The cardiac endothelin system in established pressure overload left ventricular hypertrophy

In normal hearts, endothelin-1 (ET-1) has been shown to initiate myocyte gr owth and to modulate cardiac function. However, regulation of the various c omponents of the system and the functional effects of ET-1 in established l eft ventricular hypertrophy (LVH) are less clear. We thus studied ET-1, ETA receptor, and endothelin converting enzyme (ECE-1) mRNA regulation as well as the effects of ET-1 on coronary resistance, LV contractility and relaxa tion in hypertrophied rat hearts. Cardiac pressure overload, secondary to b anding of the ascending aorta, resulted in a transient increase of cardiac ET-1 and ETA receptor mRNAs that reached a maximum at 2 days (+75% and +40% , respectively, P<0.05, each). ET-1 mRNA levels reached a second peak at 84 days of pressure overload (+60%, P<0.05), at the later time point in conju nction with elevated ECE-1 mRNA levels (+20%, P<0.05). The functional impli cations of ET-1 were examined in a study of isolated perfused hearts. Both hearts with established LVH and sham control hearts responded to ET-1 perfu sion (10-(11) to 10(-9) M) with an increase of coronary perfusion pressure (CPP; +85+/-15 and +75+/-8 mmHg; P<0.001 each) and a slight decrease of LV systolic pressure (LVP; -12+/-9 and -9+/-7 mmHg; P=NS). In contrast, ET-1 i ncreased LV end-diastolic pressure (LVEDP) only in LVH hearts (+22+/-7 mmHg , P<0.05 versus baseline and +20 +/-7 mmHg, P<0.05 versus sham). Direct sti mulation of protein kinase C mimicked the effects of ET-1, whereas inhibiti on of this kinase or the Na+-H+ exchanger blunted the effects of ET-1 on CP P, LVP, and LVEDP. Interestingly, coadministration of the vasodilator and t he nitric oxide (NO) donor nitroglycerin not only prevented the increase of CPP and LVEDP, but also uncovered a slight positive inotropic effect of ET -1 in LVH hearts. Thus, the cardiac expression of ET-1, ETA, and ECE-1 mRNA s displays a distinct pattern during early and advanced cardiac pressure ov erload. Furthermore, ET-1 mediates a slight depression of systolic, and a p rofound depression of diastolic, functional parameters in hearts with estab lished LVH, effects that appear to be secondary to ET-1-related coronary va soconstriction. The data suggest a functional role of the endothelin system in hearts with established pressure overload hypertrophy.