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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°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 μM, n = 6). Additionally, increasing doses (0.1 nM to 1 μM) 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 μM) 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.

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Obligatory Role of the Endocardial Endothelium in the Increase of Myocardial Distensibility Induced by Endothelin-1

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