{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T22:10:11Z","timestamp":1743372611194,"version":"3.40.3"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[1995,2]]},"abstract":"<jats:p><jats:italic>Abstract<\/jats:italic>Endothelins exert potent excitatory cardiac effects by acting on specific receptors on myocytes. In this study, we have examined the signal transduction mechanism for the chronotropic effect of endothelins in guinea pig atria. A competition binding of [<jats:sup>125<\/jats:sup>I]endothelin 1 ([<jats:sup>125<\/jats:sup>I]ET-1) using the recently developed ET<jats:sub>A<\/jats:sub>receptor\u2013selective antagonist BQ123 showed the presence of almost equal populations of ET<jats:sub>A<\/jats:sub>(44%) and ET<jats:sub>B<\/jats:sub>(56%) receptors in the guinea pig right atria. In a concentration-response study, endothelin 3 (ET-3), an agonist with higher affinity to ET<jats:sub>B<\/jats:sub>receptors than to ET<jats:sub>A<\/jats:sub>receptors, and sarafotoxin S6c (STXS6c), an ET<jats:sub>B<\/jats:sub>receptor\u2013selective agonist, increased the rate of spontaneous beating at all concentrations tested (10 pmol\/L to 100 nmol\/L). In contrast, ET-1, a nonselective agonist, increased the heart rate at lower concentrations (10 pmol\/L to 10 nmol\/L) but decreased it at higher concentrations (30 to 100 nmol\/L). When ET-1 (100 nmol\/L) was applied in a single amount, heart rate was strongly increased; however, this increase was followed by a rapid decline in the response. ET-1 (100 nmol\/L) but not ET-3 or STXS6c significantly reduced the heart rate when it was raised by isoproterenol (ISO, 300 nmol\/L) either in the absence or presence of a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). Correspondingly, ET-1 significantly reduced the ISO-induced elevation of cAMP accumulation (19.1\u00b11.7 pmol\/mg protein [n=8] and 12.6\u00b11.2 pmol\/mg protein [n=7] in the absence and presence of ET-1, respectively;<jats:italic>P<\/jats:italic>&lt;.01), which was also observed even in the presence of IBMX. Treatment with BQ123 (1 \u03bcmol\/L) abolished these inhibitory effects of ET-1 on both the chronotropy and the cAMP accumulation. Also, pretreatment of guinea pigs with pertussis toxin (5 \u03bcg\/100 g body wt IV) abolished the inhibitory effects of ET-1. These data showed that ET<jats:sub>A<\/jats:sub>receptors are involved in an inhibitory cardiac action of endothelins, which is coupled to a pertussis toxin\u2013sensitive G protein\/adenylate cyclase inhibition pathway. This ET<jats:sub>A<\/jats:sub>receptor\u2013mediated inhibitory action gives new insights into understanding physiological and pathophysiological modulations of cardiac functions by endothelins.<\/jats:p>","DOI":"10.1161\/01.res.76.2.284","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:47:05Z","timestamp":1339462025000},"page":"284-292","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["Negative Chronotropic Effect of Endothelin 1 Mediated Through ET<sub>A<\/sub>Receptors in Guinea Pig Atria"],"prefix":"10.1161","volume":"76","author":[{"given":"Kageyoshi","family":"Ono","sequence":"first","affiliation":[{"name":"From the Division of Chemical Pharmacology and Phytochemistry (K.O.), National Institute of Health Sciences, Tokyo, Japan; the Division of Molecular and Cellular Pharmacology (A.S., K.S., T.S., G.T.), National Children\u2019s Medical Research Center, Tokyo, Japan; the Department of Pharmacology (T.M.), Faculty of Medicine, Kyoto (Japan) University; and the Department of Pharmacology (K.E., K.H.), Yamanashi (Japan) Medical University."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Eto","sequence":"additional","affiliation":[{"name":"From the Division of Chemical Pharmacology and Phytochemistry (K.O.), National Institute of Health Sciences, Tokyo, Japan; the Division of Molecular and Cellular Pharmacology (A.S., K.S., T.S., G.T.), National Children\u2019s Medical Research Center, Tokyo, Japan; the Department of Pharmacology (T.M.), Faculty of Medicine, Kyoto (Japan) University; and the Department of Pharmacology (K.E., K.H.), Yamanashi (Japan) Medical University."