If the tension of the vessel after administration of acetylcholine (10 μmol/L) was under 20% or above 80% of the phenylephrine induced precontraction, the vessels were considered respectively as endothelium-intact or -denuded. The vessels that did not belong to any of these two groups were excluded from the present study.
After washout period allowing return to basal vascular tone, rat leptin (Sigma-Aldrich) was tested between 0.001 to 100 nmol/L (incubated during 2 minutes 30 seconds each) in thoracic aortic and pulmonary artery rings preconstricted with phenylephrine (1 μmol/L). The washout period was repeated to allow the vessel rings to return to their basal vascular tone. Subsequently, rat leptin (100 nmol/L) was tested in rings preconstricted with endothelin-1 (10 nmol/L; Sigma-Aldrich), with tension recording every 2.5 minutes during a total of 25 minutes.
The phenylephrine (1 μmol/L) and endothelin-1 (10 nmol/L) concentrations were chosen from complete concentration-response curves (from 10-9 to 10-5 mol/L in log increments; data not shown). Selected concentrations induced strong artery segment constriction (> 100 mg for the pulmonary artery and > 1000 mg for the thoracic aorta), but were inferior to the concentrations inducing maximal constriction.
In order to evaluate the role played by the endothelium in the observed variations of vascular tone, experiments were carried out in endothelium-intact and -denuded aortic and pulmonary artery segments.

Morphometry—Immunohistochemistry

Pulmonary arterial morphometry was performed as previously described [14, 15]. Medial thickness (MT) was related to arterial size with the following formula:%MT = (2MT/ED) × 100 and performed by counting at least 50 pulmonary arteries per lung section from each rat.

Real-time quantitative polymerase chain reaction (RTQ-PCR)

Total RNA was extracted from snap-frozen thoracic aortic and pulmonary artery segments by homogenization according to the method of Chomczynski and Sacchi [16], using TRIzol reagent (Invitrogen, Merelbeke, Belgium) and further purified using RNeasy® Mini kit (QIAGEN S.A., Hilden, Germany) according to the manufacturer’s instructions. RNA concentration was determined by spectrophotometry (Nanodrop® ND-1000, Isogen life science, De Meern, The Netherlands) and RNA integrity assessed by visual inspection of GelRed (Biotium, Hayward, California)-stained agarose gels.
Reverse transcription was carried out using SuperScriptTM II Reverse Transcriptase (Invitrogen), according to the manufacturer’s instructions.
For RTQ-PCR, sense and anti-sense primers were designed using Primer3 program for rattus norvegicus leptin, leptin receptor, suppressor of cytokine signaing 3 (SOCS3), preproendothelin-1 (PPET-1), endothelin-converting enzyme 1 (ECE-1), endothelin receptor type A (ETA), endothelin receptor type B (ETB), endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and hypoxanthine-guanine phosphoribosyltransferase (HPRT1) mRNA sequences amplification (Table 1). To avoid inappropriate amplification of residual genomic DNA, intron-spanning primers were selected when exon sequences were known and a BLAST analysis was run to check if primer pairs were only matching at the sequence of interest. For each sample, amplification reaction was performed in triplicate using SYBRGreen PCR Master Mix (Quanta Biosciences, Gaithersburg, Maryland), specific primers and diluted template cDNA. Result analysis was performed using an iCycler system (BioRad Laboratories, Nazareth Eke, Belgium). Relative quantification was achieved with the comparative 2-∆∆Ct method by normalization with the housekeeping gene, HPRT1 [17].
Table 1
Primers used for real-time quantitative polymerase chain reaction in rattus norvegicus thoracic aorta and pulmonary arteries
Genes
 
Sequences
Hypoxanthine phosphoribosyltransferase 1 (HPRT1)
Sense
5′ – ACAGGCCAGACTTTGTTGGA – 3′
Antisense
5′ – TCCACTTTCGCTGATGACAC – 3′
Endothelin receptor type A (ETA)
Sense
5′ – CTGGTGGCTCTTTGGATTCT – 3′
Antisense
5′ – GCTCCCATTCCTTCTGTTGA – 3′
Endothelin receptor type B (ETB)
Sense
5′ – CGATTGTATCATGCCTCGTG – 3′
Antisense
5′ – GGGACCATTTCTCATGCACT – 3′
Leptin
Sense
5′ – CCTGTGGCTTTGGTCCTATC – 3′
Antisense
5′ – ATACCGACTGCGTGTGTGAA – 3′
Leptin receptor
Sense
5′ – GGACAGCCAAACAAAAGCAC – 3′
Antisense
5′ – TATCCGAGACGATTTCAGCA – 3′
Endothelial nitric oxide synthase (eNOS)
Sense
5′ – GGTATTTGATGCTCGGGACT – 3′
Antisense
5′ – TGATGGCTGAACGAAGATTG – 3′
Inducible nitric oxide synthase (iNOS)
Sense
5′ – GTTTCCCCCAGTTCCTCACT – 3′
Antisense
5′ – CTCTCCATTGCCCCAGTTT –5′
Preproendothelin-1 (PPET-1)
Sense
5′ – CAGACCAAGGGAACAGATGC – 3′
Antisense
5′ – ACGCCTTTCTGCATGGTACT – 3′
Endothelin-converting enzyme 1 (ECE1)
Sense
5′ – GCCCACCAAGAACGAGATT – 3′
Antisense
5′ – GACCCCGATACCAAAGT – 3′
Suppressor of cytokine signaling 3 (SOCS3)
Sense
5′ – TGCAGGAGAGCGGATTCTAC – 3′
Antisense
5′ – AGCTGTCGCCCATAAGAAAG – 3′

Statistical analysis

All values are expressed as mean ± standard error of the mean (SEM). Relaxations to acetylcholine or leptin were expressed as the percentage of the maximal contractile response developed by phenylephrine or endothelin-1. The repeated relaxation response measurements in control Wistar and spontaneously hypertensive rats were analyzed with a mixed linear model to assess the effect of leptin concentrations (from 0.001 to 100 nmol/L by step of 0.1 mol/L) or the effect of time of a leptin concentration of 100 nmol/L (from 5 to 25 minutes by step of 2.5 minutes) and to compare thoracic aorta and pulmonary artery, to compare endothelium-intact and -denuded arteries and to test the interaction between these three factors. The repeated relaxation response measurements in thoracic aorta and pulmonary artery were also analyzed with a mixed linear model to assess the effect of leptin concentrations or the effect of time of a leptin concentration of 100 nmol/L and to compare spontaneously hypertensive and control rat lines, to compare endothelium-intact and -denuded arteries and to test the interaction between these three factors. Differences in maximal contraction to phenylephrine or endothelin-1, RT-QPCR and morphometric data were tested by Student t tests. A value of p < 0.05 was considered statistically significant; n represents the number of individual data.

