Differential inotropic effects of endothelin-1, angiotensin II, and phenylephrine induced by crosstalk with cAMP-mediated signaling process in dog ventricular myocardium.
Endothelin-1 (ET-1), angiotensin II (Ang II), and phenylephrine, an alpha1-adrenoceptor agonist, share the common signaling process, resulting in activation of Gq protein-coupled receptor (GqPCR) to activate the hydrolysis of phosphoinositide (PI). They do not elicit any inotropic effect in isolated dog ventricular muscle. In the presence of forskolin or IBMX (3-isobutyl-1-methylxanthine), ET-1 produced a dual effect, that is, a positive inotropic effect (PIE) and/or a negative inotropic effect (NIE) depending on concentrations of forskolin or IBMX present simultaneously with ET-1. Phenylephrine produced a definite PIE and Ang II induced a small and transient PIE in the presence of forskolin or IBMX, but they did not elicit a NIE. Facilitation of Ca2+ influx via L-type Ca2+ channel may play a crucial role in the crosstalk because GqPCR agonists produced, likewise a PIE in the presence of Bay k 8644. GqPCR agonists failed to induce a PIE in the presence of dihydroouabain or elevated [Ca2+]o. These findings indicate that the accumulation of cAMP or activation of L-type Ca2+ channels markedly modulates the inotropic response to GqPCR agonists in a manner that leads to a PIE in dog ventricular myocardium. In addition, ET-1, but not Ang II or phenylephrine, activates the signal transduction process that results in a NIE.
Chu
Li
L
Department of Cardiovascular Pharmacology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
Norota
Ikuo
I
Yomogida
Shin-Ichi
S
Ishii
Kuniaki
K
Endoh
Masao
M
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004285:Dogs; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013268:Stimulation, Chemical
D002316:Cardiotonic Agents; D019332:Endothelin-1; D000804:Angiotensin II; D010656:Phenylephrine; D000242:Cyclic AMP; D043802:GTP-Binding Protein alpha Subunits, Gq-G11