Cardiac effects of endothelin receptor antagonism in endotoxemic pigs.
Myocardial depression in sepsis is frequently encountered clinically and contributes to morbidity and mortality. Increased plasma levels of endothelin-1 (ET-1) have been described in septic shock, and previous reports have shown beneficial effects on cardiovascular performance and survival in septic models using ET receptor antagonists. The aim of the current study was to investigate specific cardiac effects of ET receptor antagonism in endotoxicosis. Sixteen domestic pigs were anesthetized and subjected to endotoxin for 5 h. Eight of these pigs were given tezosentan (dual ET receptor antagonist) after 3 h. Cardiac effects were evaluated using the left ventricular (LV) pressure-volume relationship. Endotoxin was not associated with any effects on parameters of LV contractile function [end-systolic elastance (Ees), preload recruitable stroke work (PRSW), power(max)/end-diastolic volume (PWR(max)/EDV) and dP/dt(max)/end-diastolic volume (dP/dt(max)/EDV)] but with impairments in isovolumic relaxation (time constant for pressure decay, tau) and mechanical efficiency. Tezosentan administration decreased Ees, PWR(max)/EDV, and dP/dt(max)/EDV, while improving tau and LV stiffness. Thus, dual ET receptor antagonism was associated with a decline in contractile function but, in contrast, improved diastolic function. Positive hemodynamic effects from ET receptor antagonism in acute endotoxemia may be due to changes in cardiac load and enhanced diastolic function rather than improved contractile function.
Konrad
D
D
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden. david.konrad@ki.se
Haney
M
M
Johansson
G
G
Wanecek
M
M
Weitzberg
E
E
Oldner
A
A
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004731:Endotoxins; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D034421:Sus scrofa; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects
D002317:Cardiovascular Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D004731:Endotoxins; D011725:Pyridines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013777:Tetrazoles; C120582:tezosentan; C044101:endotoxin, Escherichia coli