Functional consequence of big endothelin conversion: demonstration with isolated neutrophils but not in a postinfarction model.
The role of neutrophils in the conversion of big endothelin (Big-ET) to endothelin-1 (ET-1) was assessed in two models. In rabbit isolated hearts, ET-1 demonstrated significant increases in coronary perfusion pressure (PP) at doses greater than 100 pmol. With Big-ET, significant increases were obtained only at doses greater than 3 nmol. Similarly, this dose of Big-ET did not increase PP in isolated, perfused hearts from rabbits previously subjected to 60 min of coronary artery occlusion and 4 h of reperfusion (n = 7). However, when isolated rabbit neutrophils were incubated with Big-ET (n = 5) or vehicle (n = 4) and 3 nmol aliquots assayed in isolated hearts, results demonstrated a time-dependent conversion to a vasoactive product. These findings suggest that isolated neutrophils are capable of converting Big-ET to an ET-1-like vasoactive substance. The model may be useful in assessing antagonists of endothelin-converting enzyme activity and/or the endothelin receptor.
Uprichard
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AC
Parke-Davis Pharmaceutical Research Division, Ann Arbor, Mich.
Chi
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Lucchesi
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BR
D000818:Animals; D001794:Blood Pressure; D003331:Coronary Vessels / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D011817:Rabbits; D013997:Time Factors
D016232:Endothelins