Rate‐dependent changes of twitch force duration in rat cardiac trabeculae: a property of the contractile system

Abstract

1. We examined the mechanisms for rate-dependent changes in twitch force duration by simultaneously measuring force and [Ca2+]i in rat cardiac trabeculae. 2. Peak force decreased when the rate of stimulation was increased from 0.2 to 0.5 Hz, whilst it increased from 1 to 2 Hz. Over the same range of frequencies, peak [Ca2+]i transients increased monotonically, whilst both force and [Ca2+]i transient duration were abbreviated. 3. Changes in peak force or peak [Ca2+]i transients were not responsible for the changes in force or [Ca2+]i transient duration. 4. The changes in twitch force and [Ca2+]i transient duration were completed roughly within one beat following an abrupt change in the rate of stimulation. 5. Rate-dependent changes resembled those observed with isoproterenol (isoprenaline) application. However, kinase inhibitors (i.e. K252-a, H-89, KN-62 and KN-93) had no effect on the rate-dependent changes of twitch force and [Ca2+]i transient kinetics, suggesting that protein kinase A (PKA), protein kinase PKG) and Ca2+-calmodulin-dependent protein kinase II (CaM/kinase II) were not responsible for these kinetic changes. 6. Despite the changes in twitch force and [Ca2+]i transient kinetics, the rate-limiting step for the rate-dependent force relaxation still resides at the level of the contractile proteins. 7. Our results suggest that rate-dependent changes in force and [Ca2+]i transients do not depend on PKA or CaM/kinase II activity but might result from intrinsic features of the contractile and/or Ca2+-handling proteins.

CaMKII inhibition targeted to the sarcoplasmic reticulum inhibits frequency-dependent acceleration of relaxation and Ca2+ current facilitation

“…Both relaxation and [Ca 2+ ] i decline rates are accelerated at higher frequency in all species studied and enhanced rate of SR Ca 2+ uptake appears to drive both effects [9][10][11][12]. Some reports have shown that FDAR can be strongly suppressed by CaMKII inhibitors (KN-93, KN-62, AIP) [9,[12][13][14], while other reports could not detect effects on FDAR of organic inhibitors or KN-62 [11,[15][16][17]. CaMKII-dependent PLB phosphorylation seemed a plausible FDAR mediator and some data seemed to support that [14,18].…”

“…The contribution of PLB and CaMKII to FDAR remains controversial. CaMKII inhibition has been reported to suppress FDAR in several studies [9,12,13], but other studies did not detect FDAR inhibition with KN-93 or KN-62 [11,[15][16][17]. In isolated myocytes CaMKII dependent phosphorylation of PLB at Thr17 occurs in a frequency dependent manner [14,17].…”

Determinants of frequency-dependent contraction and relaxation of mammalian myocardium

“…Several studies indicate that the myofilament properties play a prominent role in governing the rate of myocardial relaxation [9,47]. Moreover, recent work by us [48], and others [38] argues in favor of a significant involvement of the myofilaments in FDAR. In isolated rabbit trabeculae, contracting isometrically at body temperature within the in vivo range of the rabbit, myofilament calcium sensitivity greatly decreased when stimulation frequency was increased [48].…”

“…Studies from Bassani et al [36] and De Santiago and coworkers [17] indicated that FDAR is dependent on CaMKII activation, and studies in isolated myocytes suggested that phosphorylation of the Thr 17 residue of PLN is responsible for FDAR [15]. However there are other studies that failed to show either an FDAR dependence on CaMKII activation [2,37,38] or a significant increase in PLB phosphorylation [16,37]. The role of CaMKII in FDAR was investigated using isolated trabeculae and/or myocytes from PLB-KO mouse and rat hearts [17,39].…”

Partial Inhibition of Sodium/Calcium Exchange Restores Cellular Calcium Handling in Canine Heart Failure

“…23 Although partial acceleration of SR Ca 2ϩ uptake at high Ca 2ϩ is expected because of the sigmoidal dependence of the transport kinetics on the concentration of the substrate, 17 an additional activation has been ascribed to an allosteric regulatory mechanism. The nature of the [Ca 2ϩ ] i -sensitive mediator is still unclear: a possible mechanism suggested by some, 17 but not all, 24 studies was calmodulin-dependent phosphorylation. Regardless of the mechanistic details, [Ca 2ϩ ] i -mediated SERCA activation represents an effective autoregulatory mechanism that protects against cytosolic [Ca 2ϩ ] i overload.…”