Current and future strategies for targeting the endothelin pathway in cardiovascular disease

Abstract

The first endothelin (ET)-1 receptor antagonist was approved for clinical use over 20 years ago, but to date this class of compounds has been limited to treating pulmonary arterial hypertension, a rare disease. Translational research over the last 5 years has reignited interest in the ET system as a therapeutic target across the spectrum of cardiovascular diseases including resistant hypertension, microvascular angina and post-coronavirus disease 2019 conditions. Notable developments include approval of a new ETA receptor antagonist and, intriguingly, combining the actions of ETA and an angiotensin II type 1 receptor antagonist within the same novel small molecule. Combinations of ET receptor blockers with other drugs, including phosphodiesterase-5 inhibitors and sodium–glucose co-transporter-2 antagonists, may drive synergistic benefits with the prospect of alleviating side effects. These new therapeutic strategies have the potential to dramatically widen the scope of indications targeting the ET-1 pathway.

This is a preview of subscription content, access via your institution

Access options

/* style specs start */
style{display:none!important}.LiveAreaSection-193358632 *{align-content:stretch;align-items:stretch;align-self:auto;animation-delay:0s;animation-direction:normal;animation-duration:0s;animation-fill-mode:none;animation-iteration-count:1;animation-name:none;animation-play-state:running;animation-timing-function:ease;azimuth:center;backface-visibility:visible;background-attachment:scroll;background-blend-mode:normal;background-clip:borderBox;background-color:transparent;background-image:none;background-origin:paddingBox;background-position:0 0;background-repeat:repeat;background-size:auto auto;block-size:auto;border-block-end-color:currentcolor;border-block-end-style:none;border-block-end-width:medium;border-block-start-color:currentcolor;border-block-start-style:none;border-block-start-width:medium;border-bottom-color:currentcolor;border-bottom-left-radius:0;border-bottom-right-radius:0;border-bottom-style:none;border-bottom-width:medium;border-collapse:separate;border-image-outset:0s;border-image-repeat:stretch;border-image-slice:100%;border-image-source:none;border-image-width:1;border-inline-end-color:currentcolor;border-inline-end-style:none;border-inline-end-width:medium;border-inline-start-color:currentcolor;border-inline-start-style:none;border-inline-start-width:medium;border-left-color:currentcolor;border-left-style:none;border-left-width:medium;border-right-color:currentcolor;border-right-style:none;border-right-width:medium;border-spacing:0;border-top-color:currentcolor;border-top-left-radius:0;border-top-right-radius:0;border-top-style:none;border-top-width:medium;bottom:auto;box-decoration-break:slice;box-shadow:none;box-sizing:border-box;break-after:auto;break-before:auto;break-inside:auto;caption-side:top;caret-color:auto;clear:none;clip:auto;clip-path:none;color:initial;column-count:auto;column-fill:balance;column-gap:normal;column-rule-color:currentcolor;column-rule-style:none;column-rule-width:medium;column-span:none;column-width:auto;content:normal;counter-increment:none;counter-reset:none;cursor:auto;display:inline;empty-cells:show;filter:none;flex-basis:auto;flex-direction:row;flex-grow:0;flex-shrink:1;flex-wrap:nowrap;float:none;font-family:initial;font-feature-settings:normal;font-kerning:auto;font-language-override:normal;font-size:medium;font-size-adjust:none;font-stretch:normal;font-style:normal;font-synthesis:weight style;font-variant:normal;font-variant-alternates:normal;font-variant-caps:normal;font-variant-east-asian:normal;font-variant-ligatures:normal;font-variant-numeric:normal;font-variant-position:normal;font-weight:400;grid-auto-columns:auto;grid-auto-flow:row;grid-auto-rows:auto;grid-column-end:auto;grid-column-gap:0;grid-column-start:auto;grid-row-end:auto;grid-row-gap:0;grid-row-start:auto;grid-template-areas:none;grid-template-columns:none;grid-template-rows:none;height:auto;hyphens:manual;image-orientation:0deg;image-rendering:auto;image-resolution:1dppx;ime-mode:auto;inline-size:auto;isolation:auto;justify-content:flexStart;left:auto;letter-spacing:normal;line-break:auto;line-height:normal;list-style-image:none;list-style-position:outside;list-style-type:disc;margin-block-end:0;margin-block-start:0;margin-bottom:0;margin-inline-end:0;margin-inline-start:0;margin-left:0;margin-right:0;margin-top:0;mask-clip:borderBox;mask-composite:add;mask-image:none;mask-mode:matchSource;mask-origin:borderBox;mask-position:0 0;mask-repeat:repeat;mask-size:auto;mask-type:luminance;max-height:none;max-width:none;min-block-size:0;min-height:0;min-inline-size:0;min-width:0;mix-blend-mode:normal;object-fit:fill;object-position:50% 50%;offset-block-end:auto;offset-block-start:auto;offset-inline-end:auto;offset-inline-start:auto;opacity:1;order:0;orphans:2;outline-color:initial;outline-offset:0;outline-style:none;outline-width:medium;overflow:visible;overflow-wrap:normal;overflow-x:visible;overflow-y:visible;padding-block-end:0;padding-block-start:0;padding-bottom:0;padding-inline-end:0;padding-inline-start:0;padding-left:0;padding-right:0;padding-top:0;page-break-after:auto;page-break-before:auto;page-break-inside:auto;perspective:none;perspective-origin:50% 50%;pointer-events:auto;position:static;quotes:initial;resize:none;right:auto;ruby-align:spaceAround;ruby-merge:separate;ruby-position:over;scroll-behavior:auto;scroll-snap-coordinate:none;scroll-snap-destination:0 0;scroll-snap-points-x:none;scroll-snap-points-y:none;scroll-snap-type:none;shape-image-threshold:0;shape-margin:0;shape-outside:none;tab-size:8;table-layout:auto;text-align:initial;text-align-last:auto;text-combine-upright:none;text-decoration-color:currentcolor;text-decoration-line:none;text-decoration-style:solid;text-emphasis-color:currentcolor;text-emphasis-position:over