Results

Vascular reactivity: responses to phenylephrine and endothelin-1

In control rats, the maximal contractile responses to phenylephrine (1 μmol/L) were comparable in pulmonary artery and thoracic aortic rings and were enhanced in endothelium-denuded rings (Figure 1A). After phenylephrine precontraction, acetylcholine (dose range tested from 0.001 to 10 μmol/L) induced a similar concentration-dependent relaxation in endothelium-intact pulmonary artery and thoracic aortic rings. This relaxation was similarly abolished in endothelium-denuded pulmonary artery and aortic rings. The maximal relaxation responses to acetylcholine (10 μmol/L) in endothelium-intact pulmonary artery and aorta were, respectively, 95 ± 3% and 86 ± 2% (not significant, p > 0.05) and in endothelium-denuded pulmonary artery and aorta 2 ± 1% and 1 ± 1%, (not significant, p > 0.05). In endothelium-intact and -denuded artery rings, endothelin-1 (10 nmol/L) induced a higher level of contraction in pulmonary artery compared to aorta (Figure 1B). In endothelium-denuded pulmonary artery, the contractile response to endothelin-1 (10 nmol/L) was increased compared to the one observed in endothelium-intact pulmonary artery (Figure 1B).
In spontaneously hypertensive rats (SHR), the maximal contractile response to phenylephrine (1 μmol/L) was higher in pulmonary artery compared to thoracic aortic rings. The enhanced contractile response observed in endothelium-denuded compared to –intact artery segments was abolished in SHR (Figure 1A). The maximal pulmonary artery and thoracic aortic relaxation responses to acetylcholine (10 μmol/L) after phenylephrine (1 μmol/L) precontraction were of similar magnitude in SHR compared to controls. This was observed in endothelium-intact (92 ± 2% in SHR versus 95 ± 3% in controls; not significant, p > 0.05) and endothelium-denuded (1 ± 1% in SHR versus 2 ± 1% in controls; not significant, p > 0.05) pulmonary artery rings.
As illustrated in Figure 1, the maximal contractile responses to phenylephrine (1 μmol/L) and to endothelin-1 (10 nmol/L) were respectively significantly and non significantly (but with a strong tendency; p = 0.058) enhanced in endothelium-intact pulmonary artery rings from SHR compared to controls. These maximal contractions to phenylephrine and to endothelin-1 were respectively 51% and 32% higher in endothelium-denuded compared to -intact pulmonary artery rings from controls, while these differences were respectively reduced to 16% or even abolished in SHR (Figure 1). These data suggest that the endothelial negative modulation of vasoconstriction was decreased or even abolished in SHR.

Vasoreactivity of thoracic aorta and pulmonary artery: responses to leptin

As illustrated in Figure 2A and B, leptin (tested from 0.001 to 100 nmol/L) induced a concentration-dependent relaxation after phenylephrine (1 μmol/L) precontraction, rapidly reaching a plateau in endothelium-intact pulmonary artery and aortic rings from control and hypertensive rats. This vasodilating effect was more pronounced in aorta than in pulmonary arteries in both strains of rats. No response to leptin was observed in endothelium-denuded arteries.
In controls, leptin (100 nmol/L) induced the relaxation, of endothelium-intact pulmonary artery and aortic rings after endothelin-1 (10 nmol/L) precontraction, while this was not observed in denuded rings (Figure 2C). In SHR, leptin (100 nmol/L) also induced the relaxation of endothelium-intact pulmonary artery and aortic rings after endothelin-1 (10 nmol/L) precontraction, and this effect was abolished in denuded aortic rings only. Indeed, endothelium-intact and –denuded pulmonary artery rings from SHR presented with similar vasodilating responses to leptin (100 nmol/L) after endothelin-1 (10 nmol/L) precontraction (Figure 2D). Leptin-induced vasodilating response was more pronounced in aortic compared to pulmonary artery rings (Figure 2C and D).

Vasoreactivity of arteries from spontaneously hypertensive and controls rats: response to leptin

As illustrated in Figure 3A, leptin (tested from 0.001 to 100 nmol/L) induced, in thoracic aortic rings from SHR, a stronger endothelium-dependent relaxation after phenylephrine (1 μmol/L) precontraction compared to control aortic response. This effect was totally abolished in endothelium-denuded rings. After endothelin-1 (10 nmol/L) precontraction, leptin (100 nmol/L) induced a similar endothelium-dependent relaxation in aortic rings from SHR and controls. However, after endothelin-1 (10 nmol/L), leptin had no effects on the vasoreactivity of endothelium-denuded aortic rings from controls, while it induced the contraction of denuded rings from SHR (Figure 3C).
After precontraction with phenylephrine (1 μmol/L), leptin (tested from 0.001 to 100 nmol/L) induced, in pulmonary artery rings from SHR and control rats, a similar endothelium-dependent relaxation, which rapidly reached a plateau. This effect was totally abolished in endothelium-denuded pulmonary artery rings (Figure 3B). After endothelin-1 (10 nmol/L) precontraction, leptin (100 nmol/L) induced an endothelium-dependent relaxation in pulmonary artery rings from control rats (p < 0.05), while this effect was decreased in pulmonary artery rings from SHR (Figure 3D).

