Endothelin‐1 and endothelin‐3 regulate differently vasoconstrictor responses of smooth muscle of the porcine coronary artery

Masuko Ushio‐Fukai, Junji Nishimura, Sei Kobayashi, Hideo Kanaide

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16 Scopus citations

Abstract

Using front‐surface fluorometry of fura‐2 and medial strips of the porcine coronary artery, we investigated mechanisms by which endothelin‐1 (ET‐1) and ET‐3 function as vasoconstrictors. In the presence of extracellular Ca2+(1.25 mm), ET‐1 (10−10‐10−7 m) increased cytosolic Ca2+concentrations ([Ca2+]i) and tension, in a concentration‐dependent manner. ET‐1, at concentrations greater than 10−8 m, induced an abrupt elevation of [Ca2+]i which reached a transient peak (the first component, [Ca2+]i‐rising phase) and subsequently declined ([Ca2+]i‐declining phase) to reach a lower sustained phase (the second component, steady‐state phase), while the tension rose monotonically to reach a peak and then slightly and gradually declined. ET‐1, at concentrations lower than 10−8 m, induced slowly developing and sustained increases in [Ca2+]i and tension ([Ca2+]i‐rising phase followed by steady‐state phase). All concentrations of ET‐1 increased tension more slowly than [Ca2+]i. In the presence of extracellular Ca2+, ET‐3 (10−8‐10−5 m) induced concentration‐dependent increases in [Ca2+]i and tension. However, the maximal elevations of [Ca2+]i and tension induced by ET‐3 were substantially smaller than those induced by ET‐1, indicating the involvement of an ETA receptor subtype. ET‐3, at concentrations greater than 6 × 10−7 m, caused biphasic slowly developing increases in [Ca2+]i and tension. At concentrations lower than 10−6 m, ET‐3 caused monophasic increases in [Ca2+]i and tension. At all concentrations of ET‐3, the time courses of increases in [Ca2+]i and tension were similar. The biphasic increases in [Ca2+]i and tension induced by 10−5 m ET‐3 and by 10−7 m ET‐1 were significantly inhibited by pretreatment with 10−5 m of the Ca2+ entry blocker, diltiazem, although the inhibition of the first component of ET‐1‐induced [Ca2+]i increase was partial. In the absence of extracellular Ca2+, ET‐1 induced a concentration‐dependent transient increase in [Ca2+]i, possibly due to release of Ca2+ from intracellular stores, and a sustained contraction. In contrast, ET‐3 (≥10−6 m) caused little, if any, transient increase in [Ca2+]i and a small sustained contraction. Temporal changes in the relationships between [Ca2+]i and tension ([Ca2+]i‐tension relationship) during contractions induced by ET‐1 and ET‐3 were compared with the [Ca2+]i‐tension relationship of Ca2+‐induced contractions (Ca2+‐contractions) obtained by cumulative applications of extracellular Ca2+(0–7.5 mm) to tissues depolarized in the presence of 118 mm K+. In the [Ca2+]i‐rising phase, ET‐1 increased tension more slowly than [Ca2+]i, thereby shifting the [Ca2+]i‐tension relation to the right from that for Ca2+‐contractions. In the [Ca2+]i‐declining and the steady‐state phases, ET‐1, at concentrations higher than 10−9 m, produced greater tension development than that expected from a given change in [Ca2+]i, resulting in a leftward shift of the [Ca2+]i‐tension relation. During ET‐3‐induced contractions, ([Ca2+]i‐rising, [Ca2+]i‐declining and steady‐state phases), the [Ca2+]i‐tension relation was similar to that of Ca2+‐contractions. BQ‐123, a selective ETA receptor antagonist, completely inhibited the increases in [Ca2+]i and tension induced by ET‐1 and ET‐3. These results suggest: (1) That ET‐1 elicits vasoconstriction by increasing [Ca2+]i through the activation of Ca2+ influx from the extracellular space and Ca2+ release from intracellular storage sites, and by increasing the Ca2+ sensitivity of the contractile apparatus, whereas ET‐3 induces vasoconstriction by increasing [Ca2+]i mainly through Ca2+ influx from the extracellular space. (2) Distinct mechanisms of time‐dependent modulation of the Ca2+ sensitivity function in the vasoconstrictor responses to ET‐1 and ET‐3. (3) That both ET‐1‐ and ET‐3‐induced contractions seem to be mediated via ETA‐receptors in porcine coronary artery, and that the ETA‐receptor‐mediated effects of ET‐1 and ET‐3 can be dissociated at the sub‐receptor levels of the signal transduction pathway. 1995 British Pharmacological Society

Original languageEnglish (US)
Pages (from-to)171-179
Number of pages9
JournalBritish Journal of Pharmacology
Volume114
Issue number1
DOIs
StatePublished - Jan 1995

Keywords

  • Endothelin‐1, endothelin‐3
  • cytosolic calcium concentration
  • vascular smooth muscle

ASJC Scopus subject areas

  • Pharmacology

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