Endogenous Endothelin-1 Depresses Left Ventricular Systolic and Diastolic Performance in Congestive Heart Failure1
Abstract
Endothelin-1 (ET-1) is a positive inotrope in normal hearts; however, the direct cardiac effects of endogenous ET-1 in congestive heart failure (CHF) are unknown. We evaluated the cardiac responses to endogenous ET-1 using an ETA and ETB receptor blocker (L-754,142) in seven conscious dogs before and after pacing-induced CHF. Before CHF, when the plasma ET-1 was 7.3 ± 1.7 fmol/ml, L-754,142 caused no significant alterations in heart rate, left ventricular (LV) end-systolic pressure, total systemic resistance, and the time constant of LV relaxation (τ). LV contractile performance, measured by the slopes of LV pressure (P)-volume (V) relation (EES), dP/dtmax-end-diastolic V relation (dE/dtmax), and stroke work-end-diastolic V relation, was also unaffected. After CHF, when the plasma ET-1 was significantly increased to 14.1 ± 3.0 fmol/ml (p < .05), L-754,142 produced a significant decreases in LV end-systolic pressure (101 ± 11 versus 93 ± 8 mm Hg) and total systemic resistance (0.084 ± 0.022 versus 0.065 ± 0.15 mm Hg/ml/min). The τ (42 ± 12 versus 38 ± 10 ms), mean left atrial P (22 ± 5 versus 18 ± 4 mm Hg) (p < .05), and minimum LVP were also significantly decreased. After CHF, the slopes of P-V relations, EES(3.4 ± 0.4 versus 4.8 ± 0.8 mm Hg/ml), dE/dtmax(42.4 ± 7.8 versus 50.0 ± 7.8 mm Hg/s/ml), and stroke work-end-diastolic V relation (58.1 ± 3.3 versus 72.4 ± 5.2 mm Hg) (p < .05) all increased after L-754,142, indicating enhanced contractility. Before CHF, low levels of endogenous ET-1 have little cardiac effect. However, after CHF, elevated endogenous ET-1 produces arterial vasoconstriction, slows LV relaxation, and depresses LV contractile performance. Thus, elevated endogenous ET-1 may contribute to the functional impairment in CHF in this canine model.
Footnotes
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Send reprint requests to: Che-Ping Cheng, M.D., Ph.D., Section of Cardiology, Wake Forest University School of Medicine, Bowman Gray Campus, Medical Center Boulevard, Winston-Salem, NC 27157-1045. E-mail: ccheng{at}bgsm.edu
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↵1 This study was supported in part by grants from the National Institutes of Health (HL45258 and HL53541) and the American Heart Association (94006140) and the Alcohol Beverage Medical Research Foundation. Dr. Cheng is an Established Investigator of the American Heart Association. This work was presented in abstract form at the American Heart Association Meeting in 1997.
- Abbreviations:
- ET-1
- endothelin-1
- CHF
- congestive heart failure
- HR
- heart rate
- LA
- left atrium
- LV
- left ventricular, left ventricle
- P-V
- pressure-volume
- PES
- end-systolic pressure
- PED
- end-diastolic pressure
- VES
- left ventricular end-systolic volume
- VED
- left ventricular end-diastolic volume
- SW
- stroke work
- TSR
- total systemic resistance
- dP/dt
- derivatives of left ventricular pressure
- EES
- slope of PES, end-systolic pressure-left ventricular end-systolic volume relation
- dE/dtmax
- slope of dP/dtmax-left ventricular end-diastolic volume relation
- MSW
- slope of stroke work-left ventricular end-diastolic volume relation
- EA
- arterial elastance
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- Received July 13, 1998.
- Accepted October 20, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
