Endothelin-1 inhibition of cardiac ATP-sensitive K+ channels via pertussis-toxin-sensitive G-proteins.

OBJECTIVE

Secretion of endothelin-1 (ET-1) and activation of cardiac ATP-sensitive K+ (KATP) channels are facilitated under myocardial metabolic stress. The aim of this study was to investigate the effects of ET-1 on KATP channels and to assess underlying mechanisms in ventricular myocytes.

METHODS

Single channel currents were measured with the voltage-clamp technique in cell-attached patches from enzymatically-isolated single guinea pig ventricular myocytes. In some experiments, the open-cell-attached mode was employed by permeating the membrane with streptolysin-O.

RESULTS

ET-1 concentration-dependently inhibited single KATP channel currents, which had been activated by metabolic poisoning, with an IC50 of 3.8 +/- 0.7 pM. BQ-123, an ETA receptor-selective antagonist, reduced the effects of ET-1. ET-1 effects were largely abolished in the myocytes pre-incubated with pertussis toxin. In the open-cell-attached mode, where the intracellular ATP concentration ([ATP]) could be virtually controlled, the effects of ET-1 were abolished. Muscarinic receptor stimulation inhibited the channels in a similar manner to ET-1, whereas beta-adrenoceptor stimulation accelerated channel activation. By analogy, ouabain also inhibited KATP channel activity under metabolic stress presumably because inhibition of the Na+/K+ pump spares subsarcolemmal ATP. ET-1 inhibited the KATP channels that had been reactivated in the continuous presence of ouabain.

CONCLUSIONS

ET-1 reversibly inhibited KATP channels. This effect appears to be mediated by an increase in subsarcolemmal [ATP] which results from inhibition of adenylate cyclase activities through PTX-sensitive G-proteins coupled to ETA receptors.