Localization and function of ET‐1 and ET receptors in small arteries post‐myocardial infarction: Upregulation of smooth muscle ET_B receptors that modulate contraction

Abstract

1 Endothelin-1 (ET-1) has been implicated as a mediator of increased vascular tone during development of heart failure post-myocardial infarction (MI). In the present study, expression and pharmacology of ET-1 and its receptors were studied in small mesenteric arteries from rats at 5 and 12 weeks after coronary artery ligation for induction of MI, or sham-operation. 2 In vessels from sham-operated and 5 week post-MI rats preproET-1mRNA, immunoreactive (ir) ET-1, ET B receptor mRNA and irET B receptor were con®ned to the endothelium, while ET A receptor mRNA was distributed throughout the media. At 12 weeks post-MI, preproET-1 and irET A receptor localization was similar but ET B receptor mRNA and immunoreactivity were detectable in the media, as well as the endothelium. 3 The ET-1 concentration-response curve (CRC) was progressively shifted to the right in pressurized third generation mesenteric arteries from 5 and 12 week post-MI rats relative to shamoperated rats, with no change in the maximum. The ET A receptor antagonist BQ-123 (10induced a rightward shift of the ET-1 CRC in all vessels. Desensitization of ET B receptors, by exposure to SRTX S6c (3610 78 M), had no eect on the ET-1 CRC in vessels from 5 week post-MI or sham-op rats but induced a leftward shift in vessels from 12 week post-MI rats. 4 These results identify the endothelium as the primary site of ET-1 synthesis in small arteries and the ET A receptor as mediating the eects of ET-1 in these vessels. However, ET B receptor expression increases in vascular smooth muscle post-MI and is linked to mechanisms that inhibit the contractile response to ET-1.

Endothelin receptors as drug targets in chronic cardiovascular diseases: the rationale for dual antagonism

“…In scleroderma patients, fibrosing alveolitis was associated with increased ET B receptor and decreased ET A receptor expression in lung interstitium [Abraham et al, 1997], and the same pattern was found in skin fibroblasts of patients with diffuse scleroderma [Shi-Wen et al, 2001]. In atherosclerosis [Dagassan et al, 1996;Sutherland et al, 2006], CHF [Gray et al, 2000;Sakai et al, 1996], and SAH [Roux et al, 1995], increased ET B receptor immunoreactivity in the media was also observed. With the increase in ET-1 immunoreactivity, all cellular elements are in place for a pathogenic role of the ET system in these pathologies.…”

Enhanced endothelin‐1‐induced contractions in mesenteric arteries from rats with congestive heart failure: role of ETB receptors

“…Furthermore, the increased number of ET B receptors induced an attenuated contractile response to ET 1 in CHF rats, an effect opposed by ET B ‐receptor desensitisation. The effect was not observed in sham [26]. Furthermore, it was proposed in a study by Seo [27] that ET B receptors on the smooth muscle cells inhibit or negatively modulate ET A receptor‐mediated contraction.…”

Endothelin Receptor Antagonists

“…In rats with systemic hypertension, diabetes mellitus, or hypercholesterolemia, ET B receptor immunostaining is reduced in endothelial cells and increased in vascular smooth muscle (Kakoki et al 1999). Upregulation of smooth muscle ET B receptors has been observed in animal models of heart failure (Gray et al 2000) and subarachnoid hemorrhage (Roux et al 1995) and in human diseases including chronic thromboembolic pulmonary hypertension (PH) (Bauer et al 2002), atherosclerosis (Dagassan et al 1996), ischemic heart disease (Dimitrijevic et al 2009), and scleroderma (Shi-Wen et al 2001. In such pathological situations, both ET A and ET B receptors mediate the detrimental actions of ET-1.…”