Use-dependence of ryanodine effects on postrest contraction in ferret cardiac muscle.

Abstract

During an investigation of the effect of ryanodine on contractions in cardiac muscle, it was found that long rest periods removed all or most of the drug's effect. Therefore, we studied the kinetics of block development and recovery from block produced by low concentrations of ryanodine (1-100 pM) on the postrest contractions of ferret papillary muscle. At 100 pM, ryanodine depressed steady-state contraction amplitude slightly (4.2 ± 1.1% mean ± SEM, n = 10) but strongly inhibited (40-80%) the first contraction (postrest contraction) elicited on restimulation of the preparation after rest periods of 1 second to 5 minutes. Under control conditions, the nearly maximal potentiation of the twitch occurring after a standard test rest period (30 seconds of rest) was not affected by a preceding conditioning rest of up to 20 minutes. In the presence of 100 pM ryanodine, a conditioning rest increased the amplitude of the twitch elicited after a test rest, and the test rest contraction recovered toward control (drug-free) amplitude monoexponentially (time constant, 582 ± 105 seconds). Block of postrest contraction could be reinduced by stimulation and occurred faster when higher rates were used (time constants, 758 seconds at 1 Hz and 107 ± 26 seconds at 3 Hz). Since rest potentiation of twitch tension is believed to be mostly dependent on extra calcium released from the sarcoplasmic reticulum, the results suggest that the ryanodine-induced blockade of calcium release from the sarcoplasmic reticulum is use-dependent and recovers during diastole. Such use-dependence might be mediated by modulation of the drug-receptor interaction by intracellular calcium, transsarcolemmal or transsarcoplasmic reticulum membrane potential, or the state of a sarcoplasmic reticulum membrane calcium channel. (Circulation Research 1987;60:560-567)

Diminished post-rest potentiation of contractile force in human dilated cardiomyopathy. Functional evidence for alterations in intracellular Ca2+ handling.

“…In human myocardium, several authors reported a reduced Ca 2ϩ -uptake capacity of the sarcoplasmic reticulum in failing dilated cardiomyopathy (13,21,40) To evaluate whether a functional SR is a prerequisite for post-rest potentiation in human myocardium, the influence of ryanodine on post-rest contractions was investigated. Ryanodine was shown to deplete SR Ca 2ϩ stores (48) and has been found to abolish post-rest potentiation of contractile force in ferret (49), canine (50) and rat (5, 51) myocardium. This effect was attributed to a ryanodine-induced increased leak of Ca 2ϩ from the SR by blocking the release channel in a subconducting open state (52).…”

Postrest Contraction in the Ventricular Papillary Muscle of Spontaneously Diabetic WBN/Kob Rat.

“…Currently accumulating evidence suggests that the resumption of electrical stimulation following a brief stop yields contractions highly sensitive to releasable Ca 2+ from SR [1,6,29]. In the rat ventricular muscle, PRC is recognized as a composite function of timeand beat-dependent recycling of Ca 2+ within the SR [33] combined with a small net cellular Ca 2+ gain through the Na + /Ca 2+ exchange process [38].…”

“…To our knowledge, we are the first analyzing the recovery process of PRC, to address the underlying mechanisms associated with the development of abnormal mechanics in diabetes. SR Ca 2+ release contributes largely to the mechanism of postrest potentiation [1,6,29]. Malecot et al [28] have reported that the first component of PRC may be caused by SR Ca 2+ release and the second one by increased Ca 2+ influx during the action potential via the L-type Ca 2+ channel.…”

“…However, the first contraction is larger than that of the steady-state contraction when stimulated after a short rest interval [1,3,5,11,23,24]. This potentiation of PRC is highly dependent on augmented Ca 2+ release from the sarcoplasmic reticulum (SR) [1,6,29]. Bouchard and Bose [8] have examined whether the decrease in cardiac contractility observed in STZ-induced diabetic rats is accompanied by reduced or excessive loading of the SR with Ca 2+ .…”

Preceding Stimulus Frequency-Dependent Potentiation of the Postrest Shortening of the Action Potential Duration in Rabbits.

“…[9][10][11][12] This alteration of [Ca 2+ ] i transient may be involved in changes of action potential configuration after a rest period. In fact, Bers demonstrated that the APD of rabbit papillary muscle shortened after a rest period which was accompanied by a greater and faster developed tension.…”