Biomedical subjects

S M Harrison

Publications and source records attributed to S M Harrison.

At least 55 records · Page 3Linked to original sources

PubMed1995

Control of growth hormone (GH) binding protein release from human hepatoma cells expressing full-length GH receptor.

In humans and rabbits, the circulating GH binding protein (GHBP) is released from the GH receptor by cleavage at a site proximal to the cell surface. There is evidence that GHBP status is predictive of GH responsiveness, presumably because it reflects GH receptor status. This assumes that GHBP release is not a regulated step. Here we report a model for study of GHBP release that provides some insight into this question. Human HepG2 cells were stably transfected with rabbit GH receptor and shown to be responsive to nonprimate (bovine) GH, indicating functionality of the transfected receptor. These cells released GHBP of the expected size, and this release could be increased by incubation with a phorbol ester, which stimulated receptor synthesis through the cytomegalovirus promoter. We surveyed a wide range of protease inhibitors both with and without streptolysin-O permeabilization, with the intention of defining the endogenous protease. Of 16 inhibitors, only benzamidine proved an effective inhibitor of release, indicating the existence of a novel protease. We could increase GHBP release with a membrane impermeable thiol blocker, suggesting activation of a membrane protease. We examined the ability of IGF-1, insulin, dexamethasone, sex steroids, and T4 to influence GHBP release. Although these agents are known to be effective in the parent hepatoma line, none were effective in modulating GHBP release, although GH itself decreased release by around 30% as assessed with a ligand immunofunctional assay. We conclude that GHBP release appears to be constitutive in this model and driven by receptor availability. This is consistent with an in vivo situation where circulating GHBP provides an index of hepatic receptor expression.

Animals↗

PubMed1995

Isolation of novel tissue-specific genes from cDNA libraries representing the individual tissue constituents of the gastrulating mouse embryo.

A total of 5 conventional, directionally cloned plasmid cDNA libraries have been constructed from the entire embryonic region of the mid-gastrulation mouse embryo and from its four principal tissue constituents (ectoderm, mesoderm, endoderm and primitive streak). These libraries have been validated with respect to the number of independent clones, insert-size and appropriate representation of diagnostic marker genes. Subtractive hybridisation has been used to remove clones common to the Endoderm and Mesoderm cDNA libraries resulting in an Endoderm minus Mesoderm subtracted library. Probe prepared from this subtracted library has been hybridised to a grid containing approximately 18,500 Embryonic Region library clones. Three novel clones have been recovered as well as expected genes already known to be highly expressed in the primitive endoderm lineage at this stage of development. In situ hybridisation to early postimplantation embryos has revealed the expression patterns of these novel genes. One is highly expressed exclusively in visceral endoderm, one is expressed in ectodermal and endodermal tissues, and the third proves to be an early marker of prospective and differentiated surface ectoderm as well as being expressed in endoderm and its derivatives.

Animals↗

PubMed1994

Pre treatment with MK-801, a non-competitive NMDA antagonist, prevents development of mechanical hyperalgesia in a rat model of chronic neuropathy, but not in a model of chronic inflammation.

In the rat, loose ligation of the sciatic nerve results in behavioural signs of hyperalgesia reminiscent of neuropathy in man. A further rat model, of chronic inflammatory hyperalgesia, is produced by intraplantar administration of Freund's complete adjuvant (FCA). We report here that preemptive administration of a non-competitive antagonist of the glutamate N-methyl-D-aspartate (NMDA) receptor, MK-801 (0.3 mg kg-1, s.c.) 30 min prior to and twice daily for a further 8 days following loose ligation of the sciatic nerve, blocks the development of mechanical hyperalgesia measured 27 days later. In contrast, MK-801 administration using the same dosing regimen did not significantly inhibit the hyperalgesia apparent 15 days following i.pl. administration of FCA. Our results suggest that the mechanisms responsible for the development of mechanical hyperalgesia associated with chronic nerve injury and chronic inflammation differ.

Animals↗

PubMed1994

Male-sterile phenotype of the neurological mouse mutant weaver.

