Role of endothelin-converting enzyme in the systemic hemodynamics and regional circulatory effects of proendothelin-1 (1-38) and diaspirin cross-linked hemoglobin in rats.
Diaspirin cross-linked hemoglobin (DCLHb) is a promising hemoglobin-based, oxygen-carrying resuscitative solution. DCLHb (400 mg/kg, iv) produces significant cardiovascular effects, along with an increase in plasma endothelin-1 (ET-1) level, when administered to conscious or anesthetized rats. Present studies were performed to determine whether the cardiovascular effects of DCLHb are due to an increase in the conversion of proendothelin-1 (1-38) (proET-1) to ET-1 by endothelin-converting enzyme (ECE). The regional circulatory and systemic hemodynamic effects of proET-1 (20 micrograms/kg, iv) and DCLHb (400 mg/kg, iv) were determined by using a radioactive microsphere technique in control rats and rats pretreated with phosphoramidon (ECE inhibitor). Administration of proET-1 produced an immediate increase in mean arterial pressure (MAP)(52%) and total peripheral resistance (TPR) (55%); stroke volume (SV) and cardiac output were not affected in the initial phase but were decreased subsequently. Heart rate (HR) was not affected after administration of proET-1. A significant increase in blood flow to the heart (39%), brain (46%), kidneys (74%), portal system (40%), and gastrointestinal tract (GIT) (42%) was also observed after administration of proET-1. Vascular resistance was found to be significantly increased in the mesentery and pancreas (168%) and in the musculoskeletal system (147%) and decreased in the kidneys (-11%) after administration of proET-1. Phosphoramidon (4 mg/kg, iv) pretreatment attenuated the increase in MAP and TPR induced by proET-1. Phosphoramidon pretreatment significantly attenuated the proET-1-induced increase in blood flow to the heart, brain, kidneys, portal system, and GIT. The increase in vascular resistance induced by proET-1 in the mesentery and pancreas and in the musculoskeletal system was also attenuated by phosphoramidon. DCLHb increased MAP (63%) and TPR (54%) without affecting HR. DCLHb increased blood flow to the heart (95%), GIT (45%), portal system (43%), and skin (79%) and increased vascular resistance in the musculoskeletal system (58%). In phosphoramidon-treated rats, DCLHb increased MAP (99%), HR (25%), cardiac output (37%), and TPR (60%). DCLHb increased blood flow to the heart (104%), brain (66%), kidneys (49%), GIT (59%), portal system (63%), and skin (100%) when administered to phosphoramidon-treated rats. Phosphoramidon did not attenuate any of the DCLHb-induced cardiovascular effects. It is concluded that proET-1 increases blood flow to various organs and that phosphoramidon, an ECE inhibitor, could block the proET-1-induced increases in regional blood flow.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000187:drug effects*; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology; D001784:Blood Gas Analysis; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006020:Glycopeptides / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D006454:Hemoglobins / Q000494:pharmacology*; D008297:Male; D008666:Metalloendopeptidases / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011498:Protein Precursors / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology
D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D006454:Hemoglobins; D011480:Protease Inhibitors; D011498:Protein Precursors; C093240:proendothelin 1; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C083478:diaspirin-cross-linked hemoglobin; D001241:Aspirin; C008890:phosphoramidon