Positive inotropic and negative lusitropic effects of endothelin receptor agonism in vivo.
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 ET(B) 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 +/- 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 ET(A) receptors, whereas impairment in left ventricular isovolumic relaxation (tau = 41.5 +/- 1.4 to 58.1 +/- 5.0 and t(1/2) = 23.0 +/- 0.7 to 30.9 +/- 2.6, where tau is the time constant for pressure decay and t(1/2) is the half-time for pressure decay) was ET(B) 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 (tau 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 ET(A) and ET(B) receptor activation, respectively.
Konrad
D
D
Department of Surgical Sciences, Section for Anaesthesiology and Intensive Care, Karolinska Institute, Stockholm, Sweden. david.konrad@kirurgi.ki.se
Oldner
A
A
Wanecek
M
M
Rudehill
A
A
Weitzberg
E
E
Biber
B
B
Johansson
G
G
Häggmark
S
S
Haney
M
M
D000758:Anesthesia; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D003971:Diastole / Q000187:drug effects; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007275:Injections, Intravenous; D009200:Myocardial Contraction / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D017466:Receptors, Endothelin / Q000819:agonists*; D034421:Sus scrofa; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D017725:Ventricular Pressure / Q000187:drug effects; D014757:Viper Venoms / Q000494:pharmacology
D002316:Cardiotonic Agents; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D010100:Oxygen