Increased ¹²⁵I-endothelin binding and decreased ¹²⁵I-angiotensin-II binding in myocardial homogenates prepared during experimental endotoxemia

Vascular and cardiac responses to many vasoconstrictors and inotropic agonists (catecholamines, angiotensin [AII]) are decreased during endotoxemia and shock. In contrast, endothelin (ET)-mediated responses often increase and ET blockade may improve mortality and cardiopulmonary function during endotoximia. We used guinea pigs to investigate effects of in vivo endotoxin (LPS; bacterial lipopolysaccharide, 4 mg/kg i.p.) on ET and AII receptor binding, and on ET-mediated myocardial contraction and coronary vasoconstriction in vitro. Receptor binding was studied in crude myocardial homogenates (MH) using ¹²⁵-I-ET and ¹²⁵I-AII. ET increased cardiac contraction (% cell shortening) of isolated left ventricular myocytes (beating frequency: 0.4-1.0 Hz) isolated from LPS-treated but not control animals. Coronary arteries isolated from LPS-treated animals exhibited significantly decreased (P<0.01) vasoconstrictor responses to prostaglandin F2α (10^-8 - 10^-4 M) but not to ET (10^-11 to 10^-7M). Importantly, ET-receptor binding increased from 24.72±3.3 to 33.99±5.9 fmol/mg protein (P<0.05) in control vs LPS MH, respectively. In contrast to ET, AII receptor binding decreased from 1.23±0.11 to 0.8±0.04 pmol/mg protein (P<0.05) in control vs LPS MH. Thus, experimental endotoxemia is associated with upregulation of ET receptors and downregulation of AII receptors in MH. Further studies are required to delineate vascular and/or cardiac myocyte specificity and potential functional role(s) of reciprocal regulation of ET and AII receptors.