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S M Harrison

Publications and source records attributed to S M Harrison.

At least 37 records · Page 2Linked to original sources
PubMed1998

The effect of temperature on the rate-dependent decrease of the rat ventricular calcium current.

We have investigated the effect of temperature upon the rate-dependent decrease in the L-type Ca2+ current (iCa) in isolated rat ventricular myocytes. Increasing the rate of stimulation from 0.5 to 3.0 Hz for 30s induced a reversible decrease in iCa which was temperature dependent. Compared to control (0.5 Hz), the first beat at 3 Hz was decreased by 38 +/- 7% at 22 degrees C and by 9 +/- 1% at 37 degrees C (mean +/- S.E.M., n = 5, P < 0.05) and, after 30 s of 3 Hz stimulation, iCa was reduced by a further 26 +/- 4 and 21 +/- 2% at 22 and 37 degrees C, respectively. The magnitude of this secondary decline was not significantly different at the two temperatures (P = 0.29). Corroboratory results were obtained from cell-attached patches which also illustrated that the rate-dependent decrease in iCa resulted from a reduction of open channel probability. Paired pulse experiments showed that the greater initial rate-dependent decrease in iCa at 22 degrees C occurred as a result of slower recovery from fast inactivation processes at 22 than at 37 degrees C. Recovery of the channel from fast inactivation was very temperature sensitive with a Q10 of 5.6. In contrast, the secondary, progressive decrease in iCa, which results from incomplete recovery from ultra-slow voltage-dependent inactivation, was similar at the two temperatures and appears to be much less temperature dependent.

Animals↗
PubMed1998

A method for reversible permeabilization of isolated rat ventricular myocytes.

A method is described that enables the cell membrane of isolated rat ventricular myocytes to be permeabilized and resealed while maintaining cell viability. Streptolysin O, a cholesterol-binding cytolysin, was used to form pores in the surface membrane; subsequent incubation with 5% fetal bovine serum was used to reverse this permeabilization. The efficacy of membrane permeabilization and resealing was ascertained using a simultaneous double-staining technique using propidium iodide, a marker for cells with permeabilized membranes, and fluorescein diacetate, a marker for viable cells. This procedure allowed a distinction to be made between dead cells, unpermeabilized cells and viable cells that had been successfully permeabilized and resealed. The accessibility of the cell interior during permeabilization was investigated by including fluorescein isothiocyanate (FITC)-labelled dextrans (11, 38 and 148 kDa) and bovine serum albumin (67 kDa) in the permeabilization buffer, and localizing the FITC label using confocal microscopy following resealing. The confocal images showed that these molecules entered the cells and were retained after resealing. Following the permeabilization-resealing protocol, cells appeared to have both normal morphology and response to electrical stimulation. Thus this appears to be a cheap, simple and effective method to introduce relatively large molecules into cardiac myocytes.

Animals↗
PubMed1998

Changes in contraction, cytosolic Ca2+ and pH during metabolic inhibition and upon restoration of mitochondrial respiration in rat ventricular myocytes.

Exposure of cardiac muscle to metabolic poisons reduces the availability of cellular ATP and cardiac dysfunction ensues. In this study rat ventricular myocytes were exposed to 2-deoxyglucose, iodoacetate and cyanide to induce complete metabolic blockade. Changes in contraction, cytosolic Ca2+ and pH were determined during metabolic blockade and following restoration of mitochondrial ATP production. Metabolic blockade resulted in a rapid failure of contractions and Ca2+ transients, a rise of diastolic Ca2+, a cytosolic acidosis and ultimately a rigor contracture. Washing out cyanide during the development of the rigor contracture led to a rapid relaxation of the contracture, a fall in cytosolic Ca2+ and a rapid, partial reversal of the cytosolic acidosis. The partial reversal of the cytosolic acidosis and fall of cytosolic Ca2+ were abolished in the presence of oligomycin. This suggests that the rapid partial recovery of cytosolic acidosis could result from the rephosphorylation of ADP to ATP by the mitochondrial F1,F0-ATPase (a reaction that consumes protons).

Animals↗
PubMed1997

The role of Na(+)-Ca2+ exchange current in electrical restitution in ferret ventricular cells.