Pulmonary morphometry

As illustrated in Figure 4, pulmonary artery medial thickness was increased in SHR compared to control rats.

Pathobiological comparison of thoracic aorta and pulmonary arteries: Endothelin-1 and nitric oxide related molecules

In control rats, gene expressions of the precursor of endothelin-1 (the preproendothelin-1; PPET-1) and of its converting enzyme (the endothelin converting enzyme-1; ECE-1) were lower in pulmonary arteries compared to aorta (Figure 5A-B), while endothelin-1 receptors type A (ETA) and type B (ETB) expressions were respectively higher and unchanged (Figure 5C-D).
In SHR, expressions of PPET-1, ETA and ETB receptors were increased in pulmonary arteries compared to aorta, while ECE-1 expression remained unchanged (Figure 5A-D). Gene expression of inducible nitric oxide (iNOS) was reduced in pulmonary arteries compared to aorta, while endothelial nitric oxide (eNOS) expression remained unchanged (Figure 5E-F).
In thoracic arteries, eNOS expression was decreased in SHR compared to controls, while expression of iNOS was increased (Figure 5E-F). In pulmonary arteries from SHR, expressions of PPET-1, ETA and ETB receptors were higher, while ECE-1 and iNOS expressions remained unchanged (Figure 5A-D and F). Pulmonary artery gene expression of eNOS was decreased in SHR compared to controls (Figure 5E).

Thoracic aorta and pulmonary artery expressions of leptin and related molecules

In control rat and SHR, gene expression of leptin was lower in pulmonary artery than in thoracic aorta (Figure 6A), while leptin receptor gene expression was higher (Figure 6B).
In SHR, pulmonary artery and thoracic aorta expression of leptin receptor was decreased compared to controls (Figure 6B), while leptin expression did not change (Figure 6A). Gene expression of suppressor of cytokine signaling-3 (SOCS-3), which has been shown to inhibit the signal transduction processes of leptin and to be implicated in leptin resistance [18], was increased in pulmonary arteries from SHR compared to controls (Figure 6C).

Discussion

The present study shows that vascular reactivity to endothelin-1 and leptin differs between pulmonary and systemic arteries and between pulmonary arteries from spontaneously hypertensive and normotensive rats. Indeed, the vasoconstriction induced by endothelin-1 is stronger in pulmonary compared to systemic arteries, and leptin induces more endothelium-dependent vasorelaxation in systemic compared to pulmonary arteries. In spontaneously hypertensive rats, the pulmonary artery vasoconstriction induced by phenylephrine and by endothelin-1 is enhanced due to a loss of the endothelial negative modulation of vasoconstriction. Moreover, leptin-induced pulmonary artery vasodilation after endothelin-1 precontraction is decreased in this hypertensive strain of rats, while leptin-induced thoracic aortic vasodilatation is preserved.
In the present study, pulmonary and systemic arteries were different in terms of vascular reactivity to different vasoactive agents (endothelin-1 and leptin). This is consistent with previous report showing that the mechanisms underlying the regulation of the vascular tone are different in pulmonary and systemic arteries, including calcium sensitization, channel activation/opening and superoxide effects [19]. An important role for the endothelin system has been well established in pulmonary arterial hypertension with demonstrated beneficial effects of endothelin receptor antagonists in these patients [20]. In contrast, the use of endothelin receptor antagonists has been disappointing in systemic cardiovascular diseases [21]. This is consistent with the present results and with previous results [22], showing enhanced pulmonary vasoreactivity to endothelin-1 in experimental heart failure. Here, high pulmonary vasoreactivity to endothelin-1 was associated with increased expression of ETA receptor in pulmonary compared to systemic arteries, while ETB receptor expression was similar. Indeed, it appears that the stimulation of the ETA receptors on the smooth muscle cells causes vasoconstriction that is opposed by stimulation of the ETB receptors present on the endothelial cells.
Leptin is a multifactorial adipose-derived adipokine that plays a critical role in bodyweight homeostasis and energy expenditure. Plasma leptin levels are markedly increased in obesity and associated metabolic syndrome. However, leptin levels have also been shown to be increased in patients with systemic hypertension [6, 7] and pulmonary arterial hypertension [13], independently of their body mass index. The effects of leptin on systemic vasculature have been previously reported [2326], but there is still no data regarding the pulmonary vascular effects of leptin. Under physiological conditions, leptin has no effect on systemic blood pressure, probably because its sympathetic nervous system stimulation is counteracted by depressor mechanisms, including endothelium–dependent vasorelaxation by endothelial nitric oxide and endothelium-derived hyperpolarizing factor. In contrast, in pathological chronic hyperleptinemia, the NO-mediated vasodilatory effects are impaired contributing to the development of hypertension, together with oxidative stress and overproduction of endothelin-1. Here, we found an endothelium-dependent vasodilating effect of leptin on isolated precontracted control systemic and pulmonary artery rings, with higher magnitude in systemic ones. This suggests that the systemic circulation is more prone to relax after leptin stimulation than the pulmonary circulation and that the endothelial integrity is critical for leptin vasodilation in both types of vessels. The decreased vasodilating response to leptin observed in the pulmonary arteries was associated with increased ETA receptor expressions together with increased leptin receptor expression. Indeed, despite a higher gene expression of leptin receptor in pulmonary artery, aortic rings were more responsive to leptin than pulmonary artery rings.
Beside systemic hypertension, spontaneously hypertensive rats have been shown to develop pulmonary hypertension spontaneously [27] or after exposure to chronic hypoxia [28]. In the pulmonary artery from these hypertensive rats, we found increased expressions of the endothelin-1 precursor, ETA and ETB receptors and decreased expression of endothelial NO synthase. These alterations of the vasodilator/constrictor balance (in favor of increased vasoconstriction) present some similarities with those observed in patients with pulmonary arterial hypertension [21, 2931]. Moreover, these pathobiological anomalies were associated with a slight but significant pulmonary artery remodeling. We also found increased pulmonary artery constriction to phenylephrine and endothelin-1 in hypertensive rats, due to the loss of the endothelial buffering of vasoconstriction. These pathobiological and functional alterations strongly suggest altered endothelial function in the pulmonary circulation of these hypertensive rats, probably responsible for the development of pulmonary hypertension. This may be considered as a type of pre-capillary component of pulmonary hypertension that in conjunction with the passive component due to the backward transfer of the increased pulmonary venous pressure participates to the onset of pulmonary hypertension.
Endothelial dysfunction is an important factor in the pathogenesis of pulmonary arterial hypertension [29]. In our experiments, endothelial function may be easily estimated by the difference in contraction between endothelium-denuded and -intact rings. In the present study, the endothelial blunting effect to vasoconstrictors (phenylephrine and endothelin-1) was lost in the pulmonary arteries from hypertensive rats, suggesting pulmonary endothelial dysfunction. This has already been shown in systemic aortic vessels in SHR, with variable magnitude with aging [32]. Indeed, healthy aortic endothelium negatively regulates α1-agonists- and endothelin-1-induced contraction through a basal endothelial NO release [3335], which is partly lost in spontaneously hypertensive rats [3638]. The imbalance between NO and endothelin-1 signaling pathways may, at least, partially mediate pulmonary endothelial dysfunction in this hypertensive strain, together with previously described altered calcium handling [2]. Even if we found some similar pathobiological anomalies within the pulmonary circulation of SHR compared to those observed in PAH patients, there is no clear evidence that these two conditions share common early pathogenic mechanisms.
In the present study, leptin-induced pulmonary artery vasodilation after endothelin-1 precontraction was decreased in spontaneously hypertensive rats, suggesting that, in these rats, an impairment of leptin negative modulation against endothelin-1 vasoconstriction could participate to the increase in pulmonary vascular tone. In pathologic conditions of chronic hyperleptinemia, resistance to the vasodilatory effects of leptin has already been described in the systemic circulation [26, 39] and incriminated in the development of systemic arterial hypertension owing to unopposed stimulation of the sympathetic nervous system by this hormone. This has been attributed to an abrogated effect of leptin on NO release [26, 40]. Resistance to leptin may result from different mechanisms, including an imbalance between leptin and leptin-binding proteins in the blood, a receptor downregulation or polymorphism, and post-receptor defects [41]. Suppressor of cytokine signaling 3 (SOCS3) is a critical negative feedback regulator of leptin receptor signaling that has been shown to contribute to the development of leptin resistance through inhibition of signal transduction [42]. In the present study, leptin receptor expression was downregulated and SOCS3 expression was upregulated in the pulmonary arteries of spontaneously hypertensive compared to normotensive rats. These could, therefore, contribute to the leptin resistance observed in the pulmonary vasculature of the hypertensive rats.

