Effects of endothelin-1 on K(+) currents from rat ventricular myocytes.
It has been suggested that the positive inotropic effect of the vasoactive peptide hormone, endothelin-1 (ET-1), involves inhibition of cardiac K(+) currents. In order to identify the K(+) currents modulated by ET-1, the outward K(+) currents of isolated rat ventricular myocytes were investigated using whole-cell patch-clamp recording techniques. Outward currents were elicited by depolarisation to +40 mV for 200 ms from the holding potential of -60 mV. Currents activated rapidly, reaching a peak (I(pk)) of 1310 +/- 115 pA and subsequently inactivating to an outward current level of 1063 +/- 122 pA at the end of the voltage-pulse (I(late)) (n = 11). ET-1 (20 nM) reduced I(pk) by 247.6 +/- 60.7 pA (n = 11, P < 0.01) and reduced I(late) by 323.2 +/- 43.9 pA (P < 0.001). The effects of ET-1 were abolished in the presence of the nonselective ET receptor antagonist, PD 142893 (10 microM, n = 5). Outward currents were considerably reduced and the effects of ET-1 were not observed when K(+) was replaced with Cs(+) in the experimental solutions; this indicates that ET-1 modulated K(+)-selective currents. A double-pulse protocol was used to investigate the inactivation of the currents. The voltage-dependent inactivation of the currents from potentials positive to -80 mV was fitted by a Boltzmann equation revealing the existence of an inactivating transient outward component (I(to)) and a noninactivating steady-state component (I(ss)). ET-1 markedly inhibited I(ss) by 43.0 +/- 3.8% (P < 0.001, n = 7) and shifted the voltage-dependent inactivation of I(to) by +3.3 +/- 1.2 mV (P < 0.05). Although ET-1 had little effect on the onset of inactivation of the currents elicited from a conditioning potential of -70 mV, the time-independent noninactivating component of the currents was markedly inhibited. In conclusion, the predominant effect of ET-1 was to inhibit a noninactivating steady-state background K(+) current (I(ss)). These results are consistent with the hypothesis that I(ss) inhibition contributes to the inotropic effects of ET-1.
James
A F
AF
Cardiac Physiology, Centre for Cardiovascular Biology and Medicine, The Rayne Institute, St. Thomas' Hospital, Lambeth Palace Road, London, SE1 7EH, United Kingdom. a.james@bristol.ac.uk
Ramsey
J E
JE
Reynolds
A M
AM
Hendry
B M
BM
Shattock
M J
MJ
D000818:Animals; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000166:cytology; D009842:Oligopeptides / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000494:pharmacology / Q000502:physiology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D019332:Endothelin-1; D009842:Oligopeptides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C076213:PD 142893; D011188:Potassium