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At least 703 records · Page 39Linked to original sources
PubMed1995

Central GABA-A receptors exert a tonic inhibitory control on gastric pepsinogen secretion in anaesthetized rats.

1. The purpose of the present study was to analyse the role played by central gamma-aminobutyric acid (GABA-A) receptors in the regulation of gastric basal pepsinogen secretion in anaesthetized rats. 2. The central, but not parenteral, administration of the GABA-A receptor antagonist bicuculline or SR-95531 caused a significant and dose-dependent increase in basal pepsinogen secretion without changes in acid output. The stimulant effect exerted by bicuculline was prevented by atropine or pirenzepine, but not by vagotomy. 3. The central, but not parenteral, administration of the GABA-A receptor agonist muscimol or THIP induced a significant and dose-dependent stimulation of both basal pepsinogen and acid secretion. The excitatory effect exerted by muscimol was prevented by atropine, pirenzepine, or pretreatment with omeprazole, but not by vagotomy. 4. These results suggest that central GABA-A receptors mediate a tonic inhibitory control on gastric pepsinogen secretion, while their phasic activation leads to an excitatory effect on acid output. However, the agonist-induced pepsigogue action appears to be generated peripherally as an indirect consequence of the increase in acid secretion. 5. It is also suggested that central GABA-A receptors affect the gastric secretory functions through non-vagal pathways that are sensitive to the blockade of peripheral cholinergic receptors.

Anesthesia↗
PubMed1998

Review of exertional rhabdomyolysis and a case in a rhesus monkey (Macaca mulatta).

This is the first confirmed report of exertional rhabdomyolysis in a non-human primate. The monkey was singly housed and presented with anorexia and reluctance to move. There was no external evidence of trauma. Clinicopathologic findings included mild azotemia, marked elevation in serum creatine phosphokinase (CPK), alanine aminotransferase, aspartate aminotransferase, and myoglobinuria. Two days post-incident, the peripheral skeletal muscle had marked multifocal myonecrosis and fibrillar disruption without an inflammatory reaction. Treatment included diuresis and pain relief, and urinary output was monitored. The monkey recovered over the next two weeks. The major significance of skeletal muscle damage is the potential of released myoglobin to cause acute renal failure in the presence of other co-factors such as hypovolemia, acidosis, or ischemia. CPK levels can be highly variable and are inconsistent with the degree of muscle damage; however, CPK is thought to be the most sensitive enzyme marker for muscle necrosis. Because of the potential life-threatening sequelae, exertional rhabdomyolysis should be included as a differential diagnosis when similar clinical and pathological signs are observed.

Alanine Transaminase↗
PubMed1999

Exertional rhabdomyolysis in quarter horses and thoroughbreds: one syndrome, multiple aetiologies.

The purpose of this study was to determine if chronic exertional rhabdomyolysis (ER) in Quarter Horses and Thoroughbreds represents one or several distinct myopathies. Eighteen Quarter Horses and 18 Thoroughbreds with ER were selected from cases presented to the Veterinary Hospital on the basis of a history of ER, assessment of muscle histopathology, and serum CK activity before and 4 h post exercise. In addition, 2 of 3 of the following parameters were evaluated: muscle glycogen concentrations, thyroid hormones (T3, T4), fractional excretion (FE) of sodium, potassium and chloride. The CK response to training, the metabolic response to a near maximal standardised exercise test (SET), blood glucose concentrations after an i.v. glucose challenge and a skeletal muscle in vitro caffeine contracture test were performed on 5 of the Quarter Horses, selected because of polysaccharide storage myopathy (PSSM), and 5 of the Thoroughbreds. Serum T3 and T4 were all within normal limits. Low FE of sodium and potassium were seen in < 20% of Quarter Horses and Thoroughbreds. Four hours post exercise, CK was increased in 77% of Quarter Horses and 72% of Thoroughbreds with ER. Muscle glycogen concentrations in Quarter Horses with ER were significantly higher than in normal Quarter Horses and Thoroughbreds with ER. No Thoroughbreds, but 15/18 Quarter Horses with ER had abnormal polysaccharide accumulation in muscle biopsies consistent with a diagnosis of PSSM. PSSM Quarter Horses had higher CK activity during training than Thoroughbreds and higher glycogen utilisation with the SET. PSSM Quarter Horses also had significantly enhanced glucose clearance compared to normal Quarter Horses and Thoroughbreds with ER. Thoroughbreds with ER had significantly lower thresholds for caffeine-induced contracture than normal horses and PSSM Quarter Horses. It was concluded that there are multiple causes for exertional rhabdomyolysis. In Quarter Horses, rhabdomyolysis is commonly due to a glycogen storage disorder, PSSM, and is readily expressed in untrained horses. In Thoroughbreds, ER is commonly due to an underlying abnormality of muscle contraction. Rhabdomyolysis in Thoroughbreds, however, is only expressed intermittently when key stressors are present.

