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Cardiovascular Research 1998 39(3):589-599; doi:10.1016/S0008-6363(98)00166-7
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Altered inotropic response of endothelin-1 in cardiomyocytes from rats with isoproterenol-induced cardiomyopathy

Makoto Suzukia, Nobuyuki Ohtea, Zhong-Min Wanga, David L. Williams, Jr.b, William C. Littlea and Che-Ping Chenga,*

aCardiology Section, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1045, USA
bMerck and Co., Inc., Merck Research Laboratories, West Point, PA 19486, USA

* Corresponding author. Tel.: +33-6-716-2887; Fax: +33-6-716-9188.

Objective: The positive inotropic effect of endothelin-1 (ET-1) on normal myocardial contraction may be altered in pathological states. The purpose of this study was to assess the direct effect of ET-1 on cardiomyocyte performance and its cellular mechanism in congestive heart failure (CHF). Methods: We measured the plasma levels of ET-1 and compared the effects of ET-1 (10–10–10–8 M) on contractile performance and the [Ca2+]i transient in the myocytes of left ventricles (LV) from 15 age-matched normal adult rats and 15 rats with isoproterenol (ISO)-induced CHF. Results: With CHF, the plasma levels of ET-1 (19.7±6.3 vs. 4.1±0.5 fmol/ml, p<0.05) were markedly elevated. In normal myocytes, superfusion of ET-1 caused significant increases in the systolic amplitude (SA, 8–16%) and the peak velocity of shortening (dL/dtmax, 20–35%; p<0.01) without causing a change in the peak [Ca2+]i transient. In contrast, in myocytes from CHF rats, ET-1 produced significant reductions in SA (9–13%) and in the velocity of relengthening, dR/dtmax (10–14%; p<0.05). The myocytes' dR/dtmax also decreased by 8–10% (p<0.05). These changes were associated with a significant decrease in the peak [Ca2+]i transient (20–23%, p<0.0 1). These responses to ET-1 were abolished by the incubation of myocytes with an ETA receptor antagonist (BQ123) or a protein kinase C (PKC) inhibitor (H-7 or staurosporine). Conclusion: ISO-induced CHF is associated with elevated plasma ET-1 and an altered cardiomyocyte response to ET-1. After CHF, ET-1 produces a direct depression of cardiomyocyte contractile performance that is associated with a significant decrease in the peak [Ca2+]i transient. These effects are likely to be mediated through ETA receptors and involve the PKC pathway.

KEYWORDS Rat; Isoproterenol; Congestive heart failure; Endothelin-1; Contraction; Relaxation; Cardiomyocyte; [Ca2+]i transient, Na+–H+ exchange; Protein kinase C


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[Abstract] [Full Text] [PDF]


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