right;text-emphasis-style:none;text-indent:0;text-justify:auto;text-orientation:mixed;text-overflow:clip;text-rendering:auto;text-shadow:none;text-transform:none;text-underline-position:auto;top:auto;touch-action:auto;transform:none;transform-box:borderBox;transform-origin:50% 50%0;transform-style:flat;transition-delay:0s;transition-duration:0s;transition-property:all;transition-timing-function:ease;vertical-align:baseline;visibility:visible;white-space:normal;widows:2;width:auto;will-change:auto;word-break:normal;word-spacing:normal;word-wrap:normal;writing-mode:horizontalTb;z-index:auto;-webkit-appearance:none;-moz-appearance:none;-ms-appearance:none;appearance:none;margin:0}.LiveAreaSection-193358632{width:100%}.LiveAreaSection-193358632 .login-option-buybox{display:block;width:100%;font-size:17px;line-height:30px;color:#222;padding-top:30px;font-family:Harding,Palatino,serif}.LiveAreaSection-193358632 .additional-access-options{display:block;font-weight:700;font-size:17px;line-height:30px;color:#222;font-family:Harding,Palatino,serif}.LiveAreaSection-193358632 .additional-login>li:not(:first-child)::before{transform:translateY(-50%);content:””;height:1rem;position:absolute;top:50%;left:0;border-left:2px solid #999}.LiveAreaSection-193358632 .additional-login>li:not(:first-child){padding-left:10px}.LiveAreaSection-193358632 .additional-login>li{display:inline-block;position:relative;vertical-align:middle;padding-right:10px}.BuyBoxSection-683559780{display:flex;flex-wrap:wrap;flex:1;flex-direction:row-reverse;margin:-30px -15px 0}.BuyBoxSection-683559780 .box-inner{width:100%;height:100%}.BuyBoxSection-683559780 .readcube-buybox{background-color:#f3f3f3;flex-shrink:1;flex-grow:1;flex-basis:255px;background-clip:content-box;padding:0 15px;margin-top:30px}.BuyBoxSection-683559780 .subscribe-buybox{background-color:#f3f3f3;flex-shrink:1;flex-grow:4;flex-basis:300px;background-clip:content-box;padding:0 15px;margin-top:30px}.BuyBoxSection-683559780 .subscribe-buybox-nature-plus{background-color:#f3f3f3;flex-shrink:1;flex-grow:4;flex-basis:100%;background-clip:content-box;padding:0 15px;margin-top:30px}.BuyBoxSection-683559780 .title-readcube,.BuyBoxSection-683559780 .title-buybox{display:block;margin:0;margin-right:10%;margin-left:10%;font-size:24px;line-height:32px;color:#222;padding-top:30px;text-align:center;font-family:Harding,Palatino,serif}.BuyBoxSection-683559780 .title-asia-buybox{display:block;margin:0;margin-right:5%;margin-left:5%;font-size:24px;line-height:32px;color:#222;padding-top:30px;text-align:center;font-family:Harding,Palatino,serif}.BuyBoxSection-683559780 .asia-link{color:#069;cursor:pointer;text-decoration:none;font-size:1.05em;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:1.05em6}.BuyBoxSection-683559780 .access-readcube{display:block;margin:0;margin-right:10%;margin-left:10%;font-size:14px;color:#222;padding-top:10px;text-align:center;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:20px}.BuyBoxSection-683559780 .access-asia-buybox{display:block;margin:0;margin-right:5%;margin-left:5%;font-size:14px;color:#222;padding-top:10px;text-align:center;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:20px}.BuyBoxSection-683559780 .access-buybox{display:block;margin:0;margin-right:10%;margin-left:10%;font-size:14px;color:#222;opacity:.8px;padding-top:10px;text-align:center;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:20px}.BuyBoxSection-683559780 .price-buybox{display:block;font-size:30px;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;padding-top:30px;text-align:center}.BuyBoxSection-683559780 .price-buybox-to{display:block;font-size:30px;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;text-align:center}.BuyBoxSection-683559780 .price-info-text{font-size:16px;padding-right:10px;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif}.BuyBoxSection-683559780 .price-value{font-size:30px;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif}.BuyBoxSection-683559780 .price-per-period{font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif}.BuyBoxSection-683559780 .price-from{font-size:14px;padding-right:10px;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:20px}.BuyBoxSection-683559780 .issue-buybox{display:block;font-size:13px;text-align:center;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:19px}.BuyBoxSection-683559780 .no-price-buybox{display:block;font-size:13px;line-height:18px;text-align:center;padding-right:10%;padding-left:10%;padding-bottom:20px;padding-top:30px;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif}.BuyBoxSection-683559780 .vat-buybox{display:block;margin-top:5px;margin-right:20%;margin-left:20%;font-size:11px;color:#222;padding-top:10px;padding-bottom:15px;text-align:center;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:17px}.BuyBoxSection-683559780 .tax-buybox{display:block;width:100%;color:#222;padding:20px 16px;text-align:center;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:NaNpx}.BuyBoxSection-683559780 .button-container{display:flex;padding-right:20px;padding-left:20px;justify-content:center}.BuyBoxSection-683559780 .button-container>*{flex:1px}.BuyBoxSection-683559780 .button-container>a:hover,.Button-1078489254:hover,.Button-2496381730:hover{text-decoration:none}.BuyBoxSection-683559780 .readcube-button{background:#fff;margin-top:30px}.BuyBoxSection-683559780 .button-asia{background:#069;border:1px solid #069;border-radius:0;cursor:pointer;display:block;padding:9px;outline:0;text-align:center;text-decoration:none;min-width:80px;margin-top:75px}.BuyBoxSection-683559780 .button-label-asia,.ButtonLabel-3296148077,.ButtonLabel-1651148777{display:block;color:#fff;font-size:17px;line-height:20px;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;text-align:center;text-decoration:none;cursor:pointer}.Button-1078489254,.Button-2496381730{background:#069;border:1px solid #069;border-radius:0;cursor:pointer;display:block;padding:9px;outline:0;text-align:center;text-decoration:none;min-width:80px;max-width:320px;margin-top:10px}.Button-1078489254 .readcube-label,.Button-2496381730 .readcube-label{color:#069}
/* style specs end */

