Cardiac effects of endothelin receptor antagonism in endotoxemic pigs

Abstract

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.

Mixed Endothelin Receptor Antagonism With Tezosentan Improves Intestinal Microcirculation in Endotoxemic Shock

“…Tezosentan has been found to improve diastolic function in endotoxemia [44], and in combination with the vasodilation induced by tezosentan, this explains the higher CI and lower PCWP seen in the tezosentan group. Moreover, tezosentan improved PO 2 and PCO 2 values as indication of improved pulmonary gas exchange.…”

Unlocking the Mysteries of Diastolic Function

“…Endothelin influences myocardial inotropic and lusiotropic function, and intellectually intriguing is the potential role of an endothelin receptor antagonist in the management of patients with heart failure (67,68). However, when evaluated in an etiologically heterogeneous group of heart failure patients, endothelin receptor blockers when added to standard therapy did not improve outcome, currently casting doubt on the use of endothelin receptor blockers for the management of heart failure (69 -71).…”

The influence of ETA and ETB receptor blockers on LPS-induced oxidative stress and NF-κB signaling pathway in heart

“…ROS are present in relative excess in various pathological states, including endotoxemia, myocardial ischemia, and congestive heart failure. It is well established that during these condition upregulation of endothelin-1 (ET-1) gene expression and secretion is observed (Konrad et al 2007). ET-1 is a 21-amino acid signaling molecule and growth factor produced and released by the vascular endothelium and cardiomyocytes in the heart.…”