Animals↗
PubMed2002

Symmetry of discrete and oscillatory elbow movements: does it depend on torque that the agonist and antagonist muscle can exert?

The hypothesis that strength of active muscles affects the symmetry of the velocity profiles of voluntary movements was tested. In particular, it was assumed that the duration of acceleration and deceleration phases reflects the ability of the antagonistic muscles to exert torque in such a way that stronger muscle requires less time for action. Twelve subjects performed consecutive 50 flexions and extensions in blocks of either discrete or oscillatory movements. They were tested under high and moderate speed conditions, as well as within different ranges of elbow joint angles. The symmetry ratio (SR; acceleration time divided by deceleration time) was calculated in order to assess movement symmetry. The results demonstrated SR > 1 under most of the discrete and, particularly, oscillatory movement conditions. A velocity-associated increase in SR was recorded, while different ranges of elbow movements, assumed to provide different torques of the agonist and antagonist muscles, also provided different SR. The findings were generally in line with the predicted effects of movement conditions on muscle strength, particularly those related to elbow angle and elbow angular velocity. Deviations from the ideal movement symmetricity have usually been interpreted as either weakness of various motor control models and hypotheses, or as a sub-optimal control of movements in certain subject populations; the present study suggests an alternative interpretation based upon the ability of active muscles to exert torque

Adult↗
PubMed1967

Cell division: direct measurement of maximum tension exerted by furrow of echinoderm eggs.

Tensions exerted by cleavage furrows in isometric contraction were measured by means of flexible glass needles whose characteristics of bending had already been determined. The tension of Astriclypeus manni furrows in second division is 3.04 x 10(-3) +/- 0.95 x 10(-3) dyne; that for Pseudocentrotus depressus eggs in first division is 2.00 X 10(-3) +/- 0.43 x 10(-3) dyne. The tension required for cleavage probably does not exceed 1.5 x 10(-3) dyne. According to existing morphological evidence, these values can be accounted for by a substance whose capacity for exerting tension does not exceed that of an actomyosin thread.

Animals↗
PubMed1999

Optical measurements of invasive forces exerted by appressoria of a plant pathogenic fungus

Many plant pathogenic fungi, such as the cereal pathogen Colletotrichum graminicola, differentiate highly specialized infection structures called appressoria, which send a penetration peg into the underlying plant cell. Appressoria have been shown to generate enormous turgor pressure, but direct evidence for mechanical infection of plants by fungi is lacking. A microscopic method was developed that uses elastic optical waveguides to visualize and measure forces locally exerted by single appressoria. By this method, the force exerted by appressoria of C. graminicola was found to be about 17 micronewtons.

Journal Article↗
PubMed2002

Synthetic peptides that exert antimicrobial activities in whole blood and blood-derived matrices.

Peptides that exert antimicrobial activity in artificial media may lack activity within blood or other complex biological matrices. To facilitate the evaluation of antimicrobial peptides for possible therapeutic utility, an ex vivo assay was developed to assess the extent and durability of peptide antimicrobial activities in complex fluid biomatrices of whole blood, plasma, and serum compared with those in conventional media. Novel antimicrobial peptides (RP-1 and RP-11) were designed based in part on platelet microbicidal proteins. RP-1, RP-11, or gentamicin was introduced into biomatrices either coincident with, or 2 h prior to, inoculation with an Escherichia coli target organism. Antimicrobial activities of peptides were assessed by quantitative culture 2 h after bacterial inoculation and compared to those of peptide-free and gentamicin controls. In whole blood and homologous plasma or serum, introduction of RP-1 or RP-11 coincident with E. coli was associated with a significant reduction in CFU per milliliter versus the respective peptide-free controls. Moreover, substantial antimicrobial activity remained when RP-1 or RP-11 was placed into whole blood or plasma 2 h prior to E. coli inoculation. These results suggest that the peptides were not rapidly inactivated within these biomatrices. Peptide antimicrobial activities were negatively affected by preincubation in serum or in heat-inactivated serum, compared with those of the respective controls. Peptides RP-1 and RP-11 were consistently effective at lower concentrations in biomatrices than in artificial media, indicating favorable antimicrobial interactions with components of blood or blood fractions. Collectively, these findings support the concept that synthetic peptides can be designed to exert potent antimicrobial activities in relevant and complex biological matrices.

