ET-1 increases distensibility of acutely loaded myocardium: a novel ETA and Na+/H+ exchanger-mediated effect.
This study investigated, in rabbit papillary muscles (n = 61) and human auricular strips (n = 7), effects of endothelin-1 (ET-1; 0.1-10 nM) on diastolic myocardial properties. ET-1 (1 nM) was also given in the presence of selective ET(A) or ET(B) antagonism, nonselective ET(A)/ET(B) antagonism, and Na(+)/H(+) exchanger inhibition. Effects of 6.3 mM Ca(2+) were also studied. ET-1 dose dependently increased inotropism. In contrast to baseline, in the presence of ET-1, resting tension (RT) decreased, after an isometric twitch, 3.4 +/- 1.4, 6.9 +/- 1.5, and 12.5 +/- 3.1% with 0.1, 1, and 10 nM, respectively, reflecting an increase in myocardial distensibility. ET-1 effects were abolished with selective ET(A) as well as with nonselective ET(A)/ET(B) antagonism, whereas they were still present with ET(B) antagonism. Na(+)/H(+) exchanger inhibition abolished ET-1 effects on distensibility, whereas it only partially inhibited positive inotropic effect. Ca(2+) increased inotropism to a similar extent to ET-1 (1 nM) but did not affect distensibility. ET-1 therefore increased diastolic distensibility of acutely loaded human and nonhuman myocardium. This effect is mediated by ET(A) receptors, requires Na(+)/H(+) exchanger activation, and cannot be elicited by Ca(2+).
Leite-Moreira
Adelino F
AF
Department of Physiology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal. amoreira@med.up.pt
Bras-Silva
Carmen
C
Pedrosa
Carla A
CA
Rocha-Sousa
Amandio A
AA
D000818:Animals; D001696:Biomechanical Phenomena; D002122:Calcium Chloride / Q000494:pharmacology; D003971:Diastole / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004548:Elasticity; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011817:Rabbits; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000502:physiology*; D013268:Stimulation, Chemical
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D017923:Sodium-Hydrogen Exchangers; D002122:Calcium Chloride; C072247:cyclo(Trp-Asp-Pro-Val-Leu)