EndothelinA–EndothelinB Receptor Cross Talk in Endothelin-1–Induced Contraction of Smooth Muscle

Abstract

The efficacy of selective endothelin (ET) receptor antagonists may be limited by a functional interaction between the ET(A) and ET(B) receptors. This interaction, also termed "cross talk", is characterized by the dependency of the inhibition of an ET-1 response due to antagonism of one ET receptor subtype upon concomitant antagonism of the other ET receptor subtype. Although a reduction in ET(A)-ET(B) receptor cross talk would presumably increase the efficacy of selective ET receptor antagonists, an approach that accomplishes this aim is largely absent due to a lack of mechanistic understanding. Toward this goal, we evaluated the characteristics and potential dependencies of cross talk in smooth muscle. Smooth muscle was adopted as an exemplar not only because cross talk is widely reported in this tissue type, thereby allowing numerous comparisons, but also significant controversy surrounds the use of selective versus nonselective ET receptor antagonists in ET-1-related pathophysiologies involving smooth muscle. Based on this evaluation, we suggest that ET(A)-ET(B) receptor cross talk is a dynamic process directed by either or both ET receptor subtypes and expressed to varying magnitudes depending on the ET-1 and selective ET receptor antagonist concentrations, tone due to intraluminal pressure/stretch, agonists acting at receptors other than the ET(A)/ET(B) receptors, and endothelial/epithelial function. It is speculated that ET(A)-ET(B) receptor cross talk occurs through signal transduction pathways along with changes at the receptor level. Pharmacologic intervention of the signaling pathways could increase the therapeutic efficacy of ET receptor antagonists.

Protective effects of endothelin receptor A and B inhibitors against doxorubicin-induced cardiomyopathy

“…Likewise, such a counter regulation might appear in vitro, too. Furthermore, it has to be noted that a functional interaction between ETAR and ETBR receptors was described [60] which would be interrupted by the specific knockdown of one of the endothelin receptors. This receptor crosstalk could be another reason why all ERAs used in this study protect against doxorubicin-cardiotoxicity.…”

Acute nitric oxide synthase inhibition and endothelin-1-dependent arterial pressure elevation

“…These findings raise the possibility that smooth muscle ET B receptors also mediate the elevated arterial pressure, presumably through ET-1-induced vasoconstriction. It may also be considered that cross-talk between the ET A and ET B receptors (Rapoport and Zuccarello, 2012) is responsible for the greater inhibitory effect of ET A/B versus ET A receptor antagonist (Gellai et al, 1997). …”

“…Pressure regulation by NO and ET-1 is complex and extends beyond their individual depressor and pressor actions, respectively, due to the numerous interactions between NO and ET-1. These interactions include (1) ET-1 release of NO from the vascular endothelium, mediated by endothelial ET B receptors; (2) NO inhibition of contraction to ET-1, the contraction mediated by ET A and/or ET B receptors (Rapoport and Zuccarello, 2012), and (3) NO inhibition of ET-1 formation/release (Lavallée et al, 2001; Bourque et al, 2011). …”

Adaptations of the Endothelin System After Exercise Training in a Porcine Model of Ischemic Heart Disease

“…Our findings in the different arterial treatment groups evaluated in this porcine model indicate that there may be a significant degree of “cross‐talk” or compensation by the endothelin receptor subtypes. This concept of compensation has been previously described as the limited ability of a blocked endothelin receptor subtype to decrease an endothelin‐mediated response due to compensation by the other functionally active receptor . In sedentary pigs, it is clear that single antagonism of either ET A or ET B results in a significant decrease in the ET‐1 contractile response in nonoccluded (Figure A) but not collateral‐dependent (Figure B) arteries.…”