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Circulation. 1995;92:114-119

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(Circulation. 1995;92:114-119.)
© 1995 American Heart Association, Inc.

Articles

Role of Endothelin-1 in Beagles With Dehydromonocrotaline-Induced Pulmonary Hypertension

Morihito Okada, MD; Chojiro Yamashita, MD; Masayoshi Okada, MD; Kenji Okada, MD

From the Department of Surgery, Division II, Kobe University School of Medicine, Kobe, Japan.

Correspondence to Morihito Okada, MD, Department of Surgery, Division II, Kobe University School of Medicine, Kusunoki-cho 7-5-2, Chuo-ku, 650 Kobe City, Japan.


*    Abstract
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 *Abstract
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down arrowResults
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Background Although plasma levels of endothelin-1 (ET-1) increase in patients with pulmonary hypertension (PH), its role in PH is unknown. We investigated the contribution of endogenous ET-1 to cardiopulmonary changes in beagles with dehydromonocrotaline (DMCT)-induced PH.

Methods and Results Eight 3-month-old beagles were given a single injection of 3 mg/kg DMCT via the right atrium. During the 8 weeks after injection, the mean pulmonary arterial pressure (PAP) and plasma ET-1 level increased significantly from 11.6±2.3 to 35.9±7.1 mm Hg and from 1.24±0.25 to 3.25±0.94 pg/mL, respectively. In controls, ET-1 infusion elevated the systemic arterial pressure (SAP) but did not alter PAP. In PH beagles, ET-1 infusion increased SAP, which was attenuated by FR139317 (an endothelin type [ET] A receptor antagonist), and produced a dose-dependent decrease in PAP, which was attenuated by RES-701-1 (an ETB receptor antagonist). In PH beagles, FR139317 infusion decreased PAP, and RES-701-1 infusion increased PAP. Sarafotoxin S6c (an ETB agonist) infusion decreased PAP in PH beagles.

Conclusions These results suggest that endogenous ET-1 is elevated in PH disease and may mitigate PH by acting on ETB receptors.


Key Words: pulmonary heart disease • endothelin


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
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The vascular endothelium plays an important role in the control of cardiovascular tone. Endothelin-1 (ET-1), a 21–amino acid polypeptide produced by vascular endothelial cells, has complex, potent vasoactive properties.1 ET-1 has various hemodynamic effects on the pulmonary circulation, including sustained vasoconstriction, vasorelaxation, or biphasic responses.2 3 4 5 6 7 8 These various responses may depend on factors such as age, species, preparation, dosage, route, and pulmonary vascular tone. Further investigation is needed to clarify how ET-1 acts on the pulmonary circulation.

Pulmonary hypertension (PH) is characterized by an increase in vascular tone or an abnormal proliferation of smooth muscle cells in the pulmonary vasculature. Elevated plasma concentrations of ET-1 have been associated with PH.9 10 11 12 However, the role of ET-1 release in abnormal pulmonary circulation remains unclear.

Monocrotaline, a pyrrolizine alkaloid extracted from the seeds of Crotalaria spectabilis, is converted by the mixed-function oxidase system of the liver into dehydromonocrotaline (DMCT), which passes through and injures the pulmonary vascular bed after subcutaneous injection in rats.13 14 DMCT induces severe PH in 3 to 4 weeks.13 14 15 16 17 We have established a model in which PH is induced in beagles by right atrial injection of DMCT to evaluate accurately the cardiopulmonary hemodynamics of PH.18

The purpose of the present study was to investigate the role of endogenous ET-1 in beagles with DMCT-induced PH. To investigate its effects on vascular tone, ET-1 was infused into the pulmonary artery. Furthermore, to determine the mechanism of its vasoaction, FR139317, an endothelin type (ET) A receptor antagonist,19 20 RES-701-1, an ETB receptor antagonist,21 and sarafotoxin S6c, an ETB agonist,22 were infused, and ET-1 was infused in the presence of FR139317 and RES-701-1.


