title: Intracellular mechanisms and receptor types for endothelin-1-induced positive and negative inotropy in mouse ventricular myocardium.
abstract: We examined the intracellular mechanisms for endothelin-1-induced positive and negative inotropic components that coexist in the mouse ventricular myocardium using isolated ventricular tissue and myocytes from 4-week-old mice. In the presence of SEA0400, a specific inhibitor of the Na+-Ca2+ exchanger, endothelin-1 produced positive inotropy. Endothelin-1, when applied to cardiomyocytes in the presence of SEA0400, did not change the peak amplitude of the Ca2+ transient but increased intracellular pH and Ca2+ sensitivity of contractile proteins. On the other hand, in the presence of dimethylamiloride (DMA), a specific inhibitor of the Na+-H+ exchanger, endothelin-1 produced negative inotropy. In cardiomyocytes, in the presence of DMA, endothelin-1 produced a decrease in peak amplitude of the Ca2+ transient. In the presence of both DMA and SEA0400, endothelin-1 produced neither positive nor negative inotropy. Positive inotropy was blocked by BQ-123 and negative inotropy by BQ-788. These results suggested that endothelin-1-induced positive inotropy is mediated by ET(A) receptors, activation of the Na+-H+ exchanger and an increase in intracellular pH and Ca2+ sensitivity and that the negative inotropy is mediated by ET(B) receptors, activation of the Na+-Ca2+ exchanger and decrease in Ca2+ transient amplitude.
authors.affiliation: Department of Pharmacology, Toho University Faculty of Pharmaceutical Sciences, Miyama 2-2-1 Funabashi, Chiba, 274-8510, Japan.
authors.forename: Iyuki
authors.initials: I
authors.lastname: Namekata
authors.forename: Shinpei
authors.initials: S
authors.lastname: Fujiki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Rina
authors.initials: R
authors.lastname: Moriwaki
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takeda
authors.forename: Toru
authors.initials: T
authors.lastname: Kawanishi
authors.forename: Akira
authors.initials: A
authors.lastname: Takahara
authors.forename: Koki
authors.initials: K
authors.lastname: Shigenobu
authors.forename: Hikaru
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D051379:Mice; D008815:Mice, Inbred Strains; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010647:Phenyl Ethers / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D044022:Receptor, Endothelin A / Q000502:physiology*; D044023:Receptor, Endothelin B / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000502:physiology*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000814:Aniline Compounds; D002316:Cardiotonic Agents; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010647:Phenyl Ethers; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; C039465:5-dimethylamiloride; C086539:BQ 788; D000584:Amiloride; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium