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1 Department of Experimental Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
2 Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
* To whom correspondence should be addressed. E-mail: d.merkus{at}erasmusmc.nl.
Merkus Daphne, Birgit Houweling, Anton H. van den Meiracker, Frans Boomsma, and Dirk J. Duncker. Contribution of Endothelin to Coronary Vasomotor Tone is Abolished after Myocardial Infarction. Am J Physiol Heart Circ Physiol 000:H0000-H0000, 0000. - Left ventricular dysfunction in swine with a recent myocardial infarction (MI) is associated with neurohumoral activation, including increased catecholamines and endothelin (ET). Although the increase in ET may serve to maintain blood pressure and hence perfusion of essential organs like the heart and brain, it could also compromise myocardial perfusion, by evoking coronary vasoconstriction. In the present study, we tested the hypothesis that endogenous ET contributes to the perturbations in myocardial O2 balance that occur during exercise in remodeled myocardium of swine with a recent MI. For this purpose, 23 chronically instrumented swine (8 with and 15 without MI) were studied at rest and while running on a treadmill at 1-4 km/h. Plasma ET levels increased after MI from 3.2±0.4 pM to 4.9±0.3 pM (P<0.05). In normal swine, blockade of ET,A (EMD122946) or ETA/ETB (tezosentan) receptors resulted in an increase in coronary venous O2 tension i.e. in coronary vasodilation at rest that decreased during exercise. In contrast, neither ETA nor ETA/ETB blockade resulted in coronary vasodilation in swine with MI. Coronary vasoconstriction to intravenous ET-1 infusion in awake resting swine was blunted after MI. To investigate whether factors released by cardiac myocytes contributed to the decreased vascular responsiveness to ET, we performed ET-1 dose-response curves in isolated coronary arterioles (70-200 µm). Vasoconstriction to ET-1 in the isolated arterioles from MI swine was enhanced. In conclusion, the vasoconstrictor influence of endogenous as well as exogenous ET on the coronary circulation in vivo is reduced. Since the response of isolated coronary arterioles to ET is increased after MI, the reduced vasoconstrictor influence in vivo suggests modulation of ET receptor sensitivity by cardiac myocytes, which may serve to maintain adequate myocardial perfusion.
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