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Synthesis of endogenous ET peptides.
Fig. 2: Therapeutic targets of approved and investigational ET antagonists in the human vasculature.
Fig. 3: Expression of EDN1 mRNA in human endothelial cells and unusual pharmacological properties of the peptide.
Fig. 4: Timeline of key discoveries in the ET-1 signaling pathway and identification of selective therapeutic agents.
Fig. 5: Hypothesized mechanism for increased plasma ET-1 levels observed in severe COVID-19 infection.
Fig. 6: Selectivity of ET compounds.

References

  1. Yanagisawa, M. et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332, 411–415 (1988).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  2. Dhaun, N. & Webb, D. J. Endothelins in cardiovascular biology and therapeutics. Nat. Rev. Cardiol. 16, 491–502 (2019).

    Article 
    PubMed 

    Google Scholar 

  3. Endo, H. et al. Effects of clazosentan on cerebral vasospasm–related morbidity and all-cause mortality after aneurysmal subarachnoid hemorrhage: two randomized phase 3 trials in Japanese patients. J. Neurosurg. 137, 1707–1717 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  4. Schlaich, M. P. et al. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet 400, 1927–1937 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  5. Trachtman, H. et al. DUET: a phase 2 study evaluating the efficacy and safety of sparsentan in patients with FSGS. J. Am. Soc. Nephrol. 29, 2745–2754 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  6. Gupta, R. M. et al. A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell 170, 522–533 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  7. Ford, T. J. et al. Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction. Eur. Heart J. 41, 3239–3252 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  8. Barton, M. & Yanagisawa, M. Endothelin: 30 years from discovery to therapy. Hypertension 74, 1232–1265 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  9. Davenport, A. P. et al. Endothelin. Pharmacol. Rev. 68, 357–418 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  10. Haynes, W. G. & Webb, D. J. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet 344, 852–854 (1994).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  11. Chester, A. H. & Yacoub, M. H. The role of endothelin-1 in pulmonary arterial hypertension. Glob. Cardiol. Sci. Pract. 2014, 62–78 (2014).

    PubMed 
    PubMed Central 

    Google Scholar 

  12. de Nucci, G. et al. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc. Natl Acad. Sci. USA 85, 9797–9800 (1988).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  13. Denton, C. et al. Long-term effects of bosentan on quality of life, survival, safety and tolerability in pulmonary arterial hypertension related to connective tissue diseases. Ann. Rheum. Dis. 67, 1222–1228 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  14. Mylona, P. & Cleland, J. G. Update of REACH‐1 and MERIT‐HF clinical trials in heart failure. Eur. J. Heart. Fail. 1, 197–200 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  15. Kohan, D. E., Rossi, N. F., Inscho, E. W. & Pollock, D. M. Regulation of blood pressure and salt homeostasis by endothelin. Physiol. Rev. 91, 1–77 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  16. Ge, Y. et al. Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention. Am. J. Physiol. Renal Physiol. 291, F1274–F1280 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  17. James, N. D. et al. Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial. Eur. Urol. 55, 1112–1123 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  18. Vercauteren, M. et al. Endothelin ETA receptor blockade, by activating ETB receptors, increases vascular permeability and induces exaggerated fluid retention. J. Pharmacol. Exp. Ther. 361, 322–333 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  19. Stuart, D., Chapman, M., Rees, S., Woodward, S. & Kohan, D. E. Myocardial, smooth muscle, nephron, and collecting duct gene targeting reveals the organ sites of endothelin A receptor antagonist fluid retention. J. Pharmacol. Exp. Ther. 346, 182–189 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  20. Anand, I. et al. Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial. Lancet 364, 347–354 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  21. Lüscher, T. F. et al. Hemodynamic and neurohumoral effects of selective endothelin A (ETA receptor blockade in chronic heart failure: the Heart Failure ETA Receptor Blockade Trial (HEAT). Circulation 106, 2666–2672 (2002).