Conclusions

The present study shows that endothelin-1-induced vasoconstriction is more potent in the pulmonary artery than in the aorta and that this constriction is potentiated in spontaneous hypertensive rats, probably due to pulmonary endothelial dysfunction. The endothelium-dependent vasodilation induced by leptin is less effective in the pulmonary artery than in the aorta and this effect is abrogated after endothelin-1 precontraction in spontaneously hypertensive rats. The fact that this could be related to leptin resistance needs further investigation.

Acknowlegments

This work was supported by grants from the “Fonds de la Recherche Scientifique Medicale (FNRS; Belgium)” (grant number 3.4637.09) and the Belgian Foundation for Cardiac Surgery (Brussels, Belgium). L.D. is a FNRS postdoctoral fellow (“Chargé de Recherches”; Belgium).
Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://​creativecommons.​org/​licenses/​by/​2.​0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( https://​creativecommons.​org/​publicdomain/​zero/​1.​0/​ ) applies to the data made available in this article, unless otherwise stated.

Competing interests

The authors declare that they have no competing interest.

Authors’ contributions

Study conception and design: SG, CD, PJ, KM, LD - acquisition of data: SG, CD, PJ, MM - analysis and interpretation of data: SG, CD, PJ, MM, CM, KM, LD - drafting of manuscript: SG, RN, KM, LD - critical revision: SG, NL, SP, GB, RN, KM, LD. All authors read and approved the final manuscript.
Literatur
1.
Zurück zum Zitat Olivari MT, Fiorentini C, Polese A, Guazzi MD: Pulmonary hemodynamics and right ventricular function in hypertension. Circulation. 1978, 57: 1185-1190. 10.1161/01.CIR.57.6.1185.PubMedCrossRef Olivari MT, Fiorentini C, Polese A, Guazzi MD: Pulmonary hemodynamics and right ventricular function in hypertension. Circulation. 1978, 57: 1185-1190. 10.1161/01.CIR.57.6.1185.PubMedCrossRef
2.
Zurück zum Zitat Guazzi MD, Polese A, Bartorelli A, Loaldi A, Fiorentini C: Evidence of a shared mechanism of vasoconstriction in pulmonary and systemic circulation in hypertension: a possible role of intracellular calcium. Circulation. 1982, 66: 881-886. 10.1161/01.CIR.66.4.881.PubMedCrossRef Guazzi MD, Polese A, Bartorelli A, Loaldi A, Fiorentini C: Evidence of a shared mechanism of vasoconstriction in pulmonary and systemic circulation in hypertension: a possible role of intracellular calcium. Circulation. 1982, 66: 881-886. 10.1161/01.CIR.66.4.881.PubMedCrossRef
3.
Zurück zum Zitat Guazzi MD, Alimento M, Berti M, Fiorentini C, Galli C, Tamborini G: Enhanced hypoxic pulmonary vasoconstriction in hypertension. Circulation. 1989, 79: 337-343. 10.1161/01.CIR.79.2.337.PubMedCrossRef Guazzi MD, Alimento M, Berti M, Fiorentini C, Galli C, Tamborini G: Enhanced hypoxic pulmonary vasoconstriction in hypertension. Circulation. 1989, 79: 337-343. 10.1161/01.CIR.79.2.337.PubMedCrossRef
4.
Zurück zum Zitat Cooper CJ, Jevnikar FW, Walsh T, Dickinson J, Mouhaffel A, Selwyn AP: The influence of basal nitric oxide activity on pulmonary vascular resistance in patients with congestive heart failure. Am J Cardiol. 1998, 82: 609-614. 10.1016/S0002-9149(98)00400-7.PubMedCrossRef Cooper CJ, Jevnikar FW, Walsh T, Dickinson J, Mouhaffel A, Selwyn AP: The influence of basal nitric oxide activity on pulmonary vascular resistance in patients with congestive heart failure. Am J Cardiol. 1998, 82: 609-614. 10.1016/S0002-9149(98)00400-7.PubMedCrossRef
5.
Zurück zum Zitat Ooi H, Colucci WS, Givertz MM: Endothelin mediates increased pulmonary vascular tone in patients with heart failure: demonstration by direct intrapulmonary infusion of sitaxsentan. Circulation. 2002, 106: 1618-1621. 10.1161/01.CIR.0000034444.31846.F4.PubMedCrossRef Ooi H, Colucci WS, Givertz MM: Endothelin mediates increased pulmonary vascular tone in patients with heart failure: demonstration by direct intrapulmonary infusion of sitaxsentan. Circulation. 2002, 106: 1618-1621. 10.1161/01.CIR.0000034444.31846.F4.PubMedCrossRef
6.
