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Role of nonselective cation channels as Ca2+ entry pathway in endothelin-1-induced contraction and their suppression

X F Zhang1, T Komuro, S Miwa

  • 1Department of Pharmacology, Kyoto University, Faculty of Medicine, Japan.

European Journal of Pharmacology
|August 26, 1998
PubMed

Insights

Endothelin-1 triggers rat aorta contraction via nonselective cation channels, not L-type channels. Nitric oxide (NO) inhibits this by blocking Ca2+ entry through these nonselective channels.

Area of Science:

  • Cardiovascular Physiology
  • Ion Channel Function
  • Endothelial Function

Background:

  • Endothelin-1 (ET-1) is a potent vasoconstrictor involved in regulating vascular tone.
  • Calcium (Ca2+) influx is crucial for smooth muscle contraction, but pathways can vary.
  • Nitric oxide (NO) is known to modulate vascular responses, including those to ET-1.

Purpose of the Study:

  • To investigate the specific role of nonselective cation channels in ET-1-induced rat aorta contraction.
  • To determine if L-type voltage-operated Ca2+ channels contribute to this ET-1-mediated response.
  • To elucidate the mechanism by which nitric oxide (NO) suppresses ET-1-induced vascular contraction.

Main Methods:

  • Experiments conducted on endothelium-denuded rat thoracic aorta rings.
  • Measurement of isometric contraction and intracellular calcium ([Ca2+]i) using fura 2 fluorescence.
  • Pharmacological blockade of nonselective cation channels (SK&F 96365) and L-type Ca2+ channels (nifedipine).
  • Application of NO donors (sodium nitroprusside, SIN-1) and a guanylate cyclase inhibitor (ODQ).

Main Results:

  • ET-1 induced significant contraction and [Ca2+]i increase, largely independent of extracellular Ca2+ removal.
  • Nifedipine did not affect ET-1-induced responses, indicating L-type channels are not involved.
  • SK&F 96365 abolished ET-1-induced contraction and [Ca2+]i increase, similar to Ca2+-free conditions.
  • NO donors (sodium nitroprusside, SIN-1) abolished ET-1 responses, an effect reversed by ODQ.

Conclusions:

  • Ca2+ entry via nonselective cation channels, not L-type channels, is critical for ET-1-induced rat aorta contraction.
  • Nitric oxide inhibits ET-1-induced contraction primarily by blocking Ca2+ influx through nonselective cation channels.
  • The inhibitory effect of NO is mediated via guanylate cyclase activation.

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