Regular Article
Effects of Endothelin-1 on K+ Currents from Rat Ventricular Myocytes

https://doi.org/10.1006/bbrc.2001.5083Get rights and content

Abstract

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 (Ipk) of 1310 ± 115 pA and subsequently inactivating to an outward current level of 1063 ± 122 pA at the end of the voltage-pulse (Ilate) (n = 11). ET-1 (20 nM) reduced Ipk by 247.6 ± 60.7 pA (n = 11, P < 0.01) and reduced Ilate 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 μM, 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 (Ito) and a noninactivating steady-state component (Iss). ET-1 markedly inhibited Iss by 43.0 ± 3.8% (P < 0.001, n = 7) and shifted the voltage-dependent inactivation of Ito 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 (Iss). These results are consistent with the hypothesis that Iss inhibition contributes to the inotropic effects of ET-1.

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    To whom correspondence should be addressed at Department of Physiology, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, United Kingdom. Fax: +44-(0)117-928-8923. E-mail: [email protected].

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