Anti-Bacterial Agents↗
PubMed1997

Antagonistic activity exerted in vitro and in vivo by Lactobacillus casei (strain GG) against Salmonella typhimurium C5 infection.

The aim of this study was to compare the antagonistic properties of Lactobacillus casei GG exerted in vitro against Salmonella typhimurium C5 in a cellular model, cultured enterocyte-like Caco-2 cells, to those exerted in vivo in an animal model, C3H/He/Oujco mice. Our results show that a 1-h contact between the invading strain C5 and either the culture or the supernatant of L. casei GG impeded the invasion by the Salmonella strain in Caco-2 cells, without modifying the viability of the strain. After neutralization at pH 7, no inhibition of the invasion by C5 was observed. The antagonistic activity of L. casei GG was examined in C3H/He/Oujco mice orally infected with C5 as follows: (i) L. casei GG was given daily to conventional animals as a probiotic, and (ii) it was given once to germ-free animals in order to study the effect of the population of L. casei GG established in the different segments of the gut. In vivo experiments show that after a single challenge with C5, this strain survives and persists at a higher level in the feces of the untreated conventional mice than in those of the treated group. In L. casei GG germ-free mice, establishment of L. casei GG in the gut significantly delayed the occurrence of 100% mortality of the animals (15 days after C5 challenge versus 9 days in germ-free mice [P < 0.01]). Cecal colonization level and translocation rate of C5 to the mesenteric lymph nodes, spleen, and liver were significantly reduced during the first 2 days post-C5 challenge, although the L. casei GG population level in the gut dramatically decreased in these animals.

Animals↗
PubMed2002

Exertion of the suppressive effects of IFN-gamma on experimental immune mediated blepharoconjunctivitis in Brown Norway rats during the induction phase but not the effector phase.

BACKGROUND/AIMS: Interferon gamma (IFN-gamma) knockout mice exhibit severe allergic conjunctivitis (AC), indicating that IFN-gamma regulates the development of AC. The authors examined whether this inhibitory effect of IFN-gamma is exerted during the induction or effector phase of experimental AC. METHODS: Experimental immune mediated blepharoconjunctivitis (EC) was induced in Brown Norway (BN) rats, using ovalbumin (OVA) as the antigen. To investigate the role of IFN-gamma in the induction phase, EC was induced by active immunisation and IFN-gamma (10 micro g/time, total 70 micro g), or phosphate buffered saline (PBS) as a control, was injected intraperitoneally every other day from the day of immunisation. The rats were challenged with OVA eye drops 13 days after immunisation, and 24 hours later, the eyes were harvested for histology. To examine the effects of IFN-gamma in the effector phase, OVA specific T cells were transferred into syngeneic rats and IFN-gamma (10 micro g/time, total 50 micro g) or PBS was injected each day after the transfer until induction of EC 4 days later with an OVA challenge. To investigate the role of endogenous IFN-gamma during the effector phase, an anti-IFN-gamma monoclonal antibody (3 mg/time) was injected on days 3 and 4. RESULTS: Injection of IFN-gamma into actively immunised rats suppressed eosinophilic infiltration but not infiltration of mononuclear cells. In contrast, neither IFN-gamma nor anti-IFN-gamma affected EC in passively immunised rats. CONCLUSION: IFN-gamma is a suppressive cytokine for the development of EC and exerts this suppressive effect during the induction phase.

Adoptive Transfer↗
PubMed2002

A comparison of physiological responses and rating of perceived exertion in two modes of aerobic exercise in men and women over 50 years of age.

