Although further experiments are needed to determine definit
Although further experiments are needed to determine definitively whether D–ETB receptor heterodimers exist, for example, by using fluorescence resonance toll like receptor transfer analysis or co-immunoprecipitation of receptors, the results of the study by Zeng and colleagues appear to indicate that D–ETB receptor interactions in the renal tubules facilitate D agonist-induced natriuresis. Zeng and colleagues have previously reported that ETB and AT receptors can be co-immunoprecipitated from SHR and WKY renal proximal tubular cells. Although Zeng and colleagues reported that stimulation of either the ETB or the AT receptor resulted in changes in expression and phosphorylation of the other receptor, the physiological consequences of these ETB–AT receptor interactions were not directly addressed. An intriguing possibility is that endothelin receptor–AT receptor heterodimerization could be one of the mechanisms underlying the reported ability of endothelin receptor antagonists to attenuate or abolish acute and chronic effects of angiotensin II (see, for example, Riggleman ). Several studies suggest that ETA receptor activation may impair α-adrenoceptor-mediated responses. However, this appears to occur, at least in fibroblasts, via phosphorylation of the α-adrenoceptor, and, as ET-1 did not stimulate internalization of the α-adrenoceptor, this effect may not involve the existence of ETA receptor–α-adrenoceptor heterodimers. A pictorial summary of the endothelin receptor dimers proposed to date is given in . Whether endothelin receptors form heterodimers with any other receptors, and the functional consequences of any such interactions, remains an open field of future inquiry.
Introduction At present there is a limited understanding of the factors responsible for failure of resolution of acute pulmonary embolism and the subsequent development of chronic thromboembolic pulmonary hypertension (CTEPH). The raised pulmonary vascular resistance (PVR) in CTEPH is described by a two compartment model . In some regions there are thromboembolic occlusions of the vascular lumen and a series of associated changes including clot remodelling, collagen deposition and cellular hyperplasia. The ‘closed’ arterial tree distal to these obstructions is spared from exposure to high pressures. In other regions the ‘open’ arterial tree is exposed to high pressures and demonstrates pathological changes similar to those seen in pulmonary arterial hypertension (PAH); a distal vasculopathy with muscularisation of the distal precapillary arteries and intimal hyperplasia with medial hypertrophy of some larger pulmonary arteries . Currently, CTEPH is the only form of pulmonary hypertension for which there is a potential cure; pulmonary endarterectomy (PEA), through the surgical removal of proximal chronic thromboembolic material . Endothelin-1 (ET-1) is a potent vasoconstrictor. High levels of circulating ET-1 or its precursor big ET-1 have been demonstrated in patients with idiopathic PAH , , . The ET pathway is considered an important part of the pathology of idiopathic PAH and ET receptor antagonists such as bosentan and ambrisentan ,  and more recently macitentan  are used to try to slow progression. To date there is no ET antagonist licenced for use in CTEPH patients, although they are used ‘off-label’. The BENEFIT study did show a significant haemodynamic improvement with reduction in PVR, but no functional improvement with bosentan . ET-1 acts via two receptors, ETA and ETB, which have different effects upon pulmonary artery smooth muscle cells. The ETA receptor activation results in vasoconstriction and smooth muscle cell proliferation. The ETB receptor activation prevents apoptosis of smooth muscle cells and causes vasodilatation via nitric oxide stimulation. ET-1 is a potent vasoconstrictor but is also a promoter of pulmonary artery smooth muscle cell proliferation . In agreement, Quarck et al.  found that pulmonary arterial smooth muscle cells isolated from patients with CTEPH have enhanced proliferative properties.