Cardiac effects of endothelin-1 (ET-1) and related C terminal peptide fragment: increased inotropy or contribution to heart failure?
The contrasting pattern of cardiac inotropy induced by human peptide endothelin-1 (ET-1) has not been satisfactorily explained. It is not clear whether ET-1 is primarily responsible for increased myocardial ET-1 expression and release with resultant inotropic effects, or for the induction of myocardial hypertrophy and heart failure. There are at least two subtypes of endothelin receptors (ET(A) and ET(B)) and the inotropic effects of ET-1 differ depending on the receptor involved. Along with some other groups, we reported significant subtype-ET(B) endothelin receptor down-regulation in human cardiac cells preincubated with endothelin agonists (Drímal et al. 1999, 2000). The present study was therefore designed to clarify the subtype-selective mechanisms underlying the inotropic response to ET-1 and to its ET(B)-selective fragment (8-21)ET-1 in the isolated rat heart. The hearts were subjected to (1-21)ET-1 and to (8-21)ET-1, or to 30 min of stop-flow ischemia followed by 40 min of reperfusion, both before and after selective blockade of endothelin receptors. The present study revealed that both peptides, ET-1 and its (8-21)ET-1 fragment, significantly reduced coronary blood flow in nmolar and higher concentrations. The concomitant negative inotropy and chronotropy were marked after ET-1, while the infusion of the ET-1(8-21) fragment produced a slight but significant positive inotropic effect. Among the four endothelin antagonists tested in continuous infusion only the non-selective PD145065 and ET(B1/B2) selective BQ788 (in molar concentrations) slightly reduced the early contractile dysfunction of the heart induced by ischemia, whereas ET(A)-selective PD155080 partially protected the rat heart on reperfusion.
Drímal
J
J
Institute of Experimental Pharmacology, Slovak Academy of Sciences, Dúbravská cesta 9, 842 16 Bratislava, Slovak Republic. exfadrim@savba.sk
Knezl
V
V
Drímal
J
J
Drímal
D
D
Bauerová
K
K
Kettmann
V
V
Doherty
A M
AM
Stefek
M
M
D000595:Amino Acid Sequence; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D004149:Dioxoles / Q000494:pharmacology; D019332:Endothelin-1 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016232:Endothelins / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D017725:Ventricular Pressure / Q000187:drug effects / Q000502:physiology
D004149:Dioxoles; D019332:Endothelin-1; D016232:Endothelins; D009842:Oligopeptides; C093322:PD 155080; D010446:Peptide Fragments; D010880:Piperidines; C419584:endothelin-1 (1-21); C074308:sovateltide; C082887:PD 145065; C086539:BQ 788