Zurück zum Zitat Galletti F, D’Elia L, Barba G, Siani A, Cappuccio FP, Farinaro E, Iacone R, Russo O, de Palma D, Ippolito R, Strazzullo P: High-circulating leptin levels are associated with greater risk of hypertension in men independently of body mass and insulin resistance: results of an eight-year follow-up study. J Clin Endocrinol Metab. 2008, 93: 3922-3926. 10.1210/jc.2008-1280.PubMedCrossRef Galletti F, D’Elia L, Barba G, Siani A, Cappuccio FP, Farinaro E, Iacone R, Russo O, de Palma D, Ippolito R, Strazzullo P: High-circulating leptin levels are associated with greater risk of hypertension in men independently of body mass and insulin resistance: results of an eight-year follow-up study. J Clin Endocrinol Metab. 2008, 93: 3922-3926. 10.1210/jc.2008-1280.PubMedCrossRef
7.
Zurück zum Zitat Shankar A, Xiao J: Positive relationship between plasma leptin level and hypertension. Hypertension. 2010, 56: 623-628. 10.1161/HYPERTENSIONAHA.109.148213.PubMedCrossRef Shankar A, Xiao J: Positive relationship between plasma leptin level and hypertension. Hypertension. 2010, 56: 623-628. 10.1161/HYPERTENSIONAHA.109.148213.PubMedCrossRef
8.
Zurück zum Zitat Beltowski J, Wojcicka G, Gorny D, Marciniak A: Human leptin administered intraperitoneally stimulates natriuresis and decreases renal medullary Na+, K + −ATPase activity in the rat – impaired effect in dietary-induced obesity. Med Sci Monit. 2002, 8: BR221-BR229.PubMed Beltowski J, Wojcicka G, Gorny D, Marciniak A: Human leptin administered intraperitoneally stimulates natriuresis and decreases renal medullary Na+, K + −ATPase activity in the rat – impaired effect in dietary-induced obesity. Med Sci Monit. 2002, 8: BR221-BR229.PubMed
9.
Zurück zum Zitat Lin L, Martin R, Schaffhauser AO, York DA: Acute changes in the response to peripheral leptin with alteration in the diet composition. Am J Physiol Regul Integr Comp Physiol. 2001, 280: R504-R509.PubMed Lin L, Martin R, Schaffhauser AO, York DA: Acute changes in the response to peripheral leptin with alteration in the diet composition. Am J Physiol Regul Integr Comp Physiol. 2001, 280: R504-R509.PubMed
10.
Zurück zum Zitat Ferri C, Bellini C, Desideri G, di Francesco L, Baldoncini R, Santucci A, de Mattia G: Plasma endothelin-1 levels in obese hypertensive and normotensive men. Diabetes. 1995, 44: 431-436. 10.2337/diab.44.4.431.PubMedCrossRef Ferri C, Bellini C, Desideri G, di Francesco L, Baldoncini R, Santucci A, de Mattia G: Plasma endothelin-1 levels in obese hypertensive and normotensive men. Diabetes. 1995, 44: 431-436. 10.2337/diab.44.4.431.PubMedCrossRef
11.
Zurück zum Zitat Quehenberger P, Exner M, Sunder-Plassmann R, Ruzicka K, Bieglmayer C, Endler G, Muellner C, Speiser W, Wagner O: Leptin induces endothelin-1 in endothelial cells in vitro. Circ Res. 2002, 90: 711-718. 10.1161/01.RES.0000014226.74709.90.PubMedCrossRef Quehenberger P, Exner M, Sunder-Plassmann R, Ruzicka K, Bieglmayer C, Endler G, Muellner C, Speiser W, Wagner O: Leptin induces endothelin-1 in endothelial cells in vitro. Circ Res. 2002, 90: 711-718. 10.1161/01.RES.0000014226.74709.90.PubMedCrossRef
12.
Zurück zum Zitat Beltowski J, Wojcicka G, Borkowska E: Human leptin stimulates systemic nitric oxide production in the rat. Obes Res. 2002, 10: 939-946. 10.1038/oby.2002.128.PubMedCrossRef Beltowski J, Wojcicka G, Borkowska E: Human leptin stimulates systemic nitric oxide production in the rat. Obes Res. 2002, 10: 939-946. 10.1038/oby.2002.128.PubMedCrossRef
13.
Zurück zum Zitat Huertas A, Tu L, Gambaryan N, Girerd B, Perros F, Montani D, Fabre D, Fadel E, Eddahibi S, Cohen-Kaminsky S, et al: Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension. Eur Respir J. 2012, 40: 895-904. 10.1183/09031936.00159911.PubMedCrossRef Huertas A, Tu L, Gambaryan N, Girerd B, Perros F, Montani D, Fabre D, Fadel E, Eddahibi S, Cohen-Kaminsky S, et al: Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension. Eur Respir J. 2012, 40: 895-904. 10.1183/09031936.00159911.PubMedCrossRef
14.
Zurück zum Zitat Rondelet B, Dewachter C, Kerbaul F, Kang X, Fesler P, Brimioulle S, Naeije R, Dewachter L: Prolonged overcirculation-induced pulmonary arterial hypertension as a cause of right ventricular failure. Eur Heart J. 2012, 33: 1017-1026. 10.1093/eurheartj/ehr111.PubMedCrossRef Rondelet B, Dewachter C, Kerbaul F, Kang X, Fesler P, Brimioulle S, Naeije R, Dewachter L: Prolonged overcirculation-induced pulmonary arterial hypertension as a cause of right ventricular failure. Eur Heart J. 2012, 33: 1017-1026. 10.1093/eurheartj/ehr111.PubMedCrossRef
15.