    Article 
    PubMed 

    Google Scholar 

  22. Galatius-Jensen, S. et al. Plasma endothelin in congestive heart failure: effect of the ACE inhibitor, fosinopril. Cardiovasc. Res. 32, 1148–1154 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  23. Imai, T. et al. Induction of endothelin-1 gene by angiotensin and vasopressin in endothelial cells. Hypertension 19, 753–757 (1992).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  24. Yamamoto, T. et al. Central effects of endothelin-1 on vasopressin release, blood pressure, and renal solute excretion. Am. J. Physiol. 262, E856–862 (1992).

    CAS 
    PubMed 

    Google Scholar 

  25. Krum, H. et al. Changes in plasma endothelin-1 levels reflect clinical response to beta-blockade in chronic heart failure. Am. Heart J. 131, 337–341 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  26. MacCarthy, P. A., Grocott-Mason, R., Prendergast, B. D. & Shah, A. M. Contrasting inotropic effects of endogenous endothelin in the normal and failing human heart: studies with an intracoronary ETA receptor antagonist. Circulation 101, 142–147 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  27. Seed, A. et al. The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans. Life Sci. 91, 743–748 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  28. Parvanova, A. et al. Effect on blood pressure of combined inhibition of endothelin-converting enzyme and neutral endopeptidase with daglutril in patients with type 2 diabetes who have albuminuria: a randomised, crossover, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 1, 19–27 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  29. Yuzugulen, J. et al. Characterisation of preproendothelin-1 derived peptides identifies endothelin-like domain peptide as a modulator of endothelin-1. Sci Rep. 7, 4956 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  30. Papassotiriou, J., Morgenthaler, N. G., Struck, J., Alonso, C. & Bergmann, A. Immunoluminometric assay for measurement of the C-terminal endothelin-1 precursor fragment in human plasma. Clin. Chem. 52, 1144–1151 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  31. Marques, J. S. et al. An exploratory panel of biomarkers for risk prediction in pulmonary hypertension: emerging role of CT-proET-1. J. Heart Lung Transplant. 32, 1214–1221 (2013).

    Article 

    Google Scholar 

  32. Dhaun, N. et al. Plasma pro‐endothelin‐1 peptide concentrations rise in chronic kidney disease and following selective endothelin A receptor antagonism. J. Am. Heart Assoc. 4, e001624 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  33. Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  34. Aragam, K. G. et al. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants. Nat. Genet. 54, 1803–1815 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  35. Nica, A. C. & Dermitzakis, E. T. Expression quantitative trait loci: present and future. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 368, 20120362 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  36. Emdin, C. A. et al. Phenotypic consequences of a genetic predisposition to enhanced nitric oxide signaling. Circulation 137, 222–232 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  37. Low, S. -K. et al. Genome-wide association study for intracranial aneurysm in the Japanese population identifies three candidate susceptible loci and a functional genetic variant at EDNRA. Hum. Mol. Genet. 21, 2102–2110 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  38. Verweij, N. et al. Genome-wide association study on plasma levels of midregional-proadrenomedullin and C-terminal-pro-endothelin-1. Hypertension 61, 602–608 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  39. Tu, G., Fang, Z., Zhao, Y. & Wu, Q. Association of +138I/D and Lys198Asn polymorphisms in the endothelin-1 gene with early onset of coronary artery disease among the Chinese Han population. Med. Sci. Monit. 26, e921542 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  40. Barden, A. E. et al. Association between the endothelin-1 gene Lys198Asn polymorphism blood pressure and plasma endothelin-1 levels in normal and pre-eclamptic pregnancy. J. Hypertens. 19, 1775–1782 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  41. Tiret, L. et al. The Lys198Asn polymorphism in the endothelin-1 gene is associated with blood pressure in overweight people. Hypertension 33, 1169–1174 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  42. Gumanova, N. G. et al. Levels of nitric oxide metabolites, adiponectin and endothelin are associated with SNPs of the adiponectin and endothelin genes. Biomed. Rep. 11, 154–164 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  43. Smith, K. J. et al. Coronary spasm and acute myocardial infarction due to a mutation (V734I) in the nucleotide binding domain 1 of ABCC9. Int. J. Cardiol. 168, 3506–3513 (2013).

    Article 
    PubMed 

    Google Scholar 

  44. Mitchell, A. et al. Effects of systemic endothelin A receptor antagonism in various vascular beds in men: in vivo interactions of the major blood pressure-regulating systems and associations with the GNB3 C825T polymorphism. Clin. Pharmacol. Ther. 76, 396–408 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  45. Rubin, S. et al. PHACTR-1 (phosphatase and actin regulator 1) deficiency in either endothelial or smooth muscle cells does not predispose mice to nonatherosclerotic arteriopathies in 3 transgenic mice. Arterioscler. Thromb. Vasc. Biol. 42, 597–609 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  46. Gupta, R. M. Causal gene confusion: the complicated EDN1/PHACTR1 locus for coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 42, 610–612 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  47. Adlam, D. et al. Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection. J. Am. Coll. Cardiol. 73, 58–66 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  48. Cunningham, J. W. et al. Machine learning to understand genetic and clinical factors associated with the pulse waveform dicrotic notch. Circ. Genom. Precis. Med. 16, e003676 (2023).