1. The mechanisms underlying electrical restitution (recovery of action potential duration after a preceding beat) were investigated in ferret ventricular cells. The time to 80% recovery (t80) of action potential duration was approximately 204 ms. 2. At a holding potential of -80 mV, the Ca2+ current (ICa) reactivated and the delayed rectifier K+ current (IK) deactivated very rapidly (t80: approximately 32 and approximately 93 ms, respectively). The kinetics of both currents are too fast to account for electrical restitution alone. 3. The putative inward Na(+)-Ca2+ exchange current (INa-Ca) produced by the Na(+)-Ca2+ exchanger in response to the intracellular Ca2+ transient reprimed (t80: 189 ms) with the same time course as mechanical restitution (recovery of contraction) and with a similar time course to electrical restitution. 4. Substantial reduction of inward INa-Ca, by buffering intracellular Ca2+ with the acetyl methyl ester form of BAPTA, shortened the action potential and greatly altered the electrical restitution curve. Subsequent addition of nifedipine (to block ICa) or 4-aminopyridine (4-AP) (to block the transient outward current, ITO) further altered the electrical restitution curve. 5. Any time-dependent current that contributes to the action potential is likely to affect the time course of electrical restitution. Although ICa, IK and ITO were previously thought to be the only currents involved in electrical restitution, we conclude that inward INa-Ca also plays an important role.

4-Aminopyridine↗
PubMed1997

The role of inward Na(+)-Ca2+ exchange current in the ferret ventricular action potential.

1. Inward Na(+)-Ca2+ exchange current (iNaCa) was either blocked in ferret ventricular cells by replacing extracellular Na+ with Li+ or substantially reduced by the almost complete elimination of the Ca2+ transient by buffering intracellular Ca2+ with the acetoxymethyl ester form of BAPTA (BAPTA AM). 2. During square wave voltage clamp pulses to 0 mV, replacing extracellular Na+ with Li+ or buffering intracellular Ca2+ with BAPTA AM resulted in the loss of a transient inward current. This current was increased by the application of isoprenaline (expected to increase the underlying Ca2+ transient) and displayed the voltage-dependent characteristics of inward iNaCa. 3. Replacing extracellular Na+ with Li+ or buffering intracellular Ca2+ caused a significant shortening of the action potential (at -65 mV, 44 +/- 2% with Li+ and 20 +/- 2% with BAPTA AM). The shortening can be explained by changes in iNaCa. 4. The action potential clamp technique was used to measure the BAPTA-sensitive current (putative iNaCa) and the Ca2+ current (ica; measured using nifedipine) during the action potential. Under control conditions, the inward BAPTA-sensitive current makes approximately the same contribution as iCa during much of the action potential plateau. These results suggest an important role for inward iNaCa in the ferret ventricular action potential.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1997

Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo.

Mouse delta-like 3 (Dll3), a novel vertebrate homologue of the Drosophila gene Delta was isolated by a subtracted library screen. In Drosphila, the Delta/Notch signalling pathway functions in many situations in both embryonic and adult life where cell fate specification occurs. In addition, a patterning role has been described in the establishment of the dorsoventral compartment boundary in the wing imaginal disc. Dll3 is the most divergent Delta homologue identified to date. We confirm that Dll3 can inhibit primary neurogenesis when ectopically expressed in Xenopus, suggesting that it can activate the Notch receptor and therefore is a functional Delta homologue. An extensive expression study during gastrulation and early organogenesis in the mouse reveals a diverse and dynamic pattern of expression. The three major sites of expression implicate Dll3 in somitogenesis and neurogenesis and in the production of tissue from the primitive streak and tailbud. A careful comparison of Dll3 and Dll1 expression by double RNA in situ hybridisation demonstrates that these genes have distinct patterns of expression, but implies that together they operate in many of the same processes. We postulate that during somitogenesis Dll3 and Dll1 coordinate in establishing the intersomitic boundaries. We confirm that, during neurogenesis in the spinal cord, Dll1 and Dll3 are expressed by postmitotic cells and suggest that expression is sequential such that cells express Dll1 first followed by Dll3. We hypothesise that Dll1 is involved in the release of cells from the precursor population and that Dll3 is required later to divert neurons along a specific differentiation pathway.

Amino Acid Sequence↗
PubMed1997

Attempt to correlate urine arsenic excretion with clinical course during melarsoprol therapy of patients with Rhodesian trypanosomiasis.

