Activation of purified cardiac ryanodine receptors by dihydropyridine agonists.
Prior observations have raised the possibility that dihydropyridine (DHP) agonists directly affect the sarcoplasmic reticulum (SR) cardiac Ca(2+) 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 Ca(2+)-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 Ca(2+) 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.
Sagawa
T
T
Division of Cardiology, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Nishio
M
M
Sagawa
K
K
Kelly
J E
JE
Lokuta
A J
AJ
Tsai
J
J
Kan
E
E
Wasserstrom
J A
JA
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology; D004095:Dihydropyridines / Q000819:agonists* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000737:chemistry* / Q000378:metabolism*; D009539:Nicotinic Acids / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000302:isolation & purification* / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D009539:Nicotinic Acids; D010069:Oxadiazoles; D019837:Ryanodine Receptor Calcium Release Channel; C049834:PN 202-791; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C038806:1,4-dihydropyridine; C045796:SAN 202791; D009543:Nifedipine