OBJECTIVES: To compare the physiological responses and ratings of perceived exertion to aerobic dance and walking sessions completed at a self selected pace. METHODS: Six women and six men with a sample mean (SD) age of 68 (7) years completed aerobic dance and walking sessions in random order. A treadmill test was performed by each subject from which peak oxygen uptake (.VO(2)) and maximum heart rates (HRmax) were determined. During the aerobic dance and walking sessions, heart rate and .VO(2) were measured continuously throughout. Rate of perceived exertion (RPE) was measured every three minutes throughout the session. RESULTS: The sample means (SD) for %peak .VO(2) were 67 (17)% for the aerobic dance sessions and 52 (10)% for the walking sessions, and the %HRmax sample means (SD) were 74 (12)% for the aerobic dance sessions and 60(8)% for walking sessions. The sample mean (SD) RPE for the aerobic dance sessions was 11(2), and for the walking sessions it was 10(2). CONCLUSIONS: %peak .VO(2), %HRmax, and RPE were significantly higher for aerobic dance than for walking. However, both the aerobic dance and walking sessions were of adequate intensity to improve aerobic fitness in most subjects. Further investigation into the relation between RPE and %peak .VO(2) in a field setting over representative exercise time periods would be useful.

Aged↗
PubMed2000

Bifidobacterium strains from resident infant human gastrointestinal microflora exert antimicrobial activity.

BACKGROUND AND AIMS: The gastrointestinal microflora exerts a barrier effect against enteropathogens. The aim of this study was to examine if bifidobacteria, a major species of the human colonic microflora, participates in the barrier effect by developing antimicrobial activity against enterovirulent bacteria. METHODS: Antibacterial activity was examined in vitro against a wide range of Gram negative and Gram positive pathogens. Inhibition of Salmonella typhimurium SL1334 cell association and cell invasion was investigated in vitro using Caco-2 cells. Colonisation of the gastrointestinal tract in vivo by bifidobacteria was examined in axenic C3/He/Oujco mice. Antimicrobial activity was examined in vivo in axenic C3/He/Oujco mice infected by the lethal S typhimurium C5 strain. RESULTS: Fourteen human bifidobacterium strains isolated from infant stools were examined for antimicrobial activity. Two strains (CA1 and F9) expressed antagonistic activity against pathogens in vitro, inhibited cell entry, and killed intracellular S typhimurium SL1344 in Caco-2 cells. An antibacterial component(s) produced by CA1 and F9 was found to be a lipophilic molecule(s) with a molecular weight of less than 3500. In the axenic C3/He/Oujco mice, CA1 and F9 strains colonised the intestinal tract and protected mice against S typhimurium C5 lethal infection. CONCLUSION: Several bifidobacterium strains from resident infant human gastrointestinal microflora exert antimicrobial activity, suggesting that they could participate in the "barrier effect" produced by the indigenous microflora.

Animals↗
PubMed2002

Intraduodenal conjugated bile salts exert negative feedback control on gall bladder emptying in the fasting state without affecting cholecystokinin release or antroduodenal motility.

BACKGROUND: Intraduodenal bile salts exert negative feedback control on postprandial gall bladder emptying. AIMS: We wished to examine whether a similar control mechanism occurs in the fasting state. METHODS: Intraduodenal bile salt depletion was achieved by 12 g of cholestyramine. Thereafter, in study A (seven subjects), the effects on gall bladder volume (by ultrasound) and antroduodenal motility of intraduodenal infusions of taurocholate egg yolk-phosphatidylcholine micelles were assessed. In study B (nine subjects), the effects on gall bladder volume of infusing mixed micelles composed of taurocholate (100 mM) and low (26 mM) or high (68 mM) amounts of egg yolk-phosphatidylcholine, or low amounts of dipalmitoylphosphatidylcholine were determined. RESULTS: Cholestyramine induced strong and prolonged gall bladder contraction without cholecystokinin release. In study A, micellar infusions increased gall bladder volume without affecting migrating motor complex cycle length. In study B, intraduodenal infusion induced strong increases in gall bladder volume in the case of taurocholate micelles containing low amounts of egg yolk-phosphatidylcholine, moderate increases in micelles containing low amounts of dipalmitoylphosphatidylcholine but no change in micelles containing high amounts of egg yolk-phosphatidylcholine, in all cases without altered plasma cholecystokinin levels. Phosphatidylcholine hydrolysis was significantly higher after infusion of egg yolk-phosphatidylcholine compared with infusion of dipalmitoylphosphatidylcholine containing micelles. Intermixed micellar-vesicular bile salt concentrations (responsible for detergent effects) were higher in egg yolk-phosphatidylcholine than in dipalmitoylphosphatidylcholine containing model biles and if lyso-phosphatidylcholine was included. CONCLUSIONS: Intraduodenal bile salts exert negative feedback on fasting gall bladder volume. The modulating effects of various phospholipids may relate to their effects on intermixed micellar-vesicular bile salt concentrations.