The autosomal recessive murine mutation weaver (wv) affects postnatal differentiation in at least three neuronal populations in the brain: dopamine-containing neurons in the mid-brain, and granule and Purkinje cells in the cerebellum. Neuronal populations vulnerable to the actions of weaver die in the midst of development. In addition, homozygous weaver males are sterile. We show by a histological analysis of epididymides and testes that the cause of male sterility in weaver is lack of sperm. The epididymides of the adult weaver mice examined were devoid of sperm, and few seminiferous tubules in the adult weaver's testes contained elongated spermatids. Most tubules were marked by moderate to severe degeneration of the seminiferous epithelium. A developmental study showed that the mutant phenotype emerged after the third postnatal week. By postnatal day 28, the development of weaver sperm lagged behind that of the wild-type and some seminiferous tubules contained degenerating germ cells. By postnatal day 35, terminal differentiation of spermatids appeared to be arrested in many tubules and degeneration of the seminiferous epithelium was widespread. The heterozygotes were unaffected at all ages sampled. We conclude that the normal allele at the weaver locus is necessary for spermiogenesis and the maintenance of spermatogenesis.

Age Factors↗

PubMed1994

Ultra-slow voltage-dependent inactivation of the calcium current in guinea-pig and ferret ventricular myocytes.

L-type Ca2+ current, iCa, has been recorded in guinea-pig ventricular myocytes at 36 degrees C using the whole cell patch clamp technique. Intracellular Ca2+ was buffered with ethylenebis(oxonitrilo)tetraacetate (EGTA). An increase in the rate of stimulation from 0.5 to 3 Hz resulted in an abrupt decrease in iCa in the first beat at the high rate, followed by a progressive decrease (tau approx. 7 s) over the next 30 s. The changes were not the result of Ca(2+)-dependent inactivation, because similar changes occurred with either Ba2+ or Na+ as the charge carrier. During 20-s voltage clamp pulses there was an ultra-slow phase of inactivation of Ba2+ or Na+ current through the Ca2+ channel (tau approx. 6 s at 0 mV). This was confirmed by applying test pulses after conditioning pulses of different duration: the Ba2+ current during the test pulse decreased progressively when the duration of the conditioning pulse was increased progressively to 20 s. Ultra-slow inactivation of Ba2+ current was voltage dependent and increased monotonically at more positive potentials. Recovery of Ba2+ current from ultra-slow inactivation occurred with a time constant of 3.7 s at -40 mV and 0.7 s at -80 mV. The gradual decrease in iCa on increasing the rate to 3 Hz may have been the result of the development of ultra-slow voltage-dependent inactivation.

Animals↗

PubMed1994

Increased sensitivity to the antinociceptive activity of (+/-)-baclofen in an animal model of chronic neuropathic, but not chronic inflammatory hyperalgesia.

Modulation of sensory afferent inputs to the spinal cord by GABA appears to be an important physiological mechanism and may provide an antinociceptive control system. In the present study we have evaluated the antinociceptive activity of the GABAB receptor agonist, (+/-)-baclofen, in rats with unilateral chronic inflammatory or neuropathic hyperalgesia. (+/-)-Baclofen was antinociceptive in untreated control animals and both animal models. In the neuropathic model the sensitivity to (+/-)-baclofen was significantly increased by 3-fold in the ipsilateral limb. By contrast, in animals with chronic inflammation no difference in sensitivity between ipsilateral and contralateral limbs to (+/-)-baclofen was observed. Receptor autoradiographic analysis in spinal cord sections revealed no increase in the density of GABAB receptor binding sites and no change in receptor affinity in the neuropathic model.

Analgesics↗

PubMed1994

Effects of the Anemonia sulcata toxin (ATX II) on intracellular sodium and contractility in rat and guinea-pig myocardium.

The effects of the Anemonia sulcata toxin ATX II on action potentials and contractility of isolated papillary muscles and single myocytes from rat and guinea-pig hearts have been studied. ATX II prolonged the action potential in both rat and guinea-pig papillary muscle. Although it produced a positive inotropic effect in guinea-pig papillary muscle, it failed to do so in rat papillary muscle. However, in single rat and guinea-pig ventricular cells, it both prolonged the action potential and had a positive inotropic effect. We suggest that ATX II does not cause a positive inotropic effect in rat papillary muscle, because it induces Ca2+ overload. In single cells the positive inotropic effect was reduced by approximately 50% when the contractions were triggered by voltage clamp pulses of constant duration rather than by action potentials. This suggests that the inotropic effect of ATX II is in part the result of the prolongation of the action potential. The intracellular Na+ activity (a(i)Na) in single ventricular cells was measured with the Na(+)-sensitive fluorescent dye SBFI. After exposure of the cells to ATX II, a(i)Na was increased by a maximum of 1.9 +/- 0.3 and 2.2 +/- 0.3 mM in rat and guinea-pig cells, respectively. It is suggested that the positive inotropic effect of ATX II is also in part the result of the rise in a(i)Na.