    Article 
    PubMed 

    Google Scholar 

  49. Morrow, A. J. et al. Rationale and design of the Medical Research Council’s precision medicine with Zibotentan in microvascular angina (PRIZE) trial. Am. Heart J. 229, 70–80 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  50. Zhang, C. et al. Therapeutic monoclonal antibody antagonizing endothelin receptor A for pulmonary arterial hypertension. J. Pharmacol. Exp. Ther. 370, 54–61 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  51. Dai, Y. et al. Immunotherapy of endothelin-1 receptor type A for pulmonary arterial hypertension. J. Am. Coll. Cardiol. 73, 2567–2580 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  52. Zhang, C. & Jing, S. Therapeutic antibody approach for pulmonary arterial hypertension. Int. J. Cardiol. Res. 1, 15–19 (2021).

    CAS 

    Google Scholar 

  53. Whelton, P. K. et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 71, e127–e248 (2018).

    Article 
    PubMed 

    Google Scholar 

  54. Carey, R. M. et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension 72, e53–e90 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  55. Williams, B. et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 386, 2059–2068 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  56. Clozel, M. Aprocitentan and the endothelin system in resistant hypertension. Can. J. Physiol. Pharmacol. 100, 573–583 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  57. Schiffrin, E. L. Endothetin: role in hypertension. Biol. Res. 31, 199–208 (1998).

    CAS 
    PubMed 

    Google Scholar 

  58. Trensz, F. et al. Pharmacological characterization of aprocitentan, a dual endothelin receptor antagonist, alone and in combination with blockers of the renin angiotensin system, in two models of experimental hypertension. J. Pharmacol. Exp. Ther. 368, 462–473 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  59. Letizia, C. et al. High plasma endothelin-1 levels in hypertensive patients with low-renin essential hypertension. J. Hum. Hypertens. 11, 447–451 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  60. Weber, M. A. et al. A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial. Lancet 374, 1423–1431 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  61. Bakris, G. L. et al. Divergent results using clinic and ambulatory blood pressures: report of a darusentan-resistant hypertension trial. Hypertension 56, 824–830 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  62. Sidharta, P. N., Melchior, M., Kankam, M. K. & Dingemanse, J. Single-and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects. Drug. Des. Devel. Ther. 13, 949–964 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  63. Iglarz, M. et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J. Pharmacol. Exp. Ther. 327, 736–745 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  64. Smeijer, J. D., Kohan, D. E., Webb, D. J., Dhaun, N. & Heerspink, H. J. L. Endothelin receptor antagonists for the treatment of diabetic and nondiabetic chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 30, 456–465 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  65. Heerspink, H. J. et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet 393, 1937–1947 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  66. Lee, A. Clazosentan: first approval. Drugs 82, 697–702 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  67. Bauer, A. M. & Rasmussen, P. A. Treatment of intracranial vasospasm following subarachnoid hemorrhage. Front. Neurol. 5, 72 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  68. Kessler, I. M. et al. Endothelin-1 levels in plasma and cerebrospinal fluid of patients with cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Surg. Neurol. 64, S2–S5 (2005).

    Article 

    Google Scholar 

  69. Clozel, M. & Watanabe, H. BQ-123, a peptidic endothelin ETA receptor antagonist, prevents the early cerebral vasospasm following subarachnoid hemorrhage after intracisternal but not intravenous injection. Life Sci. 52, 825–834 (1993).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  70. Matsumura, Y. et al. Phosphoramidon prevents cerebral vasospasm following subarachnoid hemorrhage in dogs: the relationship to endothelin-1 levels in the cerebrospinal fluid. Life Sci. 49, 841–848 (1991).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  71. Macdonald, R. L. et al. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1) randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke 39, 3015–3021 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  72. Macdonald, R. L. et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet. Neurol. 10, 618–625 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  73. Macdonald, R. L. et al. Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke 43, 1463–1469 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  74. Bruder, N. et al. The REACT study: design of a randomized phase 3 trial to assess the efficacy and safety of clazosentan for preventing deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. BMC. Neurol. 22, 492 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  75. Higashida, R. T. et al. Reversal of vasospasm with clazosentan after aneurysmal subarachnoid hemorrhage: a pilot study. World. Neurosurg. 128, e639–e648 (2019).

    Article 
    PubMed 

    Google Scholar 

  76. Lai, A. et al. Clazosentan for improvement of time to peak perfusion in patients with angiographically confirmed severe vasospasm. Neurocrit. Care. 36, 240–247 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  77. Ford, T. J. et al. Systemic microvascular dysfunction in microvascular and vasospastic angina. Eur. Heart J. 39, 4086–4097 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  78. Gulati, A. et al. Safety and efficacy of sovateltide (IRL-1620) in a multicenter randomized controlled clinical trial in patients with acute cerebral ischemic stroke. CNS Drugs 35, 85–104 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  79. Ranjan, A. K. & Gulati, A. Sovateltide mediated endothelin B receptors agonism and curbing neurological disorders. Int. J. Mol. Sci. 23, 3146 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  80. Keam, S. J. Sovateltide: first approval. Drugs. 83, 1239–1244 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  81. Galiè, N. et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N. Engl. J. Med. 373, 834–844 (2015).