Adult↗
PubMed1994

Gastroesophageal reflux in patients with angiographically normal coronary arteries: an uncommon cause of exertional chest pain.

OBJECTIVES: To investigate the association between exertional chest pain and gastroesophageal reflux in patients with normal coronary angiograms and in controls by measuring oesophageal pH during treadmill exercise tests and to compare the results with routine ambulatory monitoring. DESIGN: Case control study. SETTING: Tertiary referral cardiac unit. PATIENTS: 50 consecutive patients with chest pain and completely normal coronary angiograms and 16 controls with coronary artery stenoses. MAIN OUTCOME MEASURES: Episodes of acid reflux and chest pain during treadmill exercise; a symptom index expressing the percentage of episodes of pain related to acid reflux during ambulatory monitoring. RESULTS: Four (8%) patients and two (12%) controls had reflux during treadmill exercise (NS). 32 (64%) and 16 (100%) reported chest pain, but only three (6%) and two (12%) had coincident reflux (NS). Reflux was as frequent before, during, and after treadmill exercise (five (8%) v six (9%) v two (3%)) in the 66 subjects; (NS). 19 (38%) patients and three (19%) controls had abnormal reflux on ambulatory monitoring (NS). Eight (16%) and three (19%) had a symptom index > 50%, but six and two of these reported pain without coincident reflux during treadmill exercise. CONCLUSION: There are many potential causes of chest pain in patients with angiographically normal coronary arteries. Although gastroesophageal reflux is commonly implicated and many patients have a high incidence of spontaneous reflux during ambulatory monitoring, it rarely occurs during exertion and the association with chest pain is poor.

Adult↗
PubMed2001

Complement factor C5a exerts an anti-inflammatory effect in acute pancreatitis and associated lung injury.

Complement factor C5a acting via C5a receptors (C5aR) is recognized as an anaphylotoxin and chemoattractant that exerts proinflammatory effects in many pathological states. The effects of C5a and C5aR in acute pancreatitis and in pancreatitis-associated lung injury were evaluated using genetically altered mice that either lack C5aR or do not express C5. Pancreatitis was induced by administration of 12 hourly injections of cerulein (50 microg/kg ip). The severity of pancreatitis was determined by measuring serum amylase, neutrophil sequestration in the pancreas, and acinar cell necrosis. The severity of lung injury was evaluated by measuring neutrophil sequestration in the lung and pulmonary microvascular permeability. In both strains of genetically altered mice, the severity of pancreatitis and pancreatitis-associated lung injury was greater than that noted in the comparison wild-type strains of C5aR- and C5-sufficient animals. This exacerbation of injury in the absence of C5a function indicates that, in pancreatitis, C5a exerts an anti-inflammatory effect. Potentially, C5a and its receptor are capable of both promoting and reducing the extent of acute inflammation.

Acute Disease↗
PubMed2001

Perceived exertion is associated with an altered brain activity during exercise with progressive hyperthermia.

The present study tested the hypothesis that perceived exertion during prolonged exercise in hot environments is associated with changes in cerebral electrical activity rather than changes in the electromyogram (EMG) of the exercising muscles. Therefore, electroencephalogram (EEG) in three positions (frontal, central, and occipital cortex), EMG, rating of perceived exertion (RPE), and core temperature were measured in 14 subjects during submaximal exercise in normal (18 degrees C, control) and hot (40 degrees C, hyperthermia) environments. RPE increased from 11 +/- 1 units at 5 min to 20 +/- 0 units at exhaustion (50 +/- 3 min) in the trial with progressive hyperthermia, whereas exercise in the control trial was maintained with a stable core temperature for 1 h without exhausting the subjects. Altered EEG activity was observed in all electrode positions, and stepwise forward-regression analysis identified core temperature and a frequency index of the EEG over the frontal cortex as the best predictors of RPE. In contrast, there were no significant correlations between RPE and any of the measured EMG parameters (median spectral frequency, root mean square, or amplitude), and the EMG parameters were not different in hyperthermia compared with control. Thus hyperthermia does not seem to affect the activation pattern of the muscles. Rather, the linear correlation among core temperature, EEG frequency index, and RPE indicates that alterations in cerebral activity may be associated with the hyperthermia-induced development of fatigue during prolonged exercise in hot environments.

Adult↗
PubMed2005

Adenosine down-regulates giant depolarