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Modulation of systolic and diastolic function by endothelin-1: relation to coronary flow
J Offstad1, T Tønnessen, K A Kirkebøen
1Institute for Experimental Medical Research, University of Oslo, Norway.
Insights
Endothelin-1 (ET-1) enhances cardiac contractility and diastolic stiffness. However, these positive inotropic effects can be obscured by ET-1-induced coronary vasoconstriction and ischemia.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
Background:
- Conflicting findings exist regarding endothelin-1's (ET-1) impact on cardiac contractility.
- Investigating ET-1's effects under controlled coronary flow (CF) and perfusion pressure (PP) is crucial.
Purpose of the Study:
- To elucidate the direct effects of ET-1 on cardiac systolic and diastolic function.
- To determine if ET-1-induced ischemia masks its inotropic and diastolic effects.
Main Methods:
- Isolated rat hearts were perfused under constant coronary flow (cCF) or constant perfusion pressure (cPP) conditions.
- Left ventricular function was assessed isovolumically, measuring left ventricular systolic pressure (LVSP) and end-diastolic pressure (LVEDP).
- ET-1 was administered at concentrations of 10(-9) M and 10(-8) M.
Main Results:
- In cCF, ET-1 increased PP, LVSP, and [LVdP/dt] (a measure of contractility), and LVEDP (a measure of diastolic stiffness).
- In cPP, ET-1 significantly reduced CF and LVSP, while diastolic stiffness remained unchanged.
- Higher ET-1 concentrations (10(-8) M) produced effects more rapidly.
Conclusions:
- ET-1 exhibits positive inotropic effects and increases diastolic stiffness in the absence of ischemia.
- Vasoconstriction-induced ischemia can mask the direct positive effects of ET-1 on cardiac function.
Abstract:
Different conclusions have been reached with regard to the effect of endothelin (ET-1) on cardiac contractility. We examined systolic and diastolic function in response to constant known concentrations of ET-1 with or without ET-1 induced reductions in coronary flow (CF). Rat hearts (n = 21) were buffer-perfused using constant coronary flow (cCF) or constant perfusion pressure (cPP). Left ventricular function was assessed isovolumically. Addition of ET-1 (10(-9) M) in the cCF group caused a gradual increase in PP from 61 +/- 2 to 165 +/- 6 mmHg (mean +/- SE) (P < 0.01). Within 10 min left ventricular systolic pressure (LVSP) increased from 111 +/- 2 to a maximum of 134 +/- 4 mmHg (P < 0.01) and [LVdP/dt] increased from 1640 +/- 81 to a maximum of 2020 +/- 92 mmHg s-1 (P < 0.01). After 15 min left ventricular end diastolic pressure (LVEDP), a measure of diastolic stiffness (DS), also increased. With ET-1 (10(-8) M), similar haemodynamic alterations appeared more rapidly. In the cPP group, ET-1 (10(-9) M) caused a sharp decrease in CF and LVSP fell from 115 +/- 8 to 62 +/- 12 mmHg at 10 min (P < 0.001). Systolic function remained stable at a reduced level for 1 h. DS did not change. Thus, ET-1 possesses positive inotropic effects and increases diastolic stiffness. Both effects may be masked by vasoconstriction-induced ischaemia.