Positive inotropic and negative lusitropic effects of endothelin receptor agonism in vivo

Abstract

-The endothelin (ET) system is involved in the regulation of myocardial function in health as well as in several diseases, such as congestive heart failure, myocardial infarction, and septic myocardial depression. Conflicting results have been reported regarding the acute contractile properties of ET-1. We therefore investigated the effects of intracoronary infusions of ET-1 and of the selective ETB receptor-selective agonist sarafotoxin 6c with increasing doses in anesthetized pigs. Myocardial effects were measured through analysis of the left ventricular pressure-volume relationship. ET-1 elicited increases in the myocardial contractile status (end-systolic elastance value of 0.94 Ϯ 0.11 to 1.48 Ϯ 0.23 and preload recruitable stroke work value of 68.7 Ϯ 4.7 to 83.4 Ϯ 7.2) that appear to be mediated through ETA receptors, whereas impairment in left ventricular isovolumic relaxation ( ϭ 41.5 Ϯ 1.4 to 58.1 Ϯ 5.0 and t1/2 ϭ 23.0 Ϯ 0.7 to 30.9 Ϯ 2.6, where is the time constant for pressure decay and t1/2 is the half-time for pressure decay) was ETB receptor dependent. In addition, intravenous administration of ET-1 impaired ventricular relaxation but had no effect on contractility. Intracoronary sarafotoxin 6c administration caused impairments in left ventricular relaxation ( from 43.3 Ϯ 1.8 to 54.4 Ϯ 3.4) as well as coronary vasoconstriction. In conclusion, ET-1 elicits positive inotropic and negative lusitropic myocardial effects in a pig model, possibly resulting from ETA and ETB receptor activation, respectively. cardiac; inotropy; end-systolic elastance; diastolic; porcine; sarafotoxin THE ENDOTHELINS ARE A FAMILY of 21 amino acid peptides with powerful vasoactive properties, which were first described in 1988 (48). Endothelin-1 (ET-1), which is probably the most important of the endothelins as far as effects in humans are concerned, is mainly produced by the vascular endothelium. This vasoconstrictive peptide acts on two groups of receptors: ET A and ET B receptors, located on vascular smooth muscle cells mediating contraction, and ET B receptors, located on the endothelium mediating vasodilation by release of nitric oxide and prostacyclin (1, 10, 31). In the heart, the predominant ET isopeptide is ET-1 (30), and both ET A and ET B receptor mRNA are found in atrial and ventricular myocardium, the conducting system, and endocardial cells as well as in coronary arteries (3,26). The ET system and ET-1 binding properties on cardiomyocytes are largely similar in pigs and humans (25).The ET system is involved in the cardiovascular response to several disease processes. Increased plasma levels of ET-1 have been noted in association with acute myocardial infarction, congestive heart failure, pulmonary hypertension, and septic shock (44). There are numerous reports regarding the cardiac effects of ET-1. The majority of studies done in larger animals or humans seems to indicate positive inotropic effects of ET-1 under nondisease conditions. Several studies have been performed in vitro in various species with conflictin...

Ouabain stimulates atrial natriuretic peptide secretion via the endothelin-1/ETB receptor-mediated pathway in beating rabbit atria

“…Previous reports showed that ET-1 elicits the negative inotropic myocardial effect from ET B receptor activation (Konrad et al, 2005), and that this requires an intact endocardial endothelium and is mediated by nitric oxide and prostaglandins (Leite-Moreira and Brás-Silva, 2004). The present study observed that ET-1-activated atrial ANP secretion was completely blocked by BQ788, an ET B receptor inhibitor, while the ET A receptor inhibitor BQ123 only slightly attenuated the effect of ET-1-activated ANP secretion.…”

Peripheral and cardiac consequences of diminished nitric oxide production

“…This observation supports the in vitro finding that NOS inhibition enhances the inotropic response to ET-1 (Kinnunen 2000). Exogenous ET-1 infusion may increase the in vivo cardiac contractility significantly, an effect that can be prevented by ET-A receptor antagonist pretreatment (Konrad 2005). In our study, the plasma ET-1 level gradually increased up to the end of the experiments, which may suggest that, after induction by NNA treatment, it was continuously replaced from the cellular sources.…”

“…Exogenous ET-1 infusion may increase the in vivo cardiac contractility significantly, an effect that can be prevented by ET-A receptor antagonist pretreatment (Konrad 2005). The results revealed that the plasma level of ET-1 increased significantly in this setup too, and the peptide induced 37 positive inotropy through the activation of ET-A receptors (Eszlári 2008).…”

Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure

“…However, the finding of delayed benefit was based on a post hoc analysis of a small number of events observed in a subgroup of patients-characteristics that increase the likelihood of the play of chance. No biphasic response was seen in a dose-ranging trial with the more endothelin type A (ET A ) receptor-selective antagonist enrasentan (18), which noted an excess early risk of worsening heart failure, which persisted for the duration of follow-up (Figure 5).The mechanisms leading to early worsening heart failure in patients treated with endothelin antagonists(17,19,25) have not been fully elucidated.Receptor antagonism may interfere with the positive inotropic and negative lusitropic effects of endothelin(26) or may have adverse effects on neurohormonal activation or cardiac remodeling(27). In addition, endothelin receptor antagonists dilate the pulmonary arterioles(28), and thus, may interfere with the restraint that pulmonary vasoconstriction normally exerts on blood flow into the lungs and the transudation of fluid into alveoli when pulmonary venous pressures are increased(29,30).In the current trial and earlier studies(17,19,21), however, early worsening heart failure was related to fluid retention.…”