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1 Division of Cardiology, Department of Medicine, and 2 Department of Molecular Pharmacology and Biological Chemistry and the Feinberg Cardiovascular Research Institute, Northwestern University Medical School, Chicago, Illinois 60611; and 3 Department of Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53706
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.
nifedipine; BAY K 8644; PN-202-791; calcium release channels; sarcoplasmic reticulum
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