    Article 
    PubMed 

    Google Scholar 

  82. Galiè, N. et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur. Heart J. 37, 67–119 (2016).

    Article 
    PubMed 

    Google Scholar 

  83. Weatherald, J. et al. Upfront riociguat and ambrisentan combination therapy for newly diagnosed pulmonary arterial hypertension: a prospective open-label trial. J. Heart Lung Transplant. 41, 563–567 (2022).

    Article 
    PubMed 

    Google Scholar 

  84. McMurray, J. J. et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. 381, 1995–2008 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  85. Ern Yeoh, S. et al. Endothelin-1, outcomes in patients with heart failure and reduced ejection fraction, and effects of dapagliflozin: findings from DAPA-HF. Circulation. 147, 1670–1683 (2023).

    Article 

    Google Scholar 

  86. Salvatore, T. et al. An overview of the cardiorenal protective mechanisms of SGLT2 inhibitors. Int. J. Mol. Sci. 23, 3651 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  87. Heerspink, H. J. L., Kohan, D. E. & de Zeeuw, D. New insights from SONAR indicate adding sodium glucose co-transporter 2 inhibitors to an endothelin receptor antagonist mitigates fluid retention and enhances albuminuria reduction. Kidney Int. 99, 346–349 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  88. Veenit, V. et al. The sodium glucose co-transporter 2 inhibitor dapagliflozin ameliorates the fluid-retaining effect of the endothelin A receptor antagonist zibotentan. Nephrol. Dial. Transplant. 26, gfad078 (2023).

    Google Scholar 

  89. Møller, S., Gülberg, V., Henriksen, J. H. & Gerbes, A. L. Endothelin-1 and endothelin-3 in cirrhosis: relations to systemic and splanchnic haemodynamics. J. Hepatol. 23, 135–144 (1995).

    Article 
    PubMed 

    Google Scholar 

  90. Alam, I., Bass, N., Bacchetti, P., Gee, L. & Rockey, D. Hepatic tissue endothelin-1 levels in chronic liver disease correlate with disease severity and ascites. Am. J. Gastroenterol. 95, 199–203 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  91. Cavasin, M. A. et al. Acute effects of endothelin receptor antagonists on hepatic hemodynamics of cirrhotic and noncirrhotic rats. Can. J. Physiol. Pharmacol. 88, 636–643 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  92. Turco, L. et al. Lowering portal pressure improves outcomes of patients with cirrhosis, with or without ascites: a meta-analysis. Clin. Gastroenterol. Hepatol. 18, 313–327 (2020).

    Article 
    PubMed 

    Google Scholar 

  93. Cho, J. -J. et al. An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis. Gastroenterology 118, 1169–1178 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  94. Hallow, K. M., Helmlinger, G., Greasley, P. J., McMurray, J. J. & Boulton, D. W. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes. Obes. Metab. 20, 479–487 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  95. Montalvo‐Gordon, I., Chi‐Cervera, L. A. & García‐Tsao, G. Sodium‐glucose cotransporter 2 inhibitors ameliorate ascites and peripheral edema in patients with cirrhosis and diabetes. Hepatology 72, 1880–1882 (2020).

    Article 
    PubMed 

    Google Scholar 

  96. Syed, Y. Y. Sparsentan: first approval. Drugs 83, 563–568 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  97. Chen, M., Borlak, J. & Tong, W. High lipophilicity and high daily dose of oral medications are associated with significant risk for drug‐induced liver injury. Hepatology 58, 388–396 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  98. Kelland, N. & Webb, D. Clinical trials of endothelin antagonists in heart failure: publication is good for the public health. Heart 93, 2–4 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  99. Wishart, D. S. et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 46, D1074–D1082 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  100. Harding, S. D. et al. The IUPHAR/BPS guide to PHARMACOLOGY in 2022: curating pharmacology for COVID-19, malaria and antibacterials. Nucleic Acids Res. 50, D1282–D1294 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  101. Opitz, C. F., Ewert, R., Kirch, W. & Pittrow, D. Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter? Eur. Heart J. 29, 1936–1948 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  102. van Giersbergen, P. L., Halabi, A. & Dingemanse, J. Single- and multiple-dose pharmacokinetics of bosentan and its interaction with ketoconazole. Br. J. Clin. Pharmacol 53, 589–595 (2002).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  103. Spence, R., Mandagere, A., Dufton, C. & Venitz, J. Pharmacokinetics and safety of ambrisentan in combination with sildenafil in healthy volunteers. J. Clin. Pharmacol 48, 1451–1459 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  104. Sidharta, P. N., van Giersbergen, P. L., Halabi, A. & Dingemanse, J. Macitentan: entry-into-humans study with a new endothelin receptor antagonist. Eur. J. Clin. Pharmacol. 67, 977–984 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  105. Vuurmans, J. L., Boer, P. & Koomans, H. A. Effects of endothelin-1 and endothelin-1-receptor blockade on renal function in humans. Nephrol. Dial. Transplant. 19, 2742–2746 (2004).

