Endothelin isoforms and the response to myocardial stretch.
Myocardial stretch elicits a biphasic increase in developed force with a first rapid force response and a second slow force response (SFR). The rapid phase is due to an increase in myofilament Ca(2+) responsiveness; the SFR, analyzed here, is ascribed to a progressive increase in Ca(2+) transients. Experiments were performed in cat papillary muscles to further elucidate the signaling pathway underlying the SFR. Although the SFR was diminished by BQ-123, a similar endothelin (ET)-1-induced increase in force was not affected: 23 +/- 2 vs. 23 +/- 3% (not significant). Instead, BQ-123 suppressed the contractile effects of ET-2 or ET-3 (21 +/- 2 and 25 +/- 3% vs. -1 +/- 1 and -7 +/- 3% respectively, P < 0.05), suggesting that ET-2 or ET-3, but not ET-1, was involved in the SFR. Each isoform activated the Na(+)/H(+) exchanger (NHE-1), increasing intracellular Na(+) concentration by 2.0 +/- 0.1, 2.3 +/- 0.1, and 2.1 +/- 0.4 mmol/l for ET-1, ET-2, and ET-3, respectively (P < 0.05). The NHE-1 inhibitor HOE-642 prevented the increases in force and intracellular Na(+) concentration induced by all the ET isoforms, but only ET-2 and ET-3 effects were sensitive to BQ-123. Real-time RT-PCR measurements of prepro-ET-1, -ET-2, and -ET-3 were performed before and 5, 15, and 30 min after stretch. No changes in ET-1 or ET-2, but an increase of approximately 60% in ET-3, mRNA after 15 min of stretch were detected. Stretch-induced ET-3 mRNA upregulation and its mechanical counterpart were suppressed by AT(1) receptor blockade with losartan. These data suggest a role for AT(1)-mediated ET-3 released in the early activation of NHE-1 that follows myocardial stretch.
Ennis
Irene L
IL
Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, UNLP, Calle 60 y 120, 1900 La Plata, Argentina.
Garciarena
Carolina D
CD
Pérez
Néstor G
NG
Dulce
Raúl A
RA
Camilión de Hurtado
María C
MC
Cingolani
Horacio E
HE
D000818:Animals; D002415:Cats; D017931:DNA Primers; D019332:Endothelin-1 / Q000494:pharmacology*; D019333:Endothelin-2 / Q000494:pharmacology*; D019334:Endothelin-3 / Q000494:pharmacology*; D016232:Endothelins / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D016133:Polymerase Chain Reaction / Q000379:methods; D020033:Protein Isoforms / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D013314:Stress, Mechanical; D016276:Ventricular Function
D017931:DNA Primers; D019332:Endothelin-1; D019333:Endothelin-2; D019334:Endothelin-3; D016232:Endothelins; D010456:Peptides, Cyclic; D020033:Protein Isoforms; D012333:RNA, Messenger; C072485:cyclo(sulfoalanyl-prolyl-valyl-leucyl-tryptophyl)