Endothelin‐1 and endothelin‐2 initiate and maintain contractile responses by different mechanisms in rat mesenteric and cerebral arteries

Abstract

BACKGROUND AND PURPOSEEndothelin (ET)-1 and ET-2 cause potent long-lasting vasoconstrictions by tight binding to smooth muscle ETA receptors. We tested the hypotheses that different mechanisms mediate initiation and maintenance of arterial contractile responses to ET-1 and ET-2 and that this differs among vascular beds. EXPERIMENTAL APPROACHSegments of rat mesenteric resistance artery (MRA) and basilar artery (BA) were studied in wire myographs with and without functional antagonists. KEY RESULTSSensitivity and maximum of MRA contractile responses to ET-1 were not, or only moderately, reduced by stimulation of soluble GC, AC or K + -channels and by an inhibitor of receptor-operated ion channels. However, each of these reduced maintenance of ET-1 effects and relaxed ET-1-induced contractions in MRA. A calcium channel antagonist did not alter sensitivity, maximum and maintenance of ET-1 effects, but relaxed ET-1-induced contractions in MRA. A PLC inhibitor prevented contractile responses to ET-1 and ET-2 in MRA and BA, and relaxed ET-1-and ET-2-induced responses in MRA and ET-1 effects in BA. A Rho-kinase inhibitor did not modify sensitivity, maximum and maintenance of responses to both peptides in both arteries but relaxed ET-2, but not ET-1, effects in MRA and ET-1 effects in BA. CONCLUSIONS AND IMPLICATIONSPLC played a key role in arterial contractile responses to ETs, but ET-1 and ET-2 initiated and maintained vasoconstriction through different mechanisms, and these differed between MRA and BA. Selective functional antagonism may be considered for agonist-and vascular bed selective pharmacotherapy of ET-related diseases.

Dissecting genetic factors affecting phenylephrine infusion rates during anesthesia: a genome-wide association study employing EHR data

“…Different molecular mechanisms are implicated in the initiation and maintenance of vasoconstrictor response toward several vasoconstrictor agonists [31–33]. Although endothelin-2 has only two amino acids difference from endothelin-1 and shows same affinity for ET A and ET B receptors as endothelin-1, it exhibits a distinct mechanism and pathway affinity for vasoconstriction [25, 34]. Further search of the PPI network using STRING identified two highly confident interaction proteins for EDN2 (confidence score ≥ 0.9): ADRA1B and ADRA1D, which are the targets of phenylephrine (Fig.…”

Endothelin

“…There have been some limited studies that indicate that the ET peptides and sarafotoxins show some pathway bias at the ET receptors, at least in vitro, in some assays. Compeer et al (2013) proposed that ET-1 and ET-2 activate different signaling mechanisms to elicit and maintain vasoconstriction that were dependent on the vascular bed investigated. It is now recognized that signaling bias is best demonstrated by comparing the relative potencies of agonists to a standard, preferably an endogenous agonist, in assays that interrogate multiple G-protein-dependent and -independent pathways that have relevance to ET physiology or pathophysiology.…”

Bilateral Cotton Wool Spots After Use of an Endothelin Receptor Antagonist

“…17 Recent preclinical studies noted endothelins mitigate vasoconstriction by different downstream signaling pathways in cerebral versus mesenteric vasculature in an animal model. 18 Irregularities in these downstream pathways unique to this patient may also explain the observed alterations in retinal hemodynamics. A clear explanation is elusive, and an idiosyncratic reaction to endothelin receptor blockade in this patient also remains possible.…”