    Article 
    PubMed 

    Google Scholar 

  106. Stavros, F., Kramer, W. G. & Wilkins, M. R. The effects of sitaxentan on sildenafil pharmacokinetics and pharmacodynamics in healthy subjects. Br. J. Clin. Pharmacol 69, 23–26 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  107. Samara, E. et al. Single-dose pharmacokinetics of atrasentan, an endothelin-A receptor antagonist. J. Clin. Pharmacol 41, 397–403 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  108. Honing, M. L. H. et al. Selective ETA receptor antagonism with ABT-627 attenuates all renal effects of endothelin in humans. J. Am. Soc. Nephrol. 11, 1498–1504 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  109. Dingemanse, J., Clozel, M. & van Giersbergen, P. L. Pharmacokinetics and pharmacodynamics of tezosentan, an intravenous dual endothelin receptor antagonist, following chronic infusion in healthy subjects. Br. J. Clin. Pharmacol. 53, 355–362 (2002).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  110. Nakov, R., Pfarr, E. & Eberle, S., Investigators, H. Darusentan: an effective endothelinA receptor antagonist for treatment of hypertension. Am. J. Hypertens. 15, 583–589 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  111. Prasad, S. K. et al. Comparison of the dual receptor endothelin antagonist enrasentan with enalapril in asymptomatic left ventricular systolic dysfunction: a cardiovascular magnetic resonance study. Heart 92, 798–803 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  112. Dieterle, W., Mann, J. & Kutz, K. Pharmacokinetics and pharmacodynamics of the ETA-selective endothelin receptor antagonist SPP301 in healthy human subjects. J. Clin. Pharmacol. 44, 59–66 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  113. Tomkinson, H. et al. Pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with hepatic or renal impairment: two open-label comparative studies. BMC Clin. Pharmacol. 11, 3 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  114. Clarkson-Jones, J. A. et al. Disposition and metabolism of the specific endothelin A receptor antagonist zibotentan (ZD4054) in healthy volunteers. Xenobiotica 42, 363–371 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  115. Fontes, M. S. C., Dingemanse, J., Halabi, A., Tomaszewska-Kiecana, M. & Sidharta, P. N. Single-dose pharmacokinetics, safety, and tolerability of the dual endothelin receptor antagonist aprocitentan in subjects with moderate hepatic impairment. Sci. Rep. 12, 19067 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  116. Goddard, J., Johnston, N. R., Cumming, A. D. & Webb, D. J. Fractional urinary excretion of endothelin-1 is reduced by acute ETB receptor blockade. Am. J. Physiol. Renal Physiol. 293, F1433–1438 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  117. Clift, P. et al. The efficacy and safety of macitentan in Fontan-palliated patients: results of the 52-week randomised, placebo-controlled RUBATO trial. Eur. Heart J. 43, ehac544 (2022).

    Article 

    Google Scholar 

  118. Henrich, A., Juif, P. E., Dingemanse, J. & Krause, A. PK/PD modeling of a clazosentan thorough QT study with hysteresis in concentration-QT and RR-QT. J. Pharmacokinet. Pharmacodyn. 48, 213–224 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  119. Young, B. E., Padilla, J., Finsen, S. H., Fadel, P. J. & Mortensen, S. P. Role of endothelin-1 receptors in limiting leg blood flow and glucose uptake during hyperinsulinemia in type 2 diabetes. Endocrinology. 163, bqac008 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  120. Kent, W. J. et al. The human genome browser at UCSC. Genome. Res. 12, 996–1006 (2002).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  121. Cunningham, F. et al. Ensembl 2022. Nucleic Acids Res. 50, D988–D995 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  122. Canela-Xandri, O., Rawlik, K. & Tenesa, A. An atlas of genetic associations in UK Biobank. Nat. Genet. 50, 1593–1599 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  123. Maguire, J. J. et al. The CCR5 chemokine receptor mediates vasoconstriction and stimulates intimal hyperplasia in human vessels in vitro. Cardiovascular Res. 101, 513–521 (2014).