*    Methods
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 *Methods
down arrowResults
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Eight purebred beagles (mean age, 3 months; weight, 5.1±0.8 kg) were used to prepare PH models. All animals were kept in clean cages with regular food and sterile water as desired and received humane care in compliance with the Principles of Laboratory Animal Care formulated by the Institute of Laboratory Animal Resources and the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health. DMCT was prepared as described by Mattocks.23 Beagles were given a single injection of 3 mg/kg DMCT via the right atrium and were investigated before and after 4 or 8 weeks of treatment. Each beagle was anesthetized with sodium pentobarbital (25 mg/kg IV) and permitted to breathe spontaneously. Each study took place after the beagles had rested supine in a quiet laboratory for a minimum of 30 minutes at room temperature (20°C to 24°C). Under sterile conditions, a 5F Swan-Ganz catheter (Baxter Healthcare) was advanced from the femoral vein to the pulmonary artery, and another catheter was placed in the femoral artery for hemodynamic measurements. The pressures were monitored continuously with an oscillograph (363, NEC San-ei Instruments Ltd). Systemic arterial pressure, central venous pressure, pulmonary arterial pressure, pulmonary capillary wedge pressure, and cardiac output were measured. A blood sample was collected from the pulmonary artery, and its plasma ET-1 level was measured. Each blood sample was placed in a chilled tube containing EDTA and aprotinin; after centrifugation the plasma was stored at -30°C until used. After ET-1 was extracted through a C18 (Waters Associates), the concentration was measured by radioimmunoassay by using an antibody to ET-1 (Peninsula Lab Inc) and 125I-labeled ET-1 (Amersham Japan Co). This assay for ET-1 scarcely cross-reacts with ET-2, ET-3, or big ET-1 (cross-reactivity, <0.1%).

A diagrammatic representation of this study is shown in Fig 1Down. After a stable baseline was achieved, baseline values were obtained with infusion of each vehicle. These values represented the solvent values for further comparison. The vehicle for each drug was infused for 20 minutes, followed by infusion of the drug for an additional 20 minutes. Measurements were performed during the last 5 minutes of each infusion. A 24-hour recovery period was allowed between protocols. The following protocols were performed in control (baseline) and PH beagles at 4 and 8 weeks after injection of DMCT. In protocol 1, ET-1 (Peptide Institute Inc) was infused at a dose of 10 or 100 ng · kg-1 · min-1 for a 20-minute period. In protocol 2, after the first 10-minute pretreatment infusion of FR139317 (200 µg · kg-1 · min-1; Fujisawa Pharmaceutical Co, Ltd) or RES-701-1 (100 µg · kg-1 · min-1; Kyowa Hakko Kogyo Co, Ltd), ET-1 was infused at a dose of 100 ng · kg-1 · min-1 with continuing infusion of FR139317 or RES-701-1 for a 20-minute period. In protocol 3, FR139317 or RES-701-1 was infused at a dose of 200 or 100 µg · kg-1 · min-1, respectively, for a 20-minute period. In protocol 4, sarafotoxin S6c (Peptide Institute Inc) was infused at 5 and 50 ng · kg-1 · min-1 for consecutive 20-minute periods.



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  		Figure 1. Schematic of experimental protocols. ET-1 indicates endothelin-1; FR, FR139317; RES, RES-701-1; and S6c, sarafotoxin S6c.

Protocols 2, 3, and 4 were performed in a few randomly selected beagles. FR139317 at 40 µg · kg-1 · min-1 or RES-701-1 at 20 µg · kg-1 · min-1 resulted in minimum hemodynamic changes. FR139317 at 1000 µg · kg-1 · min-1, RES-701-1 at 500 µg · kg-1 · min-1, and sarafotoxin S6c at 250 ng · kg-1 ·min-1 caused changes similar to those induced by FR139317 at 200 µg · kg-1 · min-1, RES-701-1 at 100 µg · kg-1 · min-1, and sarafotoxin S6c at 50 ng · kg-1 · min-1, respectively. From these results, we selected the doses of the drugs. ET-1 and sarafotoxin S6c were dissolved with 5% dextrose in water and delivered via the pulmonary artery by an infusion pump. Control experiments were performed on each beagle by administering 5% dextrose in water alone during the infusion period. FR139317 was dissolved in 1N NaOH. RES-701-1 was dissolved in dimethyl sulfoxide. Each drug was dissolved in sterile normal saline with the above-mentioned solution and further diluted in normal saline. All solutions were prepared on the day of the study and kept on ice until administered. The constant infusion rate was 1 mL/min. The experiments were performed on every beagle in the same order at baseline and at 4 and 8 weeks after DMCT. All parameters were measured by polygraph (model 363; NEC San-ei Instruments Ltd) and continuously recorded (model 8M14; NEC San-ei Instruments Ltd). The values of arterial blood gases, which were analyzed from samples obtained from the femoral artery, remained within suitable limits. Cardiac output was measured with thermodilution techniques and expressed as the mean of the values recorded after each of five injections of saline (3 mL at 1°C to 5°C). Vascular resistances were calculated by using standard formulas. The percent change in each parameter was calculated as (postinjection value-preinjection value)/preinjection value.

