title: Obligatory role of the endocardial endothelium in the increase of myocardial distensibility induced by endothelin-1.
abstract: This study investigated how the endocardial endothelium (EE) and particularly endothelial type B (ET(B)) receptors influence the effects of endothelin-1 (ET-1) on diastolic distensibility. ET-1 (0.1, 1, and 10 nM) was tested in rabbit papillary muscles (Krebs-Ringer; 1.8 mM CaCl2, 35 degrees C) (i) with intact EE (n = 10), (ii) with damaged EE (0.5% Triton X-100, n = 11), and (iii) in the presence of RES-701-1 (selective endothelial ET(B1) receptor antagonist, 1 microM, n = 6). Additionally, increasing doses (0.1 nM to 1 microM) of Sarafotoxin S6c (SRTXc, a selective ET(B) receptor agonist) and IRL-1620 (a selective endothelial ET(B1) agonist) were studied (i) in muscles with intact EE (n = 7 and n = 6, respectively) and (ii) after damaging the EE (n = 8 and n = 7, respectively). In papillary muscles with intact EE, ET-1 induced dose-dependent positive inotropic and lusitropic effects. At 10 nM, active tension (AT) increased 78% +/- 17%, maximum velocity of tension rise (dT/dt(max)) increased 82% +/- 10%, and maximum velocity of tension decline (dT/dt(min)) increased 77% +/- 17%. These effects were maintained when ET-1 was given after damaging the EE (AT increased 70% +/- 12%, dT/dt(max) increased 93% +/- 14%, and dT/dt(min) increased 56% +/- 14%), but were significantly reduced in the presence of RES-701-1 (AT increased 30% +/- 6%, dT/dt(max) increased 37% +/- 7%, and dT/ dt(min) increased 29% +/- 9%). ET-1 reduced resting tension (RT) and increased diastolic distensibility by 3% +/- 1%, 5% +/- 1%, and 9% +/- 2% (at 0.1, 1, and 10 nM, respectively) in muscles with intact EE. This effect was abolished after damaging the EE or in the presence of RES-701-1. In muscles with intact EE, SRTXc had no significant effects, whereas, when given after damaging the EE, SRTXc (1 microM) increased inotropy and lusitropy (AT increased 116% +/- 24%, dT/dt(max) 110% +/- 28%, and dT/dt(min) 88% +/- 19%) without affecting RT. IRL-1620 dose-dependently decreased AT, dT/dt(max), and dT/dt(min) in muscles with intact EE-effects that were abolished after EE damage. No significant effects were elicited by IRL-1620 in RT. ET-1-induced increase in myocardial distensibility, previously shown to be mediated by ET(A) receptor stimulation, requires an intact EE and active endothelial ET(B1) receptors.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
authors.forename: Carmen
authors.initials: C
authors.lastname: Brás-Silva
authors.forename: Adelino F
authors.initials: AF
authors.lastname: Leite-Moreira
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004699:Endocardium / Q000166:cytology*; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004727:Endothelium / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011817:Rabbits; D044023:Receptor, Endothelin B / Q000819:agonists* / Q000378:metabolism; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D044023:Receptor, Endothelin B; D014757:Viper Venoms; C057354:sarafotoxins s6; C087120:RES 701-1