title: Improved survival from compound 48/80-induced lethal stress and inhibition of myocardial histamine and carnosine mobilization by lodoxamide.
abstract: The precise roles of carnosine and histamine in the physiologic response of the cardiovascular system to stress are unknown. We have previously shown in skeletal and cardiac muscle that carnosine serves as a histidine reservoir available for subsequent histamine synthesis following trauma and sepsis. This study was designed to quantify the effect of histamine-releasing and blocking agents on the myocardial carnosine-histamine pathway as well as on survival during severe stress. Four groups of mature (9-month-old) Sprague-Dawley rats were treated with either (1) saline, (2) lodoxamide (L, mast cell degranulation inhibitor), (3) compound 48/80 (a mast cell degranulator which causes stress), or (4) L followed by 48/80, and observed until agonal or the end of 30 min. When either endpoint was reached the animals were sacrificed and their hearts were removed for tissue analyses of histidine, histamine, 3-methylhistamine, and carnosine via high-pressure liquid chromatography. All five L-pretreated animals survived challenge with 48/80 while all five animals given 48/80 alone died (P less than .005). This mortality correlated well with the increase in the myocardial levels of histidine (P less than or equal to .0005), histamine (P less than or equal to .0077), and 3-methylhistamine (P less than or equal to .0004) and the decrease in carnosine (P less than or equal to .009) experienced by the animals treated with 48/80 alone in comparison to the control, L-only- and L + 48/80-treated groups. A protective effect of L was shown against the deleterious effects of 48/80 which is associated with prevention of myocardial carnosine mobilization to histidine and histamine. These data support the role of carnosine as a nontoxic myocardial histidine reservoir which is mobilized in response to stress-induced increases in histamine requirements.
authors.affiliation: Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick 08903.
authors.forename: L
authors.initials: L
authors.lastname: Flancbaum
authors.forename: J C
authors.initials: JC
authors.lastname: Fitzpatrick
authors.forename: H
authors.initials: H
authors.lastname: Fisher
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D002336:Carnosine / Q000378:metabolism*; D004151:Dipeptides / Q000378:metabolism*; D006632:Histamine / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010072:Oxamic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013312:Stress, Physiological / Q000139:chemically induced / Q000401:mortality*; D003189:p-Methoxy-N-methylphenethylamine / Q000633:toxicity*
chemical_list: D000596:Amino Acids; D004151:Dipeptides; D003189:p-Methoxy-N-methylphenethylamine; D006632:Histamine; D002336:Carnosine; D010072:Oxamic Acid; C021702:lodoxamide ethyl