Statistical Analysis
All data are given as mean±SD. Data and parameters were compared by using multiway ANOVA to determine the effect of study groups and time points. When ANOVA demonstrated significance, each difference was tested by using the Scheffé F test. Any value of P<.05 was accepted as statistically significant.


*    Results
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*Results
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Development of PH in DMCT Beagles
The effects of DMCT injection on hemodynamics and plasma ET-1 level are shown in Table 1Down. A single injection of DMCT produced a significant elevation in pulmonary arterial pressure compared with the preinjection value by the fourth week, after which it increased rapidly. During the 8 weeks after injection, mean pulmonary arterial pressure and pulmonary vascular resistance increased significantly from 11.6±2.3 to 35.9±7.1 mm Hg and from 193±76 to 1414±552 dyne · s · cm-5, respectively. Systemic arterial pressure and systemic vascular resistance remained relatively stable. The heart rate did not vary significantly, although it did increase by several beats per minute. The cardiac output at 8 weeks after injection was significantly reduced from the preinjection value. The plasma ET-1 level was elevated significantly from 1.24±0.25 to 3.25±0.94 pg/mL at 8 weeks.


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  		Table 1. Effects of DMCT Injection on Hemodynamics and Plasma ET-1

Hemodynamic Changes Caused by ET-1 Infusion and the Effects of FR139317 or RES-701-1 Pretreatment (Protocols 1 and 2)
Table 2Down shows the hemodynamic changes caused by ET-1 infusion and the pretreatment effects of FR139317 or RES-701-1 before and at the fourth and eighth week after DMCT injection.


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  		Table 2. Hemodynamic Changes Caused by ET-1 Infusion and the Effects of FR139317 or RES-701-1 Pretreatment (Protocols 1 and 2)

ET-1 infusion at 100 ng · kg-1 · min-1 significantly increased the mean systemic arterial pressure in both PH and control beagles at the fourth week, but it did not alter heart rate, mean pulmonary arterial pressure, cardiac output, systemic vascular resistance, or pulmonary vascular resistance. Systemic arterial pressure was not affected in either group by FR139317 or RES-701-1. By the eighth week, however, ET-1 at 100 ng · kg-1 · min-1 significantly increased the mean systemic arterial pressure and increased systemic vascular resistance, which were attenuated by FR139317, and significantly decreased mean pulmonary arterial pressure and pulmonary vascular resistance, which were attenuated by RES-701-1 (Fig 2Down). Heart rate and cardiac output were unchanged during the eighth week of PH. As a consequence, in PH beagles during the eighth week postinjection, ET-1 caused a decrease in pulmonary arterial pressure mediated by the ETB receptor in spite of an increase in systemic arterial pressure being mediated by the ETA receptor.



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  		Figure 2. Bar graph. During dehydromonocrotaline-induced pulmonary hypertension at 8 weeks after injection, a decrease in mean pulmonary arterial pressure produced by endothelin-1 (ET-1; 100 ng · kg-1 · min-1) was attenuated by RES-701-1 (100 µg · kg-1 · min-1) but not by FR139317 (200 µg · kg-1 · min-1), and an increase in mean systemic arterial pressure produced by ET-1 was attenuated only by FR139317. In controls, the pretreatment effects of FR139317 or RES-701-1 on mean pulmonary or systemic arterial pressure were not significant. Values are mean±SD. *P<.05 vs ET-1 alone.

Hemodynamic Changes Caused by FR139317, RES-701-1, or Sarafotoxin S6c Infusion (Protocols 3 and 4)
Table 3Down shows the hemodynamic changes caused by FR139317, RES-701-1, or sarafotoxin S6c infusion in control and in PH beagles at the fourth and eighth week after DMCT injection. FR139317 infusion at 200 µg · kg-1 · min-1 decreased the systemic and pulmonary arterial pressures in both control and PH beagles. There was a significant decrease in pulmonary arterial pressure in PH beagles even during the fourth postinjection week (Fig 3Down), and a significant decrease in pulmonary vascular resistance in PH at the eighth week postinjection. RES-701-1 infusion at 100 µg · kg-1 · min-1 significantly increased the pulmonary arterial pressure (Fig 3Down) and pulmonary vascular resistance in PH beagles at the eighth week postinjection. Although sarafotoxin S6c did not alter systemic hemodynamics in PH beagles, at 50 ng · kg-1 · min-1 it significantly decreased the mean pulmonary arterial pressure (Fig 4Down) and pulmonary vascular resistance. FR139317 at 200 µg · kg-1 · min-1, RES-701-1 at 100 µg · kg-1 · min-1, or sarafotoxin S6c at 50 ng · kg-1 · min-1 did not significantly alter heart rate, mean systemic arterial pressure, cardiac output, or systemic vascular resistance in any group.


