Evaluation of luminal endothelin-converting enzyme activity in the pulmonary and coronary circulations.
The endothelin-converting enzymes are distributed on both the surface of the endothelium and intracellularly. Whether circulating big-endothelin-1 can be hydrolyzed in plasma by lumen-bound endothelin-converting enzymes is unknown. The lung is the major site for hydrolysis of angiotensin-I to angiotensin-II by the angiotensin-converting enzyme; because of its high content in endothelin-converting enzymes, we hypothesized that the lung could similarly hydrolyze circulating big-endothelin-1. Since big-endothelin-1 produced by the lung can modulate coronary vascular tone, the heart may also have the capacity to hydrolyze circulating big-endothelin-1. Isolated lungs and hearts from Sprague-Dawley rats were perfused at 10 mL/min. Clearance of trace doses of human I125big-endothelin-1 was quantified using the indicator-dilution curves technique with labeled albumin as a vascular reference. Single-pass hydrolysis was assessed by bolus injection of human big-endothelin-1 (24 fmol) followed by serial ELISA determinations of big-endothelin-1 and endothelin-1 levels in effluent samples. To exclude possible uptake of produced endothelin-1, 10(-6) M BQ788 was added to the perfusate. The injections had no effect on perfusion pressures. There was no detectable clearance of I125big-endothelin-1 in the lung; however the heart extracted 14 +/- 1% of the injected tracer. There was no detectable big-endothelin-1 hydrolysis in the pulmonary as well as in the coronary circulations. The pulmonary circulation does not clear or hydrolyze circulating big-endothelin-1 suggesting that endothelin-converting enzymes are predominantly used for intracellular and/or abluminal conversion of locally produced big-endothelin-1. Mild coronary uptake of big-endothelin-1 suggests that this circulating peptide could modulate coronary vascular tone.
Jasmin
Jean-François
JF
Research Center, Montreal Heart Institute, and University of Montreal, Montreal, Quebec, Canada.
Dupuis
Jocelyn
J
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D019332:Endothelin-1 / Q000302:isolation & purification / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D006868:Hydrolysis; D008297:Male; D008666:Metalloendopeptidases; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D019332:Endothelin-1; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes