Differential Effects of Endothelin‐1 on Basal and Isoprenaline‐Enhanced Ca2+ Current in Guinea‐Pig Ventricular Myocytes

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Abstract
We examined the effect of endothelin‐1 (ET‐1) on basal and isoprenaline‐enhanced L‐type Ca2+ current (ICa,L) in guinea‐Pig ventricular myocytes under nystatin‐perforated patch configuration. ET‐1 at concentrations of 1, 5 and 10 nM had little effect on basal ICa,L. However, ICa,L enhanced by isoprenaline (500 nM) was significantly attenuated by 5 nM ET‐1 by more than 50%. This effect was reversed upon washout. ICa,L enhanced by forskolin was also decreased by ET‐1. The inhibitory effect of ET‐1 against isoprenaline was completely blocked by the ETA receptor antagonist BQ‐123 (1 μm). In myocytes incubated with pertussis toxin (PTX, 2 μg ml−1) for 5 h, ET‐1 did not inhibit isoprenaline‐enhanced ICa,L. Although ET‐1 has been shown to activate specific protein kinase C (PKC) isoforms, a significant inhibitory effect of ET‐1 was maintained in the presence of the PKC inhibitor bisindolylmaleimide (20 nm). The nitric oxide (NO) donor SIN‐1 (10 μm) attenuated but failed to prevent the ET‐1 effect. In summary, our results demonstrate that ET‐1 is devoid of any significant effects on basal ICa,L. However, it exerts a potent inhibitory effect against isoprenaline‐enhanced ICa,L. This effect is mediated through ETA receptors coupled to PTX‐sensitive G‐proteins and occurs in the presence of PKC inhibition and NO generation.