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(Circulation Research. 2003;92:1024.)
© 2003 American Heart Association, Inc.

Cellular Biology

Signal Transduction and Ca²⁺ Signaling in Contractile Regulation Induced by Crosstalk Between Endothelin-1 and Norepinephrine in Dog Ventricular Myocardium

Li Chu, Reiko Takahashi, Ikuo Norota, Takuya Miyamoto, Yasuchika Takeishi, Kuniaki Ishii, Isao Kubota, Masao Endoh

From the Department of Pharmacology (L.C., R.T., I.N., K.I., M.E.) and the First Department of Internal Medicine (T.M., Y.T., I.K.), Yamagata University School of Medicine, Yamagata, Japan.

Correspondence to Masao Endoh, MD, PhD, Department of Pharmacology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. E-mail mendou{at}med.id.yamagata-u.ac.jp

In certain cardiovascular disorders, such as congestive heart failure and ischemic heart disease, several endogenous regulators, including norepinephrine (NE) and endothelin-1 (ET-1), are released from various types of cell. Because plasma levels of these regulators are elevated, it seems likely that cardiac contraction might be regulated by crosstalk among these endogenous regulators. We studied the regulation of cardiac contractile function by crosstalk between ET-1 and NE and its relationship to Ca²⁺ signaling in canine ventricular myocardium. ET-1 alone did not affect the contractile function. However, in the presence of NE at subthreshold concentrations (0.1 to 1 nmol/L), ET-1 had a positive inotropic effect (PIE). In the presence of NE at higher concentrations (100 to 1000 nmol/L), ET-1 had a negative inotropic effect. ET-1 had a biphasic inotropic effect in the presence of NE at an intermediate concentration (10 nmol/L). The PIE of ET-1 was associated with an increase in myofilament sensitivity to Ca²⁺ ions and a small increase in Ca²⁺ transients, which required the simultaneous activation of protein kinase A (PKA) and PKC. ET-1 elicited translocation of PKC from cytosolic to membranous fraction, which was inhibited by the PKC inhibitor GF 109203X. Whereas the Na⁺-H⁺ exchange inhibitor Hoe 642 suppressed partially the PIE of ET-1, detectable alteration of pH_i did not occur during application of ET-1 and NE. The negative inotropic effect of ET-1 was associated with a pronounced decrease in Ca²⁺ transients, which was mediated by pertussis toxin-sensitive G proteins, activation of protein kinase G, and phosphatases. When the inhibitory pathway was suppressed, ET-1 had a PIE even in the absence of NE. Our results indicate that the myocardial contractility is regulated either positively or negatively by crosstalk between ET-1 and NE through different signaling pathways whose activation depends on the concentration of NE in the dog.

Key Words: endothelin-1 • norepinephrine • myocardial contractility • Ca²⁺ transients • protein kinase C

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