Activation of purified cardiac ryanodine receptors by dihydropyridine agonists

Toshio Sagawa, Manabu Nishio, Kazuko Sagawa, James E. Kelly, Andrew J. Lokuta, John Tsai, Edward Kan, J. Andrew Wasserstrom*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Prior observations have raised the possibility that dihydropyridine (DHP) agonists directly affect the sarcoplasmic reticulum (SR) cardiac Ca2+ release channel [i.e., ryanodine receptor (RyR)]. In single-channel recordings of purified canine cardiac RyR, both DHP agonists (-)-BAY K 8644 and (+)-SDZ202-791 increased the open probability of the RyR when added to the cytoplasmic face of the channel. Importantly, the DHP antagonists nifedipine and (-)-SDZ202-791 had no competitive blocking effects either alone or after channel activation with agonist. Thus there is a stereospecific effect of SDZ202-791, such that the agonist activates the channel, whereas the antagonist has little effect on channel activity. Further experiments showed that DHP agonists changed RyR activation by suppressing Ca2+-induced inactivation of the channel. We concluded that DHP agonists can also influence RyR single-channel activity directly at a unique allosteric site located on the cytoplasmic face of the channel. Similar results were obtained in human purified cardiac RyR. An implication of these data is that RyR activation by DHP agonists is likely to cause a loss of Ca2+ from the SR and to contribute to the negative inotropic effects of these agents reported by other investigators. Our results support this notion that the negative inotropic effects of DHP agonists result in part from direct alteration in the activity of RyRs.

Original languageEnglish (US)
Pages (from-to)H1201-H1207
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume280
Issue number3 49-3
DOIs
StatePublished - 2001

Keywords

  • BAY K 8644
  • Calcium release channels
  • Nifedipine
  • PN-202-791
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Activation of purified cardiac ryanodine receptors by dihydropyridine agonists'. Together they form a unique fingerprint.

Cite this