Zurück zum Zitat Rondelet B, Dewachter L, Kerbaul F, Dewachter C, Hubloue I, Fesler P, Franck S, Remmelink M, Brimioulle S, Naeije R: Sildenafil added to sitaxsentan in overcirculation-induced pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol. 2010, 299: H1118-H1123. 10.1152/ajpheart.00418.2010.PubMedCrossRef Rondelet B, Dewachter L, Kerbaul F, Dewachter C, Hubloue I, Fesler P, Franck S, Remmelink M, Brimioulle S, Naeije R: Sildenafil added to sitaxsentan in overcirculation-induced pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol. 2010, 299: H1118-H1123. 10.1152/ajpheart.00418.2010.PubMedCrossRef
16.
Zurück zum Zitat Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987, 162: 156-159.PubMedCrossRef Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987, 162: 156-159.PubMedCrossRef
17.
Zurück zum Zitat Dewachter L, Adnot S, Fadel E, Humbert M, Maitre B, Barlier-Mur AM, Simonneau G, Hamon M, Naeije R, Eddahibi S: Angiopoietin/Tie2 pathway influences smooth muscle hyperplasia in idiopathic pulmonary hypertension. Am J Respir Crit Care Med. 2006, 174: 1025-1033. 10.1164/rccm.200602-304OC.PubMedCrossRef Dewachter L, Adnot S, Fadel E, Humbert M, Maitre B, Barlier-Mur AM, Simonneau G, Hamon M, Naeije R, Eddahibi S: Angiopoietin/Tie2 pathway influences smooth muscle hyperplasia in idiopathic pulmonary hypertension. Am J Respir Crit Care Med. 2006, 174: 1025-1033. 10.1164/rccm.200602-304OC.PubMedCrossRef
18.
Zurück zum Zitat Morris DL, Rui L: Recent advances in understanding leptin signaling and leptin resistance. Am J Physiol Endocrinol Metab. 2009, 297: E1247-E1259. 10.1152/ajpendo.00274.2009.PubMedPubMedCentralCrossRef Morris DL, Rui L: Recent advances in understanding leptin signaling and leptin resistance. Am J Physiol Endocrinol Metab. 2009, 297: E1247-E1259. 10.1152/ajpendo.00274.2009.PubMedPubMedCentralCrossRef
19.
Zurück zum Zitat Snetkov VA, Smirnov SV, Kua J, Aaronson PI, Ward JP, Knock GA: Superoxide differentially controls pulmonary and systemic vascular tone through multiple signalling pathways. Cardiovasc Res. 2011, 89: 214-224. 10.1093/cvr/cvq275.PubMedPubMedCentralCrossRef Snetkov VA, Smirnov SV, Kua J, Aaronson PI, Ward JP, Knock GA: Superoxide differentially controls pulmonary and systemic vascular tone through multiple signalling pathways. Cardiovasc Res. 2011, 89: 214-224. 10.1093/cvr/cvq275.PubMedPubMedCentralCrossRef
20.
Zurück zum Zitat Galie N, Manes A, Branzi A: The endothelin system in pulmonary arterial hypertension. Cardiovasc Res. 2004, 61: 227-237. 10.1016/j.cardiores.2003.11.026.PubMedCrossRef Galie N, Manes A, Branzi A: The endothelin system in pulmonary arterial hypertension. Cardiovasc Res. 2004, 61: 227-237. 10.1016/j.cardiores.2003.11.026.PubMedCrossRef
21.
Zurück zum Zitat Rich S, mcLaughlin VV: Endothelin receptor blockers in cardiovascular disease. Circulation. 2003, 108: 2184-2190. 10.1161/01.CIR.0000094397.19932.78.PubMedCrossRef Rich S, mcLaughlin VV: Endothelin receptor blockers in cardiovascular disease. Circulation. 2003, 108: 2184-2190. 10.1161/01.CIR.0000094397.19932.78.PubMedCrossRef
22.
Zurück zum Zitat Ray L, Mathieu M, Jespers P, Hadad I, Mahmoudabady M, Pensis A, Motte S, Peters IR, Naeije R, McEntee K: Early increase in pulmonary vascular reactivity with overexpression of endothelin-1 and vascular endothelial growth factor in canine experimental heart failure. Exp Physiol. 2008, 93: 434-442.PubMedCrossRef Ray L, Mathieu M, Jespers P, Hadad I, Mahmoudabady M, Pensis A, Motte S, Peters IR, Naeije R, McEntee K: Early increase in pulmonary vascular reactivity with overexpression of endothelin-1 and vascular endothelial growth factor in canine experimental heart failure. Exp Physiol. 2008, 93: 434-442.PubMedCrossRef
23.
Zurück zum Zitat Sahin AS, Bariskaner H: The mechanisms of vasorelaxant effect of leptin on isolated rabbit aorta. Fundam Clin Pharmacol. 2007, 21: 595-600. 10.1111/j.1472-8206.2007.00541.x.PubMedCrossRef Sahin AS, Bariskaner H: The mechanisms of vasorelaxant effect of leptin on isolated rabbit aorta. Fundam Clin Pharmacol. 2007, 21: 595-600. 10.1111/j.1472-8206.2007.00541.x.PubMedCrossRef
24.
Zurück zum Zitat Lembo G, Vecchione C, Fratta L, Marino G, Trimarco V, d’Amati G, Trimarco B: Leptin induces direct vasodilation through distinct endothelial mechanisms. Diabetes. 2000, 49: 293-297. 10.2337/diabetes.49.2.293.PubMedCrossRef Lembo G, Vecchione C, Fratta L, Marino G, Trimarco V, d’Amati G, Trimarco B: Leptin induces direct vasodilation through distinct endothelial mechanisms. Diabetes. 2000, 49: 293-297. 10.2337/diabetes.49.2.293.PubMedCrossRef
25.
