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 ETBreceptor-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 ± 0.11 to 1.48 ± 0.23 and preload recruitable stroke work value of 68.7 ± 4.7 to 83.4 ± 7.2) that appear to be mediated through ETAreceptors, whereas impairment in left ventricular isovolumic relaxation (τ = 41.5 ± 1.4 to 58.1 ± 5.0 and t1/2= 23.0 ± 0.7 to 30.9 ± 2.6, where τ is the time constant for pressure decay and t1/2is the half-time for pressure decay) was ETBreceptor 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 (τ from 43.3 ± 1.8 to 54.4 ± 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 ETAand ETBreceptor activation, respectively.