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aiji","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"From the Division of Chemical Pharmacology and Phytochemistry (K.O.), National Institute of Health Sciences, Tokyo, Japan; the Division of Molecular and Cellular Pharmacology (A.S., K.S., T.S., G.T.), National Children\u2019s Medical Research Center, Tokyo, Japan; the Department of Pharmacology (T.M.), Faculty of Medicine, Kyoto (Japan) University; and the Department of Pharmacology (K.E., K.H.), Yamanashi (Japan) Medical University."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoh","family":"Masaki","sequence":"additional","affiliation":[{"name":"From the Division of Chemical Pharmacology and Phytochemistry (K.O.), National Institute of Health Sciences, Tokyo, Japan; the Division of Molecular and Cellular Pharmacology (A.S., K.S., T.S., G.T.), National Children\u2019s Medical Research Center, Tokyo, Japan; the Department of Pharmacology (T.M.), Faculty of Medicine, Kyoto (Japan) University; and the Department of Pharmacology (K.E., K.H.), Yamanashi (Japan) Medical University."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsushi","family":"Shibata","sequence":"additional","affiliation":[{"name":"From the Division of Chemical Pharmacology and Phytochemistry (K.O.), National Institute of Health Sciences, Tokyo, Japan; the Division of Molecular and Cellular Pharmacology (A.S., K.S., T.S., G.T.), National Children\u2019s Medical Research Center, Tokyo, Japan; the Department of Pharmacology (T.M.), Faculty of Medicine, Kyoto (Japan) University; and the Department of Pharmacology (K.E., K.H.), Yamanashi (Japan) Medical University."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshio","family":"Sada","sequence":"additional","affiliation":[{"name":"From the Division of Chemical Pharmacology and Phytochemistry (K.O.), National Institute of Health Sciences, Tokyo, Japan; the Division of Molecular and Cellular Pharmacology (A.S., K.S., T.S., G.T.), National Children\u2019s Medical Research Center, Tokyo, Japan; the Department of Pharmacology (T.M.), Faculty of Medicine, Kyoto (Japan) University; and the Department of Pharmacology (K.E., K.H.), Yamanashi (Japan) Medical University."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keitaro","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"From the Division of Chemical Pharmacology and Phytochemistry (K.O.), National Institute of Health Sciences, Tokyo, Japan; the Division of Molecular and Cellular Pharmacology (A.S., K.S., T.S., G.T.), National Children\u2019s Medical Research Center, Tokyo, Japan; the Department of Pharmacology (T.M.), Faculty of Medicine, Kyoto (Japan) University; and the Department of Pharmacology (K.E., K.H.), Yamanashi (Japan) Medical University."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gozoh","family":"Tsujimoto","sequence":"additional","affiliation":[{"name":"From the Division of Chemical Pharmacology and Phytochemistry (K.O.), National Institute of Health Sciences, Tokyo, Japan; the Division of Molecular and Cellular Pharmacology (A.S., K.S., T.S., G.T.), National Children\u2019s Medical Research Center, Tokyo, Japan; the Department of Pharmacology (T.M.), Faculty of Medicine, Kyoto (Japan) University; and the Department of Pharmacology (K.E., K.H.), Yamanashi (Japan) Medical University."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1002\/med.2610120405"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/348730a0"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/348732a0"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(91)90158-4"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.69.4.1657440"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(89)91377-6"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)53554-7"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.72.3.7679333"},{"key":"e_1_3_2_9_2","first-page":"1885","volume":"130","year":"1992","unstructured":"Hori S, Komatsu Y, Shigemoto R, Mizuno N, Nakanishi S. 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