Control of interval‐force relation in canine ventricular myocardium studied with ryanodine

Abstract

1 The mechanism of post-extrasystolic, rest and frequency potentiation was studied in canine isolated ventricular muscle. 2 Ryanodine, which impairs Ca availability from the sarcoplasmic reticulum (SR), reduced the amplitude of the extrasystole less than that of the steady state contraction. Ryanodine also inhibited post-extrasystolic potentiation and converted rest-potentiation into rest depression. Restpotentiation was blocked preferentially by ryanodine compared to post-extrasystolic potentiation. An increase in the contribution of extracellular Ca to the extrasystolic contraction could not entirely account for the post-extrasystolic potentiation. 3 Prolonged rest, by itself, also caused depression of the first post-rest contraction. During restpotentiation, SR Ca seemed to play a greater role in contraction than transmembrane Ca influx. However, the ability of the 'release pool' of Ca in the SR to be reprimed after a contraction was reduced. This was seen as a decrease in post-extrasystolic potentiation elicited immediately after rest.4 A decrease in stimulus interval was associated with a transient decrease in contraction amplitude followed by an increase. An abrupt increase in stimulus interval had the opposite effect. Ryanodine blocked the initial transient changes and accelerated the delayed changes. These results suggest that the transient changes in contraction after sudden changes in drive interval are dependent on the SR. 5 Transmembrane Ca entry and the rate of recovery of the Ca release process (repriming) in the SR after a contraction seem to be interval-dependent. The data also indicate that different mechanisms are involved in post-extrasystolic and rest-potentiation. 6 The results are consistent with a model which proposes 'recirculation' of activator Ca within the SR after a contraction or of the presence of an appreciable amount of inactivation of the SR Ca release process during normal stimulation. An increased pool of releasable Ca due to longer recirculation time or a time-dependent decay in the level of inactivation of Ca release from the SR may give rise to rest-potentiation.

Investigations of Calsequestrin as a Target for Anthracyclines: Comparison of Functional Effects of Daunorubicin, Daunorubicinol, and Trifluoperazine

“…TFP at 300 M inhibits both steady-state and PRP30 contractions. Because the ability of a rest interval to augment contractility depends more on SR Ca 2ϩ than on Ca 2ϩ from other sites (Bers, 1985;Sutko et al, 1986;Bose et al, 1988;, these results also suggest the TFP-dependent inhibition observed in these experiments involves changes to the regulation of SR Ca 2ϩ . Analogous experiments, performed in our laboratory and designed to evaluate the effects of daunorubicin on cardiac contractility, yielded results similar to those observed with TFP .…”

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

“…After complete mechanical stabilization of the muscle at a basal stimulation frequency of 1 Hz, the experimental protocol was started. For post-rest contractions, electrical stimulation of the muscle strips was switched off at steady state conditions for increasing intervals (2,5,10,20,30,40,50,60, 120, and 240 s). Upon restimulation, the first beat was evaluated for post-rest changes in isometric twitch tension (mN/mm 2 ), maximum rate of tension rise ( ϩ dT/dt max ), maximum rate of tension decline ( Ϫ dT/dt max ) time to peak tension (TPT) and time to 50% and 95% relaxation.…”

Postextrasystolic potentiation in patients with ischaemic heart disease: influence of inotropic agents.

“…However, many patients in whom the extent of PESP might potentially be of importance are studied during treatment with a range of inotropically active drugs. It has been demonstrated, on the basis of in vitro studies, that calcium availability at the level of the myofibrils is a critical determinant of PESP [2,[10][11][12]. Consistent with this, it appears that calcium antagonist drugs and ryanodine inhibit PESP [2,10,13].…”

“…This phenomenon has been extensively investigated both in vitro [2][3][4] and in vivo [5,6]. The maximum rate of rise of left ventricular pressure (LV+dP/dtmax) of a postextrasystole is a function of both the extrasystolic test pulse interval (ETPI), and the interval preceding the postextrasystole.…”

“…It has been demonstrated, on the basis of in vitro studies, that calcium availability at the level of the myofibrils is a critical determinant of PESP [2,[10][11][12]. Consistent with this, it appears that calcium antagonist drugs and ryanodine inhibit PESP [2,10,13]. However no data are available in man concerning the potential effects of agents which may affect Ca2+ availability secondary to changes in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) concentrations, including ,3-adrenoceptor antagonists and phosphodiesterase inhibitors.…”