{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T15:16:20Z","timestamp":1781190980043,"version":"3.54.1"},"reference-count":40,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,3,4]],"date-time":"2019-03-04T00:00:00Z","timestamp":1551657600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cinaciguat, a soluble guanylate cyclase (<jats:styled-content style=\"fixed-case\">sGC<\/jats:styled-content>) activator, was under clinical development for use in acute decompensated heart failure (<jats:styled-content style=\"fixed-case\">ADHF<\/jats:styled-content>), but was discontinued due to occurrence of hypotension. We hypothesized that short\u2010term activation of <jats:styled-content style=\"fixed-case\">sGC<\/jats:styled-content> in <jats:styled-content style=\"fixed-case\">ADHF<\/jats:styled-content> patients would exert a vasodilative effect without hypotension irrespective of disease state, using a novel short\u2010acting <jats:styled-content style=\"fixed-case\">sGC<\/jats:styled-content> activator, <jats:styled-content style=\"fixed-case\">TY<\/jats:styled-content>\u201055002. The objective of this study was to investigate the vasodilation and hemodynamic effects of <jats:styled-content style=\"fixed-case\">TY<\/jats:styled-content>\u201055002 in comparison with those of cinaciguat. <jats:styled-content style=\"fixed-case\">TY<\/jats:styled-content>\u201055002 and cinaciguat activated both normal and heme\u2010oxidized <jats:styled-content style=\"fixed-case\">sGC<\/jats:styled-content> in a dose\u2010dependent manner and caused rapid relaxation of phenylephrine\u2010contracted rat aorta. However, <jats:styled-content style=\"fixed-case\">TY<\/jats:styled-content>\u201055002 had a milder effect than cinaciguat in enhancing the dose\u2010activity response between normal and oxidized <jats:styled-content style=\"fixed-case\">sGC<\/jats:styled-content>. Therefore, we suggest that the pharmacological effect of <jats:styled-content style=\"fixed-case\">TY<\/jats:styled-content>\u201055002 is less subject than cinaciguat to oxidative stress associated with complications such as cardiovascular disease or diabetes. In normal dogs, the effects of intravenous <jats:styled-content style=\"fixed-case\">TY<\/jats:styled-content>\u201055002 or cinaciguat on blood pressure were evaluated in conjunction with the plasma concentrations of the compounds, and pharmacokinetic (<jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>)\u2010pharmacodynamic (<jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>) analyses were carried out. The plasma\u2010to\u2010effect\u2010site transfer rate constant (Ke<jats:sub>0<\/jats:sub>) for <jats:styled-content style=\"fixed-case\">TY<\/jats:styled-content>\u201055002 was three times greater than for cinaciguat. On the other hand, there was a small difference in blood half\u2010life (T<jats:sub>1\/2<\/jats:sub>) between the compounds. It is possible that the rapid fall in blood pressure after the initial administration of <jats:styled-content style=\"fixed-case\">TY<\/jats:styled-content>\u201055002 and the quick recovery after cessation were due to the pharmacodynamic property of the compound. In heart failure\u2010model dogs, <jats:styled-content style=\"fixed-case\">TY<\/jats:styled-content>\u201055002 and cinaciguat improved the condition to the same degree, and the short\u2010term action of <jats:styled-content style=\"fixed-case\">TY<\/jats:styled-content>\u201055002 was replicated. In conclusion, <jats:styled-content style=\"fixed-case\">TY<\/jats:styled-content>\u201055002 is a novel short\u2010acting <jats:styled-content style=\"fixed-case\">sGC<\/jats:styled-content> activator, which offers the possibility of easy dose management without excessive hypotension. It therefore holds potential to serve as an innovative drug in the pharmacotherapy of ADHF.<\/jats:p>","DOI":"10.1002\/prp2.463","type":"journal-article","created":{"date-parts":[[2019,3,5]],"date-time":"2019-03-05T03:36:49Z","timestamp":1551757009000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A novel soluble guanylate cyclase activator with reduced risk of hypotension by short\u2010acting vasodilation"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0374-7674","authenticated-orcid":false,"given":"Toshihiro","family":"Sawabe","sequence":"first","affiliation":[{"name":"R&amp;D Department TOA EIYO LTD. Fukushima Research Laboratories Fukushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiki","family":"Chiba","sequence":"additional","affiliation":[{"name":"R&amp;D Department TOA EIYO LTD. 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