(Circulation. 1996;93:1214-1222.)
© 1996 American Heart Association, Inc.
Articles |
Endogenous Endothelin-1 Participates in the Maintenance of Cardiac Function in Rats With Congestive Heart Failure
Marked Increase in Endothelin-1 Production in the Failing Heart
Presented in part at the 58th Annual Meeting of the Japanese Circulation Society, Tokyo, Japan, March 28, 1994, and published in abstract form in Jpn Circ J (1994;58:523) and presented in part at the 68th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 14, 1995, and published in abstract form in Circulation (1995;92:I-182).
From the Department of Internal Medicine (S.S., T.M., I.Y., Y.S.), Institute of Clinical Medicine, and the Department of Pharmacology (T.S., Y.K., K.G.), Institute of Basic Medical Sciences, University of Tsukuba (Japan); and Tsukuba Research Institute (M.I.), Banyu Pharmaceutical Co, Tsukuba, Japan.
Correspondence to Takashi Miyauchi, MD, PhD, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305, Japan.
Background Although it was demonstrated that circulating endothelin-1 (ET-1) levels are elevated in congestive heart failure (CHF), the production and roles of ET-1 in the failing heart are not known. We investigated the production of ET-1 in the heart and the density of myocardial ET receptors in rats with CHF. We also investigated the effects of intravenously infused BQ-123, an endothelinA (ETA) receptor antagonist, on both heart rate and myocardial contractility in rats with CHF.
Methods and Results We used the left coronary artery–ligated rat model of CHF (CHF rats). Three weeks after surgery, the rats developed CHF. Plasma ET-1 concentration was significantly higher in the CHF rats than in the sham-operated rats (P<.01). In the left ventricle, the expression of prepro–ET-1 mRNA was markedly higher in the CHF rats than in the sham-operated rats. The peptide level of ET-1 in the left ventricle was also significantly higher in the CHF rats than in the sham-operated rats (500±41 versus 102±10 pg/g tissue, P<.01). Myocardial ET receptors were significantly higher in the CHF rats than in the sham-operated rats (243±20 versus 155±17 fmol/mg protein, P<.05). In the CHF rats, intravenous BQ-123 infusion (0.1 mg·kg-1·min-1 for 120 minutes) significantly decreased both heart rate (P<.01) and LV+dP/dtmax (P<.05) but not mean blood pressure. BQ-123 infusion did not affect these hemodynamic parameters in the sham-operated rats.
Conclusions In the present study, we demonstrated that the production of ET-1 in the heart is markedly increased and that the density of myocardial ET receptors is significantly elevated in the CHF rats. Intravenous BQ-123 infusion significantly reduced both heart rate and LV+dP/dtmax in the CHF rats but not in the sham-operated rats. Therefore, the ET receptor–mediated signal transduction system in the heart appears to be markedly stimulated in the CHF rats, and endogenous ET-1 may be involved in the maintenance of the cardiac function in these rats.
Key Words: endothelin • heart failure • heart rate • genes • contractility
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