Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension

Abstract

It is well known that endothelin (ET)-1 mediates vascular remodelling in various kinds of clinical and experimental pulmonary hypertension. The aim of this study was to investigate whether ET-1 is associated with the development of pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension.Pulmonary hypertension was induced in 10 mongrel dogs by repeated embolization with ceramic beads. In five of the dogs, bosentan, a nonselective ET receptor antagonist, was administered throughout the study. Haemodynamic measurements and plasma ET-1 assays were performed every 2 months. Eight months after initial embolization, computer-assisted morphometry and immunohistochemistry were performed on the lung tissue including that from three control dogs.Pulmonary arterial pressure and pulmonary vascular resistance were increased in all embolized dogs, compared to baseline. In nontreated embolized dogs, plasma ET-1 concentration and pulmonary arterial wall thickness were increased compared to control animals, and ET-1 immunoreactivity was detected in thickened pulmonary arteries. In bosentan treated dogs, pulmonary arterial walls were not significantly thickened.Pulmonary vascular remodelling, associated with elevated plasma endothelin-1 levels and positive endothelin-1 immunoreactivity in lung tissue is attenuated by the endothelin receptor antagonist, bosentan. These findings suggest that endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension. Eur Respir J 2000; 15: 640±648. There is increasing evidence that remodelling occurs in the pulmonary vascular bed of patients with chronic thromboembolic pulmonary hypertension (CTEPH) and may contribute to the progression of the disease [1±5]. The mechanisms responsible for this remodelling are, however, poorly understood.Endothelin (ET)-1 is a potent endogenous vasoconstrictor in the pulmonary circulation and also a growth factor in the pulmonary vasculature [6]. These constrictor and proliferative responses are mainly mediated by ET A receptors [7,8], and blocked by selective and nonselective antagonists [9,10]. Previous studies have shown that ET-1 is upregulated in the lungs of primary and secondary pulmonary hypertensive patients [11±13], and ET antagonists have been shown to attenuate the development of pulmonary vascular remodelling and pulmonary hypertension (PH) in various animal models [14±16]. In the CTEPH, however, the role of ET-1 is still unclear.Using a canine model of thromboembolic PH, which the authors have previously developed [17,18], this study was performed to: 1) see whether pulmonary vascular remodelling occurs in a canine model of chronic embolic pulmonary hypertension (CEPH); 2) examine the changes of ET-1 in association with the development of CEPH; and 3) evaluate the effects of bosentan, a nonselective ET receptor antagonist, on pulmonary vascular remodelling in CEPH. Material and methods Study animalsA total of 10 mongrel dogs (body weight 19±23 kg) were used ...

Development and Characterization of an Inducible Rat Model of Chronic Thromboembolic Pulmonary Hypertension

“…In the past, different substrates had been used to induce acute or chronic PE including autologous clots, n-butyl-2-cyanoacrylat, and beads of other solid materials, administrated to rodents, dogs, sheep, and piglets. [8][9][10][11][12] Although most of these models present with clinical features of acute PE, only the work by Mercier et al 8 shows data on long-term pulmonary vascular hypertrophy, RV remodeling, and PH. Yet a valid animal model, the complex surgical approach, and the use of a large animal model limit its general and widespread use.…”

Managing chronic thromboembolic pulmonary hypertension: pharmacological treatment options

“…It is interesting to note that survival rates for patients given medical treatments, with or without surgery, appear to have improved in recent years. This was revealed by a study of 469 patients with CTEPH, of whom 148 (32%) had distal, nonsurgically treated disease [39]. Survival rates from time of diagnosis to 1 or 3 yrs later were 82% and 70% for the nonsurgical group and 88% and 76% in surgically treated patients, respectively.…”

“…Studies examining the pathophysiology of CTEPH in humans and animal models have provided the following rationales for the use of endothelin-receptor antagonists in CTEPH: 1) endothelin is a potent endogenous vasoconstrictor [37]; 2) endothelin signalling pathway components are upregulated in CTEPH [38]; and 3) endothelinmediated pulmonary vascular remodelling has been demonstrated in a canine model of CTEPH [39]. Bosentan, administered for 16 weeks, reduced pulmonary vascular resistance by 24% compared with placebo (p,0.0001), although there was no significant benefit in terms of 6-min walking distance [35,36].…”

Evaluation and Management of the Patient with Pulmonary Arterial Hypertension

“…Endothelin-1 is a potent vasoconstrictor and smoothmuscle mitogen that may contribute to increased vascular tone and proliferation in PAH (69). Endothelin-1 expression, production, and concentration in plasma (70) and lung tissue (71) are elevated in PAH, and levels correlate with disease severity (72).…”