Mechanical effects of ET-1 in cardiomyocytes isolated from normal and heart-failed rabbits.
Endothelin (ET-1) is found at elevated concentrations in the plasma of patients with heart failure and in animal models of cardiomyopathy. The peptide is a potent positive inotropic agent, the effects of which are mediated by increases in cytosolic Ca2+ in cardiomyocytes. The object of this study was to investigate at the cellular level, the actions of ET-1 on contractile function and on Ca2+ currents in heart-failed ventricular myocardium. Male New Zealand White rabbits (8 wks) were treated with twice weekly injections of epirubicin (4 mg/kg/wk, n = 7) or with saline (n = 7) for 6 wks, followed by a washout period of 2 wks. Ventricular cardiomyocytes were isolated from rabbit hearts using Langendorff perfusion with collagenase; contractile function was examined using a video microscopy method, and L-type Ca2+ currents were recorded using a whole-cell patch-clamp technique. ET-1 produced a concentration-dependent increase in contractile response (% increase from basal value) to a maximum at 1 nM ET-1 of 69 +/- 11% (mean +/- S.D.) in control cardiomyocytes and 33 +/- 6% in heart-failed cells. However, there was no significant change in the EC50 obtained with ET-1 for healthy (0.31 +/- 0.1 nM) and for failed cardiomyocytes (0.24 +/- 0.1 nM). The effects of ET-1 on L-type Ca2+ channels were similar with a peak amplitude at 1 nM ET-1 of -3.26 +/- 0.8 nA in control cardiomyocytes and -3.32 +/- 0.9 nA in heart-failed cells. The attenuation of the contractile response to ET-1 in heart-failed cells may reflect a desensitization of ET receptors as a consequence of elevated circulating levels of ET and was not reflected by alteration of transmembrane Ca2+ conductance. It is probable, therefore, that multiple signalling pathways are involved in the actions of ET on ventricular myocardium.
Kelso
E J
EJ
Department of Therapeutics and Pharmacology, Queen's University, Belfast, Northern Ireland.
Geraghty
R F
RF
McDermott
B J
BJ
Trimble
E R
ER
Nicholls
D P
DP
Silke
B
B
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology*; D020746:Calcium Channels, L-Type; D002478:Cells, Cultured; D016232:Endothelins / Q000494:pharmacology*; D015251:Epirubicin; D006321:Heart / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D006333:Heart Failure / Q000503:physiopathology*; D006352:Heart Ventricles; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology; D011817:Rabbits; D012016:Reference Values
D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D016232:Endothelins; D015251:Epirubicin; D002118:Calcium