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  		Table 3. Hemodynamic Changes Caused by FR139317, RES-701-1, or Sarafotoxin S6c Infusion (Protocols 3 and 4)



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  		Figure 3. Bar graphs. FR139317 (200 µg · kg-1 · min-1) significantly decreased and RES-701-1 (100 µg · kg-1 · min-1) significantly increased mean pulmonary arterial pressure during pulmonary hypertension (PH). Values are mean±SD. *P<.05 vs preinfusion.



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  		Figure 4. Bar graph. Sarafotoxin S6c produced dose-dependent decreases in mean pulmonary arterial pressure in pulmonary hypertension (PH). Values are mean±SD. *P<.05 vs preinfusion.


*    Discussion
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 up arrowMethods
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*Discussion
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Although PH is known to occur in many diseases, a form of PH exists that has no known cause, ie, the mechanism by which PH develops when there is no underlying disease remains unknown. To understand PH, which is basically an ongoing and fluctuating physiological abnormality, experimental approaches are useful. Some known examples of experimental PH occur with arteriovenous shunt, pulmonary vessel banding, hypoxia, and monocrotaline injection.13 14 15 16 17 Following subcutaneous injection into rats, monocrotaline is swiftly converted by the mixed-function oxidase system in the liver into DMCT, which first passes through and injures the pulmonary vascular bed. To model PH, relatively large animals are needed to accurately measure cardiopulmonary hemodynamics. However, an injection of monocrotaline in beagles did not result in progressive PH. We have established PH in beagles by using DMCT.18 Vascular endothelial injury caused by DMCT is nonspecific, and because DMCT-induced PH is established after the causative agent is removed, this experimental model has promising similarities to PH in humans, which develops long after its induction by various factors. Serial hemodynamic measurements made after injection of DMCT revealed that PH developed by the fourth week after injection. The right ventricle/left ventricle plus septum weight ratio (calculated as an index of right ventricular hypertrophy) and the medial thickness in the muscular pulmonary arteries showed transition patterns simultaneous with the increase in pulmonary artery pressure. The progressively increasing plasma ET-1 concentration suggested that ET-1 may be involved in either the cause of or response to PH. Patients with either the primary or secondary form of PH have elevated plasma ET-1 levels9 10 11 12 and have injured vascular endothelial cells in the pulmonary but not the systemic circulation.24 A study of ET-1–like immunoreactivity by immunocytochemical analysis and ET-1 mRNA by in situ hybridization in lung specimens has demonstrated that PH is associated with the increased expression of ET-1 by vascular endothelial cells and that local production of ET-1 might contribute to the vascular abnormalities associated with this disorder.25 Circulating ET-1 may play a selective role in cardiopulmonary system changes. Despite a threefold rise in the plasma ET-1 level in DMCT-induced PH, the decrease, rather than the increase, in systemic arterial pressure may have been due to severe PH disease.

Endothelins are endothelial cell–derived peptides with potent vasoactions. Most reports show that ET-1 causes vasoconstriction,1 26 27 28 but systemic as well as pulmonary vasodilatation have been reported with some preparations.4 8 29 30 31 32 The present study indicates that while ET-1 does not change pulmonary hemodynamics in control subjects, it does cause dose-dependent pulmonary vasodilatation in DMCT-induced canine PH. Miyauchi et al33 report that the vasocontractile response to ET-1 is significantly smaller in monocrotaline-treated than in control rats on day 25 in the ring preparation of the pulmonary artery, although it did not differ significantly on either day 6 or day 14 in the pulmonary artery or on day 25 in the aorta. Their report indicates that the reduction in the vasoconstrictive response to ET-1 occurs specifically in the pulmonary artery at the progressive PH stage.

The pulmonary vasodilatation observed in the present study is consistent with the finding that ET-1 produces relaxation of pulmonary vessels that have a high basal tone, such as in the neonatal pulmonary circulation,2 8 34 during hypoxia,32 and after the administration of U46619.4 Therefore, the vasodilator response to ET-1 may depend on a high baseline vasomotor tone. Particularly in the pulmonary circulation, hemodynamic responses to ET-1 have been inconsistent and conflicting.2 3 4 8 32 34 35 36 37 38 39 The differences in results may be explained by differences in the species and age of the animal, the experimental model, and the route and dose of ET-1. This is the first in vivo study of PH response to ET-1 in beagles. Systemic arterial pressure and vascular resistance increased with or without PH, suggesting that ET-1 induced systemic vasoconstriction independent of vascular tone. In the present study, DMCT did not affect the response to ET-1 by the systemic circulation, indicating that the vasodilatory response to ET-1 was specific to the pulmonary circulation. Although the cause of the differences in results is unclear, DMCT may alter the response of the pulmonary endothelium to ET-1 after injury.

Endothelin receptors are ubiquitous in mammalian tissue. The existence of at least two receptor subtypes, ETA and ETB, has been demonstrated and their cDNAs cloned.40 41 ETA receptors appear to be present mainly on vascular smooth muscle cells, mediating the vasoconstrictor effects of ET-1, whereas ETB receptors on endothelial cells mediate the vasodilator response to ET-1. Under certain conditions, however, ETB receptors may also mediate the vasoconstrictor response to ET-1.42 43 Reports that monocrotaline injures the endothelium of the pulmonary artery but not of systemic arteries and causes an elevation in pulmonary vascular permeability and the exudation of plasma components through the pulmonary vascular wall44 45 suggest that increased ET-1 in DMCT beagles can easily penetrate the pulmonary vessel wall. It is likely that this event changes endothelin receptor regulation, thereby altering the response to ET-1 in the pulmonary artery. Endothelin antagonists are crucial tools for elucidating the pathophysiological role of endothelin. FR139317, a newly synthesized selective ETA receptor antagonist,19 decreases systemic and pulmonary vascular tone with or without PH, although the differences are not statistically significant. At 8 weeks after DMCT, the vasodepressor effects of FR139317 on systemic arterial pressure and vascular resistance were not significant, but the effects on pulmonary arterial pressure and vascular resistance were significant. These data indicate that in PH, vasodilation by FR139317 primarily affects the pulmonary rather than the systemic circulation. On the other hand, RES-701-1, an ETB receptor antagonist,21 increases pulmonary vascular tone in PH and does not affect the other hemodynamics. The fact that in the eighth week of DMCT-induced PH the systemic vasoconstrictor response to ET-1 was attenuated by FR139317 and the pulmonary vasodilator response to ET-1 was attenuated by RES-701-1 suggested that when PH was well established, the vasoresponse mediated by ETA receptors might be dominant in the systemic circulation, and via ETB receptors might be dominant in the pulmonary circulation. Furthermore, to investigate ETB receptors, we used sarafotoxin S6c, a highly selective agonist of brain ETB receptors.22 Sarafotoxin S6c produced vasodilatation not in baseline arteries but in PH arteries, which indicated that the vasodilatory response in PH appeared to be mediated via ETB receptors. These findings suggest an important role of ET-1 in suppressing PH. It is possible that ETB receptors predominate in the pulmonary circulation of DMCT-induced PH. Li et al46 indicate enhancement of pulmonary ET-1 gene expression associated with upregulation of ETB receptor expression and maintenance of normal ETA receptor expression in rat lung during chronic hypoxic PH.

The present study suggests that complex interactions of vasoactive materials locally produced by endothelial cells regulate vascular tone. Any imbalance of this regulation can induce disorders such as essential hypertension or PH.47 The role of ET-1 in these regulatory mechanisms is unclear. In addition, it remains unclear whether endogenous ET-1, the circulating plasma levels of which are increased in PH, is responsible for the vascular tone or is serving in counterregulation.9 11 DMCT induces damage to endothelial cells and may alter normal ET-1 responses, including the production and effects of ET-1, and receptor density. The major finding is that endogenous ET-1 tends to improve PH through ETB receptors. One potential disadvantage of the ETB receptor antagonist may be the blockade of this improvement. This study helps elucidate the pathogenesis of PH and has important implications for drug development and the potential therapeutic use of endothelin antagonists. Although further investigation in humans is necessary, our results suggest that ETB receptors play an important role in PH.


*    Acknowledgments
 
We thank Fujisawa Pharmaceutical Co, Ltd, Tsukuba, Japan, for supplying FR139317, and Kyowa Hakko Kogyo Co, Ltd, Tokyo, Japan, for supplying RES-701-1.

Received October 12, 1994; revision received December 20, 1994; accepted December 29, 1994.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

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