sea-0400 and 5-dimethylamiloride

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.

Topics: Amiloride; Analysis of Variance; Aniline Compounds; Animals; Calcium; Cardiotonic Agents; Dose-Response Relationship, Drug; Endothelin-1; Heart Ventricles; Hydrogen-Ion Concentration; In Vitro Techniques; Mice; Mice, Inbred Strains; Myocardial Contraction; Myocytes, Cardiac; Oligopeptides; Peptides, Cyclic; Phenyl Ethers; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Sodium-Calcium Exchanger; Sodium-Hydrogen Exchangers