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    • The ETA receptor has a

    2022-07-02

    The ETA receptor has a higher affinity for endothelin-1 than the two other agonists, with an affinity order of endothelin-1>endothelin-2>endothelin-3, while the ETB receptor exhibits similar affinities for all three isopeptides (Arai et al., 1990b, Sakurai et al., 1990). Earlier studies of the selectivity of endogenous endothelins for ETA and ETB receptor revealed that ET-1 and ET-2 bind with equal selectivity to the ETA and ETB receptors, whereas ET-3 is the only one of the endothelin isoforms which distinguishes between the receptors. ET-3 has a higher selectivity for the ETB receptor than the ETA receptor (Davenport 2002). Incubation of coronary (±)-CPSI 1306 did not change the contractile responses to ET-1, which is in accordance with earlier studies (Wackenfors et al., 2004, Johnsson et al., 2008). However, the specific ETA receptor antagonist BQ123 induced parallel rightward shift of the ET-1 concentration–response curve after 1½h of incubation, and interestingly induced a biphasic ET-1 response in LAD incubated for 7h. This indicates that the ETA receptor dominates the vasocontractile response to ET-1 in rat coronary arteries, whereas, the ETB receptor may be involved in the ET-1 induced contraction after 7h of incubation. Studies have shown that atherosclerotic human coronary arteries have upregulated ETB receptor (Dagassan et al. 1996b) Based on our results, one could imagine that a local selective blockade of ETA receptor in atherosclerotic coronary arteries with upregulated ETB receptors will only displace a part of the endothelin-1 induced contraction. Whereas, targeting both receptors with a dual ETA/B receptor blockade could be more efficient. Interestingly, we also demonstrate for the first time that the contractile responses to ET-3 is significantly enhanced by incubation for 7h, which is in accordance with the selectivity of this ligand for ETB over ETA receptor. The enhanced contractile responses to S6c after 24h organ culture of both cerebral and mesenteric arteries has been shown to be the result of a transcriptional upregulation of ETB receptors with increased ETB receptor mRNA levels (Moller et al., 2002, Henriksson et al., 2003) and increased ETB receptor protein after organ culture (Johnsson et al. 2008). In the present study, we likewise demonstrated by immunohistochemistry that ETB receptor protein levels were increased after 7 and 24h of incubation of the coronary arteries. In order to investigate if the rapid upregulation of contractile ETB receptors in coronary arteries during 7h incubation occurs via transcriptional mechanisms, we studied the effects of the transcriptional inhibitor actinomycin D on S6c-induced contractions after 7h incubation. Actinomycin D abolished the functional ETB receptor upregulation after 7h incubation in both LAD and SCA. Interestingly, the inhibitor was not able to completely reverse the ETB receptor-mediated response to the levels observed in fresh segments, indicating that the increased ETB receptor activity after 7h incubation is not solely due to transcriptional ETB receptor upregulation, but may involve other mechanisms as well. ERK1/2 has previously been shown to be an upstream mediator of ETB receptor upregulation in cerebral and mesenteric arteries (Henriksson et al., 2004, Uddman et al., 2003). In the present study, the level of phosphorylated ERK1/2 increased very early during the incubation and peaked after 4h of incubation. Incubation with the MEK1/2 inhibitor U0126 (10μM) completely abolished the phosphorylation of ERK1/2, decreased the S6c-mediated vasoconstriction after 7h incubation, and significantly decreased ETB receptor protein expression after 24h incubation. Together; these findings strongly suggest that signalling via the MEK-ERK1/2 pathway is involved in functional ETB receptor upregulation during organ culture of coronary arteries. However, since the S6c-mediated vasoconstriction after 7h incubation was not completely abolished in presence of U0126, this initial functional upregulation might involve additional mechanisms. Studies have shown that even fresh coronary arteries from healthy rats contain ETB receptor protein in VSMC (Wendel-Wellner et al., 2002, Wendel et al., 2005). Hence, we speculate that a part of the contractile ETB receptor upregulation may involve post-translational modifications of already expressed ETB receptors.