This study enrolled 28 CNS-involved patients with Trypanosoma brucei rhodesiense at the Kenya Trypanosomiasis Research Institute (Alupe, Kenya) to examine treatment efficacy and toxicity of melarsoprol in relation to renal excretion/dose relationships. This study complied with World Health Organization treatment recommendations, initially treating with suramin followed by three courses of melarsoprol. Traced study patients had a relapse rate of 4.1%. The toxicity and crude death rate was 7.1%. Total urine arsenic output was measured between 24 and 48 hr after the last dose for each course. The range of means of total urine arsenic output between the three treatment courses was 356-511 micrograms. There was no correlation comparing melarsoprol dose, estimated creatine clearance, or urine arsenic output. Urinary pharmacokinetic parameters are not predictive of toxicity or therapeutic efficacy.

Adolescent↗
PubMed1996

Neuropeptide changes persist in spinal cord despite resolving hyperalgesia in a rat model of mononeuropathy.

We have previously described the changes in spinal cord neuropeptides in the unilateral sciatic chronic constriction injury (CCI) model of Bennett and Xie [Pain, 33 (1988) 87-108] at 28 days, a time of maximum mechanical hyperalgesia. In this study we examine the same model 100-120 days post injury by which time resolution of the hyperalgesia and peripheral nerve injury has occurred according to previous studies. Rats underwent either CCI of the sciatic nerve (n = 12) or else sham operation (n = 8) which involved exposure but no ligation of the nerve. Mechanical hyperalgesia was assessed with a Ugo-Basile analgesymeter and immunohistochemistry performed on the spinal cord sections of the animals and quantified using a confocal microscope. At this late time point CCI rats were no longer significantly mechanically hyperalgesic compared to the sham animals (P > or = 0.09). However, examination of the lumbar spinal cord revealed the following changes. (i) The neuropeptides substance P (SP) (P < 0.0001) and galanin (P < 0.003) both showed decreases of about 30% ipsilaterally in immunoreactivity in laminae 1 and 2 of the dorsal horn compared to the sham operated animals. (ii) Calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY) in laminae 1 and 2 showed no significant changes compared to sham animals. (iii) NPY levels in laminae 3 and 4 of the spinal cord showed a 15% increase in immunoreactivity compared to sham animals (P = 0.008). These results indicate that changes in neuronal markers in the spinal cord can persist after apparent resolution of a peripheral nerve injury. We suggest that these changes may form a substrate for subsequent development of abnormal pain states.

Animals↗
PubMed1996

Neuron death in the substantia nigra of weaver mouse occurs late in development and is not apoptotic.

Weaver is a spontaneous mutation in mice characterized by the postnatal loss of external granule cells in the cerebellum and dopaminergic neurons of the midbrain, especially in the substantia nigra. We have shown previously that natural cell death with the morphology of apoptosis occurs in the substantia nigra of normal rodents during postnatal development. We therefore sought to determine whether the loss of dopaminergic neurons in homozygous weaver mice occurs during the period of natural cell death in the substantia nigra and whether it has the morphology of apoptosis. We have found, using a silver stain technique, that although apoptotic cell death does occur early postnatally in homozygous weaver substantia nigra, it also does so with equal magnitude in wild-type and heterozygous weaver littermates. Unique to homozygous weavers is the occurrence of degenerating neurons in the nigra that are not apoptotic. These degenerating neurons are observed at postnatal day 7, and they are most abundant on postnatal days 24-25. The nonapoptotic nature of this cell death is confirmed by negative in situ end labeling of nuclear DNA fragmentation and by ultrastructural analysis. Ultrastructural studies reveal irregular chromatin aggregates in the nucleus, as well as marked cytoplasmic changes, including the formation of vacuoles and distinctive stacks of dilated cisternae of endoplasmic reticulum. We interpret these changes as indicative of either a variant morphology of programmed cell death or a pathological degenerative process mediated by an as yet unknown mechanism related to the recently described mutation in the GIRK2 potassium channel.

Aging↗
PubMed1996

Tyrosine hydroxylase phosphorylation in bovine adrenal chromaffin cells. Clonidine stimulates basal but inhibits nicotinic receptor evoked phosphorylation.

Clonidine inhibited the uptake of calcium and the overall phosphorylation of tyrosine hydroxylase induced by nicotinic receptor activation in bovine adrenal medullary chromaffin cells in culture. However, clonidine did not inhibit the increase in these parameters that accompanied K+ depolarisation of the cells. There was also no effect of clonidine on the overall phosphorylation of tyrosine hydroxylase when cells were stimulated by muscarine. Nicotinic receptor activation increased the phosphorylation of Ser-19, Ser-31, and Ser-40 on tyrosine hydroxylase, and this was inhibited by clonidine in a concentration-dependent manner. On the other hand, clonidine had no effect on calcium uptake, yet increased the phosphorylation of Ser-19 under basal conditions. Using calcium and calmodulin-stimulated protein kinase II obtained from rat brain clonidine increased the autophosphorylation of the alpha-subunit of the kinase by 37%, and also its activity against an exogenous peptide substrate by 29%. These data are consistent with the hypothesis that clonidine inhibits nicotinic receptor-induced tyrosine hydroxylase phosphorylation by decreasing calcium influx into chromaffin cells, perhaps by an action at the nicotinic receptor. Clonidine also increases the basal phosphorylation of tyrosine hydroxylase at Ser-19, perhaps by directly activating calcium and calmodulin-stimulated protein kinase II.

Adrenal Medulla↗
PubMed1996

Mn2+ can substitute for Ca2+ in causing catecholamine secretion but not for increasing tyrosine hydroxylase phosphorylation in bovine adrenal chromaffin cells.

The ability of the divalent cation manganese (Mn2+) to substitute for calcium (Ca2+) both in triggering catecholamine release and in stimulating catecholamine synthesis, as indicated by an increase in tyrosine hydroxylase (TOH) phosphorylation, has been determined in bovine adrenal medullary chromaffin cells maintained in tissue culture. Mn2+ was found to enter chromaffin cells through pathways activated by nicotinic receptor stimulation and potassium depolarisation, and via the Na1:Ca0 exchange mechanism in Na(+)-loaded cells. Like Ca2+, entry of Mn2+ through these pathways triggered immediate catecholamine release and, like Ca2+, maintained quantitatively comparable release at least up to 40 min. Unlike Ca2+, Mn2+ did not stimulate an increase in TOH phosphorylation in intact chromaffin cells, even over a prolonged time course, but Mn2+ did stimulate increased TOH phosphorylation in lysed cell preparations showing that its lack of effect in the intact cells was not due to inhibition of the specific phosphorylation pathway. In lysed cell preparations, Mn2+ stimulated also phosphorylation of a different spectrum of proteins to Ca2+, and of the same proteins to different extents. In particular, P80 (MARCKS protein) was more intensely phosphorylated in the presence of Mn2+ than in the presence of Ca2+. Since TOH phosphorylation always occurs when intracellular Ca2+ is increased, the absence of an increase with Mn2+ indicates that none of its intracellular effects could have occurred as a consequence of Mn2+ mobilisation of intracellular Ca2+. In summary, the data show that Mn2+ is a surrogate for Ca2+ in triggering and maintaining catecholamine release, but does not substitute for Ca2+ in stimulating TOH phosphorylation.

Adrenal Glands↗
PubMed1996

Comparison of ultra-slow, voltage-dependent inactivation of the cardiac L-type Ca2+ channel with Ca2+ or Ba2+ as the charge carrier in ferret ventricular myocytes.

The whole-cell patch clamp technique was used to investigate the effect of different charge carriers upon ultra-slow voltage-dependent inactivation of L-type Ca2+ channel current in ferret ventricular myocytes at 37 degrees C. Intracellular Ca2+ was buffered with 10 mM EGTA and the membrane potential held at -40 mV. With Ba2+ as the charge carrier, the L-type current decayed throughout 20 s pulses to 0 mV as a result of ultra-slow voltage-dependent inactivation. In contrast, with Ca2+ as the charge carrier, there was no such slow decay of the current as the current decayed almost completely in the first approximately 100 ms as a result of Ca(2+)-dependent inactivation. However, with Ca2+ as the charge carrier it is still possible that ultra-slow voltage-dependent inactivation occurs. A conditioning-test pulse protocol and a second protocol were used to test for the development of ultra-slow inactivation during 20 or 30 s pulses to 0 mV with Ca2+ as the charge carrier. Ultra-slow inactivation did occur and it was qualitatively similar to that with Ba2+ as the charge carrier. The onset of ultra-slow inactivation with Ca2+ as the charge carrier could be described by the sum of two exponentials with time constants of 0.3 and 6.7 s. Recovery from ultra-slow inactivation with Ca2+ as the charge carrier was also measured with a conditioning-test pulse protocol and was best described by the sum of two exponentials with time constants of 0.5 and 6.2 s. We conclude that ultra-slow inactivation of the L-type current does occur with the physiological charge carrier, Ca2+, but it is normally masked by Ca(2+)-dependent inactivation.

Animals↗
PubMed1995

Peri-administration of clonidine or MK801 delays but does not prevent the development of mechanical hyperalgesia in a model of mononeuropathy in the rat.

Following loose ligation of the sciatic nerve, rats develop a persistent hyperalgesia which mimics some of the features of traumatic neuropathy seen in man. Previously, we have shown that administration of MK801 or clonidine prior to and 30 min following loose ligation of the sciatic nerve prevented the development of hyperalgesia up to 30 days following surgery. In the current study, we have extended our observation and examined the effect of administration of clonidine (1 mg/kg, s.c.) or MK801 (0.3 mg/kg, s.c.) 30 min prior to and 6 h following loose ligation of the sciatic nerve on the development of hyperalgesia assessed at 9 time points between 16 and 150 days after loose ligation. We have found that compared with saline treatment, the degree of hyperalgesia apparent in animals receiving MK801 was significantly reduced when tested 16, 28, or 42 days after surgery. No significant difference between the 2 treatment groups was detected at any other time points during the study. Similarly, when compared with saline treated controls, the degree of hyperalgesia measured in animals following peri-administration of clonidine was significantly less when measured 16 and 28 days after surgery, but did not differ significantly at any of the time points tested between 42 and 150 days following surgery. Our results indicate that peri-administration of MK801 or clonidine significantly delay, but do not prevent, the onset of neuropathic hyperalgesia.

Animals↗
PubMed1995

The role of the Na(+)-Ca2+ exchanger in the rate-dependent increase in contraction in guinea-pig ventricular myocytes.

1. The intracellular sodium activity (alpha Na1), contraction and membrane current were recorded simultaneously in voltage-clamped guinea-pig ventricular myocytes. 2. Increasing the frequency (from 0.5 to 3 Hz) of voltage clamp pulses to 0 mV from a holding potential of -80 mV led to an increase in both alpha Na1 and contraction. The rate-dependent increase in contraction was reduced by 25 microM tetrodotoxin (TTX) and abolished with a holding potential of -40 mV. There was no rate-dependent rise in alpha Na1 with a holding potential of -40 mV. These results suggest an important role for alpha Na1 and in particular Na+ influx via Na+ channels during rate-dependent changes in contraction. 3. After an increase in frequency from 0.5 to 3 Hz, membrane current at the end of voltage clamp pulses became progressively more outward and the tail current upon at repolarization became progressively more inward compared with those recorded at 0.5 Hz. TTX reduced the magnitude of both the outward and inward rate-dependent shifts of current. 4. The addition of extracellular CsCl blocked the inward rectifier potassium current (IK.1) and the delayed rectifier (IK), but did not change the rate-dependent shift in current. 5. The difference between current-voltage relationships at 0.5 and 3 Hz showed that the rate-dependent outward shift of current at the end of voltage clamp pulses was small at potentials negative to -20 mV, was larger at more positive potentials and was reduced by TTX at most potentials. The TTX-sensitive component reversed at -47 mV. 6. These results are consistent with a net increase in outward Na(+)-Ca2+ exchange current during a voltage clamp pulse in response to the rise of alpha Na1. The increase in outward current (resulting from either enhanced Ca2+ influx or reduced Ca2+ efflux) will augment the Ca2+ load of the cell and contribute to the rate-dependent increase in contraction.

Animals↗
PubMed1995

Changes in neuronal markers in a mononeuropathic rat model relationship between neuropeptide Y, pre-emptive drug treatment and long-term mechanical hyperalgesia.

Using the chronic constriction model (CCI) of Bennett and Xie (1988), changes in the lumbar spinal cord in neuropeptides and lectin IB4 were examined at 28 days post-nerve constriction and were compared with the degree of mechanical hyperalgesia. Animals following nerve ligation were significantly more hyperalgesic than sham-operated animals (P < 0.0001). Lectin IB4, a marker of primary afferent C fibres, showed a qualitative decrease in staining intensity in laminae 1-2 with ligation compared with both the unoperated contralateral side and with sham animals. Using fluorescent immunohistochemistry to quantify changes in neuropeptides in the dorsal horn we found that substance P showed significant decreases with ligation compared to sham operation (P < 0.002). CGRP and galanin showed no significant changes in laminae 1-2 compared to sham-operated animals. Neuropeptide Y (NPY) showed no significant changes in intensity in laminae 1-2; however, in laminae 3-4 there was a significant increase with nerve ligation compared to sham (P < 0.005). We examined how pre-emptive drug treatment affected these neuronal markers at 28 days. We used (1) clonidine, an alpha 2-adrenoreceptor agonist (1 mg/kg, i.p.), (2) morphine, a mu-opioid agonist (5 mg/kg, i.p.) or (3) MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist (0.3 mg/kg, s.c.) administered 30 min prior and 6 h following nerve ligation or sham-operation. Hyperalgesia in the ligated group at 28 days was suppressed by treatment with pre-emptive clonidine (P = 0.003) or MK-801 (P = 0.003) but not morphine. With the exception of NPY there was no effect of pre-emptive drug treatment on any neuronal marker examined. Pre-emptive MK-801 reduced the magnitude of the increase in NPY in laminae 3-4 in the ligated group (P < 0.005) and clonidine showed a similar trend but this did not reach significance. Morphine had no effect on NPY staining. There was a significant correlation between the increase in NPY staining in laminae 3-4 and the degree of hyperalgesia (r = 0.6, P < 0.001). These results suggest that the increased NPY expression in laminae 3-4 of the spinal cord (the territory of the myelinated sensory input) may be crucial to the development of hyperalgesia in this model.

Analgesics↗
PubMed1995

The voltage dependence of contraction at different stimulation rates in guinea-pig ventricular myocytes.

Ventricular myocytes, isolated from the guinea-pig, were stimulated to contract by 100 ms long voltage clamp pulses from -80 to 0 mV at 0.5 and 3 Hz. An increase in frequency from 0.5 to 3 Hz led to a positive inotropic effect. Contraction-voltage relationships (CVR) were determined at each frequency. The CVR at 0.5 Hz was bell shaped and peaked between 0 and +20 mV, displaying a voltage dependence similar to the L-type Ca2+ current (ICa). At 3 Hz, contractions continued to increase at positive voltages, giving a more sigmoidal CVR. At 0.5 Hz, TTX reduced the size of steady-state contractions to 91 +/- 2% of control values, but had no effect on the shape of the CVR. At 3 Hz, TTX significantly reduced (P < 0.05) the magnitude of contractions at positive voltages (> or = +20 mV) but had no significant effect on contractions at voltages negative to 0 mV. These data illustrate that intracellular sodium activity (aNa(i)) and, in particular, Na+ entry due to the sodium current (INa) are important in determining the voltage dependence of contraction at positive voltages. Thapsigargin (2.5 microM), a blocker of the sarcoplasmic reticulum (SR) Ca(2+)-ATPase, reduced the size of steady-state contractions at 0 mV to 65 +/- 7% at 0.5 Hz. Increasing frequency to 3 Hz abolished the positive inotropy seen under control conditions. With thapsigargin present, contractions at 0.5 Hz were reduced at all potentials and the CVR was bell shaped. At 3 Hz the CVR was sigmoidal in shape. Contractions were significantly inhibited by thapsigargin at all potentials, but most significantly at more positive potentials (> or = +20 mV). These data show that, at normal body temperature, the shape of the CVR of guinea-pig ventricular myocytes changes with stimulation rate. Due to the voltage dependence of ICa, contractions evoked at positive voltages at 3 Hz must be supported by other mechanisms. The sensitivity of such contractions to TTX and thapsigargin suggests the involvement of both a Na(+)-dependent process and the SR. One possibility is that when aiNa and the Ca2+ content of the SR are raised at higher stimulation rates, enhanced Ca2+ entry via reverse Na(+)-Ca2+ exchange leads to a direct activation of the myofilaments and, to a lesser extent, the release of Ca2+ from the SR.

Animals↗