Action Potentials↗

PubMed1994

Subcutaneous phycomycosis.

Subcutaneous phycomycosis, a uncommon fungal infection of the human skin, is discussed and a representative case is described. Subcutaneous phycomycosis is a chronic, progressive fungal infection of the deeper layers of the human skin that causes localized, mobile, firm and non-tender swellings. The causative organism is the Basidiobolus haptosporus, a fungus commonly found in rotting vegetation in the soil.

Child, Preschool↗

PubMed1993

Pre-emptive administration of clonidine prevents development of hyperalgesia to mechanical stimuli in a model of mononeuropathy in the rat.

Traumatic nerve injury in man can often result in the development of neuropathy. An animal model of neuropathic hyperalgesia is produced by loose ligation of the sciatic nerve in the rat. We have examined the effect of pre-emptive treatment with a number of drugs on the development of hyperalgesia in this model. Animals received clonidine (1 mg.kg-1, s.c.), morphine (5 mg.kg-1, s.c.), (+/-)-baclofen (40 mg.kg-1, s.c.), carbamazepine (50 mg.kg-1, s.c.) or vehicle (4 ml.kg-1, s.c.) 30 min prior to loose ligation or sham-operation. Morphine- and clonidine-treated animals were administered a second dose of drug 6h following surgery. Twenty-six or twenty-nine days following surgery, the ipsilateral (ipsi.) and contralateral (contra.) paw withdrawal thresholds were determined using an Algesymeter. In vehicle-treated animals the ipsilateral paw withdrawal threshold (118 +/- 7 g) was significantly lower (P < 0.0001, paired t-test) than the contralateral (195 +/- 7 g). In contrast, in animals pre-treated with clonidine no significant difference between ipsilateral (200 +/- 9 g) and contralateral (191 +/- 7 g) paw withdrawal thresholds was detected. Morphine pre-treatment was less effective in preventing development of hyperalgesia; however, whilst the ipsilateral (146 +/- 18 g) paw withdrawal threshold tended to be lower than the contralateral (183 +/- 8 g), this was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1993

A direct negative inotropic effect of acetylcholine on rat ventricular myocytes.

Acetylcholine (ACh) decreased the contraction of rat ventricular cells within 20 s. ACh (3.1 x 10(-8) M) produced a half-maximal effect and 10(-6) M ACh produced a maximal effect (a 23.8 +/- 5.4% decrease; mean +/- SE, n = 11). During a 3-min exposure to ACh, the inotropic effect faded. Parallel changes were observed in action potential duration: ACh caused an immediate shortening of the action potential, but then the effect faded with time. The changes in action potential duration were the cause of the changes in contraction, because ACh had no effect on contraction when the contractions were triggered by voltage-clamp pulses of constant duration. The changes in action potential duration were the result of the activation of a K+ current (iK,ACh) by ACh. During an exposure to ACh, this current faded as a result of desensitization. iK,ACh was 6.3 times smaller in ventricular than in atrial cells. This may explain why the negative inotropic effect of ACh on atrial cells was greater: 1.0 x 10(-8) M ACh produced a half-maximal effect on atrial cells, and 10(-6) M ACh produced a near maximal effect (a 74.5 +/- 9.5% decrease; n = 4).

Acetylcholine↗

PubMed1992

[Ca2+] and [Na+] in rat ventricular myocytes showing negative and positive force frequency relationships.

Ventricular cells that show a positive force-frequency relationship show graded changes of intracellular [Ca2+] (Cai), [Na+] (Nai) and sarcoplasmic reticulum Ca2+ content with changes of stimulation frequency. Cells that show a negative force-frequency relationship show smaller changes of Nai and no change in the Ca2+ load of the sarcoplasmic reticulum as stimulation frequency is changed.

Animals↗

PubMed1992

Protein phosphorylation in bovine adrenal medullary chromaffin cells: histamine-stimulated phosphorylation of tyrosine hydroxylase.

Histamine can cause the release of catecholamines from bovine adrenal medullary chromaffin cells by a mechanism distinct from that of the depolarizing agents nicotine or high K+ buffer. It was the aim of this study to determine the protein phosphorylation responses to histamine in these cells and to compare them with those induced by depolarization. A number of proteins showed increases in phosphorylation in response to histamine especially when analyzed on two-dimensional polyacrylamide gel electrophoresis or by phosphopeptide mapping; one protein of 20,000 daltons was markedly dephosphorylated. Emphasis was given to the effects of histamine on tyrosine hydroxylase (TOH) phosphorylation, because this protein showed the most prominent changes on one-dimensional gels. Histamine acted via H1 receptors to increase TOH phosphorylation; the response was blocked by the H1 antagonist mepyramine and could be mimicked by the H1 agonist thiazolylethylamine, but not by the H2 agonist dimaprit. The H3 agonist (R) alpha-methylhistamine increased TOH phosphorylation at high concentrations, but the response was blocked entirely by mepyramine. Histamine rapidly increased the phosphorylation of TOH, with a maximum reached within 5 s and maintained for at least 30 min. This was in marked contrast to nicotine-stimulated protein phosphorylation of TOH, which was rapidly desensitized. The initial phosphorylation response to histamine was independent of extracellular Ca2+ for at least 3 min, but the sustained response required extracellular Ca2+. This was in contrast to the situation with both nicotine and high K+ buffer, which under the conditions used here caused a response which was dependent on extracellular Ca2+ at all times investigated. In the presence of histamine, the phosphopeptide profiles for TOH were essentially the same with or without Ca2+, suggesting that the same protein kinases were involved, but at longer times there was evidence of new phosphorylation sites. The mechanism or mechanisms whereby histamine modulates TOH phosphorylation are discussed with emphasis on the differences from depolarizing agents.

Adrenal Medulla↗

PubMed1992

The non-peptide NK1 receptor antagonist, (+/-)-CP-96,345, produces antinociceptive and anti-oedema effects in the rat.

The non-peptide NK1 receptor antagonist, (+/-)-CP-96,345, has been evaluated for antinociceptive activity in two well-characterized inflammatory pain models in the rat. (+/-)-CP-96,345 abolished carrageenin-induced mechanical hyperalgesia, significantly reduced carrageenin-induced paw oedema and attenuated the second phase of the formalin response. The results suggest that NK1 receptor activation occurs during the induction of inflammatory pain states in the rat.

Analgesics↗

PubMed1992

GR94839, a kappa-opioid agonist with limited access to the central nervous system, has antinociceptive activity.

1. The pharmacological profile of GR94839, a kappa-opioid agonist with limited access to the central nervous system, has been investigated. Its antinociceptive activity has been compared with that of GR103545, a centrally-penetrating kappa-agonist and ICI204448, the previously described peripherally-selective kappa-agonist. 2. GR94839 was a potent agonist in the rabbit vas deferens in vitro assay for kappa-opioid receptors (IC50: 1.4 +/- 0.3 nM; n = 6), but had limited activity at mu- or delta-opioid receptors. 3. In the mouse abdominal constriction test, GR94839 was 238 fold more potent when given i.c.v. (ED50: 0.008 (0.004-0.029) mg kg-1; n = 18) than when s.c. (ED50: 1.9 (0.7-3.1) mg kg-1; n = 30). In comparison, GR103545 was equipotent when given i.c.v. or s.c. 4. After intravenous administration, the maximum plasma to brain concentration-ratio attained by GR94839 was 18 compared with 2 for GR85571, a structurally-related kappa-agonist that is centrally-penetrating. 5. GR94839 inhibited the 2nd phase of the rat formalin response at doses 7 fold lower than those required to inhibit the 1st phase (ED50 vs 1st phase: 10.2 (6.7-17.1) mg kg-1, s.c.; ED50 vs 2nd phase: 1.4 (1.0-1.8) mg kg-1, s.c.; n = 18). GR103545 was equipotent against the two phases. 6. Intraplantar administration of the opioid antagonists, norbinaltorphimine (100 micrograms) or naltrexone (1 microgram), reversed the antinociceptive effect of systemic GR94839 (3 mg kg-1, s.c.) against the 2nd phase of the formalin response and intraplantar injection of GR94839 (30-100 micrograms) selectively inhibited the 2nd phase.7. GR94839 and IC1204448 reversed the hyperalgesia in the zymosan-inflamed rat paw at doses (ED50 GR94839: 2.0 (1.1-3.2) mg kg-', s.c.; ED50 IC1204448: 1.2 (0.8-1.7) mg kg-', s.c.), lower than those required to raise the noxious pressure threshold in the non-inflamed paw (EDSO GR94839: 16.4 (8.6-46.7) mg kg', s.c.; ED50 IC1204448: 68.0 (22.1-32000) mg kg', s.c.). GR103545 raised the noxious presure threshold in the inflamed and non-inflamed paws at the same doses.8. GR94839 was sedative in the rat rotarod test (ED50: 35 (12-245) mg kg-', s.c.) at doses higher than those required to inhibit the 2nd phase of the formalin response or reverse hyperalgesia in the zymosan-inflamed rat paw. The doses were comparable to those that inhibited the 1st phase of the formalin response and raised the noxious pressure threshold in the non-inflamed paw.9. The results suggest that GR94839 is a selective kappa-agonist which has antinociceptive activity against inflammatory pain at doses that produce limited central effects. These antinociceptive effects are probably mediated at peripheral opioid receptors.

