Original Article

Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 360, Issue 6, pp 654-664

First online:

Characterization of the endothelin-1-induced regulation of L-type Ca2+ current in rabbit ventricular myocytes

  • T. WatanabeAffiliated withDepartment of Pharmacology, Yamagata University School of Medicine, Yamagata 990-9585, Japan
  • , M. EndohAffiliated withDepartment of Pharmacology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan

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Abstract.

The effects of endothelin-1 (ET-1) on the L-type Ca2+ current (I Ca) and the interaction of ET-1 with β-adrenoceptor stimulation were investigated in rabbit ventricular myocytes by the whole-cell patch-clamp technique. ET-1 (10–8 M) had a biphasic effect on I Ca (direct effect), causing a transient decrease that was followed by a long-lasting increase which is much smaller than the increase induced by isoprenaline (ISO). The effect of ET-1 on I Ca was abolished by a selective ETA receptor antagonist, FR139317 (10–6 M). The increase in I Ca induced by ET-1 (10–8 M) was enhanced by a selective ETB receptor antagonist, BQ-788 (10–6 M), as the transient decrease but not the increase in I Ca induced by ET-1 (10–8 M) was suppressed by BQ-788. In the presence of ISO (10–6 M), ET-1 elicited a more pronounced inhibitory effect: at 10–9–10–7 M ET-1 inhibited the ISO-induced increase in I Ca in a concentration-dependent manner (anti-adrenergic effect). The maximum inhibition induced by ET-1 at 10–7 M was approximately 80% of the ISO-induced response, and the IC50 value for anti-adrenergic effect of ET-1 was 4.2×1O–9 M. The anti-adrenergic effect of ET-1 (10–8 M) was antagonized by the ETA antagonist FR139317 (10–9–10–6 M) in a concentration-dependent manner and was partially inhibited by the ETB antagonist BQ-788 (10–6 M). The anti-adrenergic effect of ET-1 was markedly attenuated by pretreatment of ventricular myocytes with pertussis toxin. The increases in I Ca induced by forskolin (10–6 M), 3-isobutyl-1-methylxanthine (10–4 M), and 8-bromo-cyclic AMP (3×10–4 M) were also suppressed by ET-1 (10–8 M). In summary, ET-1 has a differential effect on I Ca in the absence and in the presence of ISO: ET-1 has a feeble biphasic action on the baseline I Ca and, in addition, it elicits a pronounced anti-adrenergic effect on the ISO-induced increase in I Ca. Pertussis toxin-sensitive G protein is responsible for the anti-adrenergic effect of ET-1 on I Ca, but the anti-adrenergic effect of ET-1 may involve also the regulation at the level of signaling process beyond the cyclic AMP generation. Anti-adrenergic effect of ET-1 on I Ca is mainly due to activation of ETA receptors but ETB receptors are also involved partially in the anti-adrenergic effect of ET-1 on I Ca in rabbit ventricular myocytes.

Cyclic AMP ETA and ETB receptors Pertussis toxin-sensitive G protein Forskolin 8-bromo-cyclic AMP 3-isobutyl-1-methylxanthine