Inotropic effects of ETB receptor stimulation and their modulation by endocardial endothelium, NO, and prostaglandins.
Endothelin (ET)-1 acts on ETA and ETB receptors. The latter include ETB1 (endothelial) and ETB2 (muscular) subtypes, which mediate opposite effects on vascular tone. This study investigated, in rabbit papillary muscles (n = 84), the myocardial effects of ETB stimulation. ET-1 (10(-9) M) was given in the absence or presence of BQ-123 (ETA antagonist). The effects of IRL-1620 (ETB1 agonist, 10(-10)-10(-6) M) or sarafotoxin S6c (ETB agonist, 10(-10)-10(-6) M) were evaluated in muscles with intact or damaged endocardial endothelium (EE); intact EE, in the presence of NG-nitro-L-arginine (L-NNA); and intact EE, in the presence of indomethacin (Indo). Sarafotoxin S6c effects were also studied in the presence of BQ-788 (ETB2 antagonist). ET-1 alone increased 64 +/- 18% active tension (AT) but decreased it by 4 +/- 2% in the presence of BQ-123. In muscles with intact EE, sarafotoxin S6c alone did not significantly alter myocardial performance. Sarafotoxin S6c (10(-6) M) increased, however, AT by 120 +/- 27% when EE was damaged and by 39 +/- 8% or 23 +/- 6% in the presence of l-NNA or Indo, respectively. In the presence of BQ-788, sarafotoxin S6c decreased AT (21 +/- 3% at 10(-6) M) in muscles with intact EE, an effect that was abolished when EE was damaged. IRL-1620 also decreased AT (22 +/- 3% at 10(-6) M) in muscles with intact EE, an effect that was abolished when EE was damaged or in the presence of L-NNA or Indo. In conclusion, the ETB-mediated negative inotropic effect is presumably due to ETB1 stimulation, requires an intact EE, and is mediated by NO and prostaglandins, whereas the ETB-mediated positive inotropic effect, observed when EE was damaged or NO and prostaglandins synthesis inhibited, is presumably due to ETB2 stimulation.
Leite-Moreira
Adelino F
AF
Department of Physiology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal. amoreira@med.up.pt
Brás-Silva
Carmen
C
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004699:Endocardium / Q000502:physiology*; D019332:Endothelin-1 / Q000494:pharmacology; D016232:Endothelins / Q000008:administration & dosage / Q000494:pharmacology; D004727:Endothelium / Q000502:physiology; D006321:Heart / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D011817:Rabbits; D044023:Receptor, Endothelin B / Q000378:metabolism*; D014757:Viper Venoms / Q000008:administration & dosage / Q000494:pharmacology
D019332:Endothelin-1; D016232:Endothelins; D010446:Peptide Fragments; D010455:Peptides; D011453:Prostaglandins; D020033:Protein Isoforms; D044023:Receptor, Endothelin B; D014757:Viper Venoms; C089502:sarafotoxin-c; C074308:sovateltide; D009569:Nitric Oxide