1. The effect of endothelin on the performance of the isolated perfused working rat heart has been examined.
2. A low concentration of endothelin (60 pmol/l) produced a gradual but sustained increase in cardiac output; coronary vascular resistance was unaffected.
3. A high concentration of endothelin (600 pmol/l) produced a rapid increase in cardiac output, followed by a marked fall in cardiac output as progressive, severe coronary vasoconstriction developed.
4. The coronary vasoconstriction induced by endothelin (600 pmol/l) was partially blocked by nicardipine (0.5 pmol/l)
5. In the presence of either nicardipine (0.5 μmol/l) or verapamil (0.2 μmol/l), the increment in cardiac output induced by endothelin (600 pmol/l) was greater than that induced by the addition of the same concentration of endothelin to hearts which had not been exposed to calcium-entry blockers.
6. The effect of endothelin on myocardial contractility has a different time course, concentration dependence and response to calcium-entry blockade than the effect on the coronary vasculature. This suggests that different mechanisms are involved in the generation of the myocardial and vascular responses to endothelin.