    Article 
    CAS 

    Google Scholar 

  124. Longmore, J. et al. Comparison of the vasoconstrictor effects of the selective 5-HT1D-receptor agonist L-775,606 with the mixed 5-HT1B/1D-receptor agonist sumatriptan and 5-HT in human isolated coronary artery. Br. J. Clin. Pharmacol. 49, 126–131 (2000).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  125. Maguire, J. J., Kuc, R. E. & Davenport, A. P. Orphan-receptor ligand human urotensin II: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1. Br. J. Pharmacol. 131, 441–446 (2000).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  126. Fisk, M. et al. Endothelin antagonism and sodium glucose co-transporter 2 inhibition. A potential combination therapeutic strategy for COVID-19. Pulm. Pharmacol. Ther. 69, 102035 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  127. Calabretta, E. et al. COVID‐19‐induced endotheliitis: emerging evidence and possible therapeutic strategies. Br. J. Haematol. 193, 43–51 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  128. Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  129. Ackermann, M. et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19. N. Engl. J. Med. 383, 120–128 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  130. Varga, Z. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 395, 1417–1418 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  131. Fox, S. E., Falgout, L. & Vander Heide, R. S. COVID-19 myocarditis: quantitative analysis of the inflammatory infiltrate and a proposed mechanism. Cardiovasc. Pathol. 54, 107361 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  132. Thwaites, R. S. et al. Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19. Sci. Immunol. 6, eabg9873 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  133. Goshua, G. et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet. Haematol. 7, e575–e582 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  134. Willems, L. et al. Sustained inflammation, coagulation activation and elevated endothelin-1 levels without macrovascular dysfunction at 3 months after COVID-19. Thromb. Res. 209, 106–114 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  135. Abraham, G. R. et al. Endothelin-1 is increased in the plasma of patients hospitalised with Covid-19. J. Mol. Cell. Cardiol. 167, 92–96 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  136. Méndez, R. et al. Acute and sustained increase in endothelial biomarkers in COVID-19. Thorax 77, 400–403 (2022).

    Article 
    PubMed 

    Google Scholar 

  137. Gregoriano, C. et al. Association of endothelial activation assessed through endothelin-I precursor peptide measurement with mortality in COVID-19 patients: an observational analysis. Respir. Res. 22, 148 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  138. van Oers, J. A. et al. Endothelium-associated biomarkers mid-regional proadrenomedullin and C-terminal proendothelin-1 have good ability to predict 28-day mortality in critically ill patients with SARS-CoV-2 pneumonia: a prospective cohort study. J. Crit. Care 66, 173–180 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  139. Wagner, O. F. et al. Polar secretion of endothelin-1 by cultured endothelial cells. J. Biol. Chem. 267, 16066–16068 (1992).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  140. Stow, L. R., Jacobs, M. E., Wingo, C. S. & Cain, B. D. Endothelin‐1 gene regulation. FASEB J. 25, 16–28 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  141. Inoue, A. et al. The human preproendothelin-1 gene. Complete nucleotide sequence and regulation of expression. J. Biol. Chem. 264, 14954–14959 (1989).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  142. Shahbazi, S., Vahdat Shariatpanahi, Z. & Shahbazi, E. Bosentan for high-risk outpatients with COVID-19 infection: a randomized, double blind, placebo-controlled trial. EClinicalMedicine 62, 102117 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  143. Lu, I. N. et al. muLTi-Arm Therapeutic study in pre-ICu patients admitted with COVID-19-Experimental drugs and mechanisms (TACTIC-E): a structured summary of a study protocol for a randomized controlled trial. Trials 21, 690 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  144. Morrow, A. J. et al. A multisystem, cardio-renal investigation of post-COVID-19 illness. Nat. Med. 28, 1303–1313 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  145. Haffke, M. et al. Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS). J. Transl. Med. 20, 138 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  146. Miedema, J. et al. Antibodies against angiotensin II receptor type 1 and endothelin a receptor are associated with an unfavorable COVID-19 disease course. Front. Immunol. 12, 684142 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  147. Wallukat, G. et al. Functional autoantibodies against G-protein-coupled receptors in patients with persistent Long-COVID-19 symptoms. J. Transl. Autoimmun. 4, 100100 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  148. Civieri, G., Iop, L. & Tona, F. Antibodies against angiotensin II type 1 and endothelin 1 type A receptors in cardiovascular pathologies. Int. J. Mol. Sci. 23, 927 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  149. Maguire, J. J. & Davenport, A. P. Endothelin receptors and their antagonists. Semin. Nephrol 35, 125–136 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

Download references

Acknowledgements

The authors are grateful for the following support: The Jon Moulton Charity Trust (to G.R.A. and A.P.D.); National Institute of Health Research, Cambridge Biomedical Research Centre (BRC-1215-20014; to A.P.D.); Biomedical Resources Grant, University of Cambridge (Cardiovascular Theme RG64226; to A.P.D.); British Heart Foundation (TG/18/4/33770; to A.P.D. and J.J.M.). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. We thank CMC Connect (a division of IPG Health Medical Communications) funded by AstraZeneca who, under the direction of the authors, carried out a search of clinical trials, formatted text, diagrams and references.

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed to the literature review, writing, editing and approved the final version for submission.

Corresponding author

Correspondence to
Anthony P. Davenport.

Ethics declarations

Competing interests

G.R.A., T.L.W. and J.J.M. declare no competing interests. P.J.G. and P.A. are employees of AstraZeneca (UK). A.P.D. is a co-investigator for the Medical Research Council PRIZE trial and a member of the scientific advisory boards of Janssen, ENB Therapeutics and Pharmazz.

Peer review

Peer review information

Nature Cardiovascular Research thanks Matthias Barton, Rajat M. Gupta and Markus Schlaich for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abraham, G.R., Williams, T.L., Maguire, J.J. et al. Current and future strategies for targeting the endothelin pathway in cardiovascular disease.
Nat Cardiovasc Res (2023). https://doi.org/10.1038/s44161-023-00347-2

Download citation

  • Received: 05 April 2023

  • Accepted: 07 September 2023

  • Published: 02 November 2023

  • DOI: https://doi.org/10.1038/s44161-023-00347-2

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Leave a Reply

Your email address will not be published. Required fields are marked *