Analgesics↗

PubMed1992

The relationship between contraction and intracellular sodium in rat and guinea-pig ventricular myocytes.

1. The contraction, measured optically, and the intracellular Na+ activity (aNai), measured with the Na(+)-sensitive fluorescent dye SBFI, have been recorded simultaneously in rat and guinea-pig ventricular myocytes. 2. In rat and guinea-pig ventricular myocytes at rest, aNai was 7.8 +/- 0.3 mM (n = 4) and 5.1 +/- 0.3 mM (n = 16), respectively. 3. When both rat and guinea-pig ventricular myocytes were stimulated at 1 Hz after a rest there was usually a gradual increase in twitch shortening (referred to as a 'staircase') over several minutes accompanied by an increase in aNai over a similar time course. Twitch shortening increased by 21 +/- 3% (n = 6) and 20 +/- 4% (n = 16) (of steady-state twitch shortening during 1 Hz stimulation) per millimolar rise in aNai in rat and guinea-pig ventricular myocytes, respectively. 4. When rat and guinea-pig ventricular myocytes were exposed to strophanthidin to block the Na(+)-K+ pump, there were increases in twitch shortening and aNai over similar time courses. Twitch shortening increased by 24 +/- 4% (n = 5) and 20 +/- 3% (n = 10) (of control twitch shortening) per millimolar rise in aNai in rat and guinea-pig ventricular myocytes respectively. 5. The inotropic effect of cardiac glycosides, such as strophanthidin, is widely regarded to be principally the result of the rise in aNai. The similarity of the relation between twitch shortening and aNai during the staircase and on application of strophanthidin suggests that the progressive increase in the strength of contraction during the staircase was also linked to the rise in aNai. 6. In guinea-pig, but not rat, ventricular myocytes there was hysteresis in the relation between twitch shortening and aNai on application and wash-off of strophanthidin. This indicates that strophanthidin has another inotropic action in guinea-pig ventricular myocytes. 7. A computer model of excitation-contraction coupling has been developed to simulate the staircase and the action of cardiac glycoside and to account for the relation between contraction and intracellular Na+.

Animals↗

PubMed1992

Contraction and intracellular Ca2+, Na+, and H+ during acidosis in rat ventricular myocytes.

