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Circulation Research. 1997;81:211-218

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(Circulation Research. 1997;81:211-218.)
© 1997 American Heart Association, Inc.

Articles

Endothelin-1 Inhibits the Slow Component of Cardiac Delayed Rectifier K+ Currents via a Pertussis Toxin–Sensitive Mechanism

Takashi Washizuka, Minoru Horie, Masato Watanuki, , Shigetake Sasayama

From the Department of Cardiovascular Medicine, Kyoto (Japan) University Graduate School of Medicine.

Correspondence to Minoru Horie, Division of Cardiac Electrophysiology, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Shogoin, Kyoto 606-01, Japan. E-mail horie{at}kuhp.kyoto-u.ac.jp

Abstract Endothelin-1 (ET-1) is a 21–amino acid peptide hormone released from myocardial and endothelial cells, whose receptors (both ETA and ETB) are expressed in the myocardium. We report here that ET-1 inhibits the cardiac delayed rectifier K+ current (IK) via a pertussis toxin (PTX)–sensitive mechanism. Ventricular myocytes enzymatically isolated from guinea pig hearts were voltage-clamped by the conventional whole-cell and nystatin–perforated patch technique (intrapipette and extrapipette K+ concentrations, 150 and 5.4 mmol/L, respectively) in the presence of nifedipine (2 µmol/L). Amplitudes of tail and steady state (2-second pulse) currents were measured as IK. ET-1 suppressed the basal IK by 20.9±2.3% in a concentration-dependent manner, with an IC50 of 1.1±0.3 nmol/L (n=19), although it did not suppress the basal IK using the nystatin method. E-4031 (5 µmol/L), a blocker of the rapid component of IK (IKr), did not prevent the inhibitory action of ET-1. ET-1 reduced by 63.4±6.5% the slow component of IK (IKs) that had been enhanced to {approx}2-fold by isoproterenol (ISO, 20 nmol/L). The action was concentration dependent, with an IC50 of 0.7±0.4 nmol/L (n=22), and was also observed using the nystatin method. The effect of ET-1 appeared to be mediated by an ETA receptor, because it was prevented by FR139317, an ETA-selective antagonist (1 µmol/L, n=4), and sarafotoxin S6c, an ETB-selective agonist (100 nmol/L, n=4), could not inhibit the ISO-enhanced IK. ET-1 antagonized IKs enhanced by histamine (250 nmol/L, n=7) and forskolin (500 nmol/L, n=7) but did not inhibit IKs enhanced by the internal application of cAMP (100 µmol/L, n=6). Preincubation of myocytes with PTX (5 µg/mL for >60 minutes at 36°C) completely abolished the inhibitory action of ET-1 on the ISO-enhanced IKs (n=4). Thus, nanomolar ET-1 inhibits IKs via the ETA receptor/PTX–sensitive G protein/PKA pathway.


Key Words: endothelin-1 • delayed rectifier K+ current • endothelin A receptor • G protein • protein kinase A




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