Intracellular mechanisms and receptor types for endothelin-1-induced positive and negative inotropy in mouse ventricular myocardium.
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.
Namekata
Iyuki
I
Department of Pharmacology, Toho University Faculty of Pharmaceutical Sciences, Miyama 2-2-1 Funabashi, Chiba, 274-8510, Japan.
Fujiki
Shinpei
S
Kawakami
Yuko
Y
Moriwaki
Rina
R
Takeda
Kentaro
K
Kawanishi
Toru
T
Takahara
Akira
A
Shigenobu
Koki
K
Tanaka
Hikaru
H
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*
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