Zurück zum Zitat Kimura K, Tsuda K, Baba A, Kawabe T, Boh-oka S, Ibata M, Moriwaki C, Hano T, Nishio I: Involvement of nitric oxide in endothelium-dependent arterial relaxation by leptin. Biochem Biophys Res Commun. 2000, 273: 745-749. 10.1006/bbrc.2000.3005.PubMedCrossRef Kimura K, Tsuda K, Baba A, Kawabe T, Boh-oka S, Ibata M, Moriwaki C, Hano T, Nishio I: Involvement of nitric oxide in endothelium-dependent arterial relaxation by leptin. Biochem Biophys Res Commun. 2000, 273: 745-749. 10.1006/bbrc.2000.3005.PubMedCrossRef
26.
Zurück zum Zitat Galvez-Prieto B, Somoza B, Gil-Ortega M, Garcia-Prieto CF, de Las Heras AI, Gonzalez MC, Arribas S, Aranguez I, Bolbrinker J, Kreutz R, et al: Anticontractile Effect of Perivascular Adipose Tissue and Leptin are Reduced in Hypertension. Front Pharmacol. 2012, 3: 103-PubMedPubMedCentralCrossRef Galvez-Prieto B, Somoza B, Gil-Ortega M, Garcia-Prieto CF, de Las Heras AI, Gonzalez MC, Arribas S, Aranguez I, Bolbrinker J, Kreutz R, et al: Anticontractile Effect of Perivascular Adipose Tissue and Leptin are Reduced in Hypertension. Front Pharmacol. 2012, 3: 103-PubMedPubMedCentralCrossRef
27.
Zurück zum Zitat Aharinejad S, Schraufnagel DE, Bock P, MacKay CA, Larson EK, Miksovsky A, Marks SC: Spontaneously hypertensive rats develop pulmonary hypertension and hypertrophy of pulmonary venous sphincters. Am J Pathol. 1996, 148: 281-290.PubMedPubMedCentral Aharinejad S, Schraufnagel DE, Bock P, MacKay CA, Larson EK, Miksovsky A, Marks SC: Spontaneously hypertensive rats develop pulmonary hypertension and hypertrophy of pulmonary venous sphincters. Am J Pathol. 1996, 148: 281-290.PubMedPubMedCentral
28.
Zurück zum Zitat McMurtry IF, Petrun MD, Tucker A, Reeves JT: Pulmonary vascular reactivity in the spontaneously hypertensive rat. Blood Vessels. 1979, 16: 61-70.PubMed McMurtry IF, Petrun MD, Tucker A, Reeves JT: Pulmonary vascular reactivity in the spontaneously hypertensive rat. Blood Vessels. 1979, 16: 61-70.PubMed
29.
Zurück zum Zitat Morrell NW, Adnot S, Archer SL, hDupuis J, Jones PL, MacLean MR, McMurtry IF, Stenmark KR, Thistlethwaite PA, Weissmann N, et al: Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol. 2009, 54: S20-S31. 10.1016/j.jacc.2009.04.018.PubMedPubMedCentralCrossRef Morrell NW, Adnot S, Archer SL, hDupuis J, Jones PL, MacLean MR, McMurtry IF, Stenmark KR, Thistlethwaite PA, Weissmann N, et al: Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol. 2009, 54: S20-S31. 10.1016/j.jacc.2009.04.018.PubMedPubMedCentralCrossRef
30.
Zurück zum Zitat Giaid A, Saleh D: Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995, 333: 214-221. 10.1056/NEJM199507273330403.PubMedCrossRef Giaid A, Saleh D: Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995, 333: 214-221. 10.1056/NEJM199507273330403.PubMedCrossRef
31.
Zurück zum Zitat Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ: Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993, 328: 1732-1739. 10.1056/NEJM199306173282402.PubMedCrossRef Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ: Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993, 328: 1732-1739. 10.1056/NEJM199306173282402.PubMedCrossRef
32.
Zurück zum Zitat Safar M, Chamiot-Clerc P, Dagher G, Renaud JF: Pulse pressure, endothelium function, and arterial stiffness in spontaneously hypertensive rats. Hypertension. 2001, 38: 1416-1421. 10.1161/hy1201.096538.PubMedCrossRef Safar M, Chamiot-Clerc P, Dagher G, Renaud JF: Pulse pressure, endothelium function, and arterial stiffness in spontaneously hypertensive rats. Hypertension. 2001, 38: 1416-1421. 10.1161/hy1201.096538.PubMedCrossRef
33.
Zurück zum Zitat Bullock GR, Taylor SG, Weston AH: Influence of the vascular endothelium on agonist-induced contractions and relaxations in rat aorta. Br J Pharmacol. 1986, 89: 819-830. 10.1111/j.1476-5381.1986.tb11187.x.PubMedPubMedCentralCrossRef Bullock GR, Taylor SG, Weston AH: Influence of the vascular endothelium on agonist-induced contractions and relaxations in rat aorta. Br J Pharmacol. 1986, 89: 819-830. 10.1111/j.1476-5381.1986.tb11187.x.PubMedPubMedCentralCrossRef
34.
Zurück zum Zitat Luscher TF, Dohi Y, Tschudi M: Endothelium-dependent regulation of resistance arteries: alterations with aging and hypertension. J Cardiovasc Pharmacol. 1992, 19 (Suppl 5): S34-S42.PubMedCrossRef Luscher TF, Dohi Y, Tschudi M: Endothelium-dependent regulation of resistance arteries: alterations with aging and hypertension. J Cardiovasc Pharmacol. 1992, 19 (Suppl 5): S34-S42.PubMedCrossRef
35.
Zurück zum Zitat Yamaguchi T, Rodman D, O’Brien R, McMurtry I: Modulation of pulmonary artery contraction by endothelium-derived relaxing factor. Eur J Pharmacol. 1989, 161: 259-262. 10.1016/0014-2999(89)90856-X.PubMedCrossRef Yamaguchi T, Rodman D, O’Brien R, McMurtry I: Modulation of pulmonary artery contraction by endothelium-derived relaxing factor. Eur J Pharmacol. 1989, 161: 259-262. 10.1016/0014-2999(89)90856-X.PubMedCrossRef
36.
Zurück zum Zitat Dohi Y, Kojima M, Sato K: Endothelial modulation of contractile responses in arteries from hypertensive rats. Hypertension. 1996, 28: 732-737. 10.1161/01.HYP.28.5.732.PubMedCrossRef Dohi Y, Kojima M, Sato K: Endothelial modulation of contractile responses in arteries from hypertensive rats. Hypertension. 1996, 28: 732-737. 10.1161/01.HYP.28.5.732.PubMedCrossRef
37.
Zurück zum Zitat Ibarra M, Lopez-Guerrero JJ, Mejia-Zepeda R, Villalobos-Molina R: Endothelium-dependent inhibition of the contractile response is decreased in aorta from aged and spontaneously hypertensive rats. Arch Med Res. 2006, 37: 334-341. 10.1016/j.arcmed.2005.06.015.PubMedCrossRef Ibarra M, Lopez-Guerrero JJ, Mejia-Zepeda R, Villalobos-Molina R: Endothelium-dependent inhibition of the contractile response is decreased in aorta from aged and spontaneously hypertensive rats. Arch Med Res. 2006, 37: 334-341. 10.1016/j.arcmed.2005.06.015.PubMedCrossRef
38.
Zurück zum Zitat Osugi S, Shimamura K, Sunano S: Decreased modulation by endothelium of noradrenaline-induced contractions in aorta from stroke-prone spontaneously hypertensive rats. Arch Int Pharmacodyn Ther. 1990, 305: 86-99.PubMed Osugi S, Shimamura K, Sunano S: Decreased modulation by endothelium of noradrenaline-induced contractions in aorta from stroke-prone spontaneously hypertensive rats. Arch Int Pharmacodyn Ther. 1990, 305: 86-99.PubMed
39.
Zurück zum Zitat Rodriguez A, Fruhbeck G, Gomez-Ambrosi J, Catalan V, Sainz N, Diez J, Zalba G, Fortuno A: The inhibitory effect of leptin on angiotensin II-induced vasoconstriction is blunted in spontaneously hypertensive rats. J Hypertens. 2006, 24: 1589-1597. 10.1097/01.hjh.0000239295.17636.6e.PubMedCrossRef Rodriguez A, Fruhbeck G, Gomez-Ambrosi J, Catalan V, Sainz N, Diez J, Zalba G, Fortuno A: The inhibitory effect of leptin on angiotensin II-induced vasoconstriction is blunted in spontaneously hypertensive rats. J Hypertens. 2006, 24: 1589-1597. 10.1097/01.hjh.0000239295.17636.6e.PubMedCrossRef
40.
Zurück zum Zitat Wold LE, Relling DP, Duan J, Norby FL, Ren J: Abrogated leptin-induced cardiac contractile response in ventricular myocytes under spontaneous hypertension: role of Jak/STAT pathway. Hypertension. 2002, 39: 69-74. 10.1161/hy0102.100777.PubMedCrossRef Wold LE, Relling DP, Duan J, Norby FL, Ren J: Abrogated leptin-induced cardiac contractile response in ventricular myocytes under spontaneous hypertension: role of Jak/STAT pathway. Hypertension. 2002, 39: 69-74. 10.1161/hy0102.100777.PubMedCrossRef
41.
Zurück zum Zitat Beltowski J: Leptin and the regulation of endothelial function in physiological and pathological conditions. Clin Exp Pharmacol Physiol. 2012, 39: 168-178. 10.1111/j.1440-1681.2011.05623.x.PubMedCrossRef Beltowski J: Leptin and the regulation of endothelial function in physiological and pathological conditions. Clin Exp Pharmacol Physiol. 2012, 39: 168-178. 10.1111/j.1440-1681.2011.05623.x.PubMedCrossRef
42.
Zurück zum Zitat Myers MG, Cowley MA, Munzberg H: Mechanisms of leptin action and leptin resistance. Annu Rev Physiol. 2008, 70: 537-556. 10.1146/annurev.physiol.70.113006.100707.PubMedCrossRef Myers MG, Cowley MA, Munzberg H: Mechanisms of leptin action and leptin resistance. Annu Rev Physiol. 2008, 70: 537-556. 10.1146/annurev.physiol.70.113006.100707.PubMedCrossRef
Metadaten
Titel
Pulmonary vasoreactivity in spontaneously hypertensive rats - Effects of endothelin-1 and leptin
verfasst von
Samantha Gomart
Cécile Damoiseaux
Pascale Jespers
Martine Makanga
Nathalie Labranche
Stéphanie Pochet
Charles Michaux
Guy Berkenboom
Robert Naeije
Kathleen McEntee
Laurence Dewachter
Publikationsdatum
01.12.2014
Verlag
BioMed Central
Erschienen in
Respiratory Research / Ausgabe 1/2014
Elektronische ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-15-12

Weitere Artikel der Ausgabe 1/2014

Respiratory Research 1/2014 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.