ET-1 in the myocardial interstitium: relation to myocyte ECE activity and expression.
Increased plasma levels of endothelin-1 (ET-1) have been identified in congestive heart failure (CHF), but local myocardial interstitial ET-1 levels and the relation to determinants of ET-1 synthesis remain to be defined. Accordingly, myocardial interstitial ET-1 levels and myocyte endothelin-converting enzyme (ECE)-1 activity and expression with the development of CHF were examined. Pigs were instrumented with a microdialysis system to measure myocardial interstitial ET-1 levels with pacing CHF (240 beats/min, 3 wk; n = 9) and in controls (n = 14). Plasma ET-1 was increased with CHF (15 +/- 1 vs. 9 +/- 1 fmol/ml, P < 0.05) as was total myocardial ET-1 content (90 +/- 15 vs. 35 +/- 5 fmol/g, P < 0.05). Paradoxically, myocardial interstitial ET-1 was decreased in CHF (32 +/- 4 vs. 21 +/- 2 fmol/ml, P < 0.05), which indicated increased ET-1 uptake by the left ventricular (LV) myocardium with CHF. In isolated LV myocyte preparations, ECE-1 activity was increased by twofold with CHF (P < 0.05). In LV myocytes, both ECE-1a and ECE-1c mRNAs were detected, and ECE-1a expression was upregulated fivefold in CHF myocytes (P < 0.05). In conclusion, this study demonstrated compartmentalization of ET-1 in the myocardial interstitium and enhanced ET-1 uptake with CHF. Thus a local ET-1 system exists at the level of the myocyte, and determinants of ET-1 biosynthesis are selectively regulated within this myocardial compartment in CHF.
Ergul
A
A
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425, USA.
Walker
C A
CA
Goldberg
A
A
Baicu
S C
SC
Hendrick
J W
JW
King
M K
MK
Spinale
F G
FG
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D002304:Cardiac Pacing, Artificial; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D005110:Extracellular Space / Q000378:metabolism*; D006333:Heart Failure / Q000097:blood / Q000503:physiopathology; D007527:Isoenzymes / Q000235:genetics; D008666:Metalloendopeptidases; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013552:Swine; D016277:Ventricular Function, Left
D019332:Endothelin-1; D007527:Isoenzymes; D012333:RNA, Messenger; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes