Big ET-1 processing into vasoactive peptides in arteries and veins.
The endothelin (ET) peptides are more potent in contracting veins than arteries. The precursor big ET-1 is metabolized by endothelin converting enzyme [ECE; to ET-1 (1-21)], matrix metalloproteases [MMPs; to ET-1 (1-32)] and chymase [to ET-1(1-31)]. We hypothesized that arteries and veins were differently dependent in conversion of big ET-1 to vasoconstrictors. Immunohistochemical, western, zymographic and isometric contractile assays in rat aorta and vena cava were used. Big ET-1 contracted aorta [60+/-17% phenylephrine contraction] but was more efficacious in vena cava [478+/-61% norepinephrine contraction]. ECE and its product ET-1(1-21) were detected in aorta and vena cava, and the ECE inhibitors phosphoramidon and CGS-26393 reduced big ET-1-induced contraction. ET-1 (1-32) contracted aorta and vena cava but inhibition of MMPs with minocycline or GM6001 did not reduce big ET-1-induced contraction; zymography confirmed active tissue MMPs. Aorta and vena cava contracted to the product of chymase, ET-1 (1-31). Chymase was detected in aorta and only weakly in vena cava. Inhibition of chymase (chymostatin, 100 muM) reduced arterial (19% control) but not venous constriction to big ET-1. These results suggest at least one potential significant difference - the role of chymase - in in vitro enzymatic processing of big ET-1 in arteries and veins.
Watts
Stephanie W
SW
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA. wattss@msu.edu
Thakali
Keshari
K
Smark
Chuck
C
Rondelli
Catherine
C
Fink
Gregory D
GD
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D053818:Chymases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D019332:Endothelin-1 / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000072396:Endothelin-Converting Enzymes; D006020:Glycopeptides / Q000494:pharmacology; D066298:In Vitro Techniques; D007537:Isometric Contraction; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D008911:Minocycline / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D063065:Organophosphonates / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology; D014682:Vena Cava, Inferior / Q000187:drug effects / Q000502:physiology*
D004151:Dipeptides; D019332:Endothelin-1; D006020:Glycopeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D063065:Organophosphonates; D010446:Peptide Fragments; D011480:Protease Inhibitors; D013777:Tetrazoles; C419584:endothelin-1 (1-21); C114932:endothelin-1 (1-31); C098285:CGS 26393; D053818:Chymases; D016282:Aspartic Acid Endopeptidases; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D008911:Minocycline; C008890:phosphoramidon