We have investigated the effect of a CO2-induced (respiratory) acidosis on contraction and on intracellular Ca2+, Na+, and pH (measured using the fluorescent dyes fura-2, sodium-binding benzofuran isophthalate, and 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein, respectively) in ventricular myocytes isolated from rat hearts. Initial exposure to acidosis led to a rapid decrease in intracellular pH that was accompanied by an abrupt decline in contractility. There were no consistent changes of intracellular Na+ or Ca2+ during this period. The rapid decline of contractility was followed by a slower partial recovery, which was accompanied by increases in intracellular Na+, systolic and diastolic Ca2+, and an increase in the Ca2+ content of the sarcoplasmic reticulum (estimated using caffeine). Intracellular pH did not change during this slow recovery. The slow rise of intracellular Na+ and the recovery of the twitch were blocked by the Na(+)-H+ exchange inhibitor amiloride. The sarcoplasmic reticulum inhibitor ryanodine blocked the recovery of the twitch but had no effect on the rise of intracellular Na+ induced during acidosis. It is concluded that a major cause of the initial decline of the twitch during acidosis is a decrease in the response of the contractile proteins to Ca2+ due to the decrease of intracellular pH. The subsequent slow recovery of the twitch is due to the decrease of intracellular pH activating the Na(+)-H+ exchange mechanism. This elevates intracellular Na+ and presumably, via the Na(+)-Ca2+ exchange mechanism, intracellular Ca2+. This in turn may lead to increased Ca2+ loading of, and hence release from, the sarcoplasmic reticulum, and it is this that underlies the partial recovery of contraction during acidosis in this preparation.

Acidosis↗

PubMed1991

Prevalence of serum antibody to the type-specific glycopeptidolipid antigens of Mycobacterium avium in human immunodeficiency virus-positive and -negative individuals.

An enzyme-linked immunosorbent assay was constructed by using as antigens the type-specific immunodominant glycopeptidolipids of selected serotypes of Mycobacterium avium. This assay system was used to determine the prevalence of raised antibody levels to these antigens in groups of controls, human immunodeficiency (HIV)-negative and -positive homosexual men, and HIV-negative patients with active M. avium infections as a possible indicator of potential exposure and/or colonization by M. avium in these individuals. The results indicate that while antibody levels were raised in only 2.4% of control individuals, 33% of HIV-negative homosexual men and 44% of HIV-positive patients exhibited raised levels. Moreover, further examination of the HIV-positive group revealed no correlation between antiglycopeptidolipid antibody activity and helper T cell numbers. These data indicate that exposure to M. avium is prevalent among the homosexual male population, regardless of their HIV status. Moreover, the data are suggestive that the emergence of disseminated M. avium disease in HIV-positive patients may sometimes arise from earlier colonization, rather than as a newly acquired infection during terminal immunodeficiency.

Adult↗

PubMed1991

Citrate decreases contraction and Ca current in cardiac muscle independent of its buffering action.

Extracellular Ca (Cao) depletions that occur during cardiac muscle contractions are indicative of net Ca entry. Buffering Cao concentration ([Ca]o) with citrate can limit the magnitude of these Cao depletions [e.g., Shattock and Bers. Am. J. Physiol. 256 (Cell Physiol. 25): C813-C822, 1989] which theoretically would allow more Ca entry and consequently greater force at the same free [Ca]o. However, Shimoni and Ginsburg [Am. J. Physiol. 252 (Cell Physiol. 21): C248-C252, 1987] have shown that citrate inhibits cardiac contractions and suggested that this was due to its Ca-buffering action (i.e., dissipating a local elevation of [Ca] at the outer sarcolemmal surface and thereby decreasing Ca influx). To examine the effects of Ca buffering per se, we compared the effects of four low-affinity Ca buffers [citrate, nitrilotriacetic acid (NTA), dipicolinic acid (DPA), and acetamidoiminodiacetic acid (ADA)] on several cardiac preparations. In Mg-free medium with 2 mM free Ca (measured using murexide), citrate, DPA, and ADA (10 mM) decreased the force of twitch contractions in rabbit ventricle to 76 +/- 2, 60 +/- 2, and 85 +/- 2%, respectively, but 10 mM NTA increased force slightly to 105 +/- 2%. No simple correlation was observed between the Ca affinity of the buffer and its effect on tension. These effects were not due to changes in sarcoplasmic reticulum (SR) Ca loading because rapid cooling contractures were not affected and similar results were observed in the presence of caffeine or ryanodine. The depressant effects of citrate and ADA on tension were greater at pH 5.5-6 and ADA had no effect at pH 8.5. Thus the depressant effect is stronger with more protonated forms of citrate and ADA, which are also poorer Ca buffers. Citrate (but not NTA) decreased Ca current in whole cell voltage clamp and shifted the current-voltage relationship and reversal potential to more negative potentials. Citrate decreased Ca current more effectively at higher citrate and lower Ca concentrations. We conclude that citrate (and some other weak Ca buffers) may directly decrease Ca current and contraction in a manner independent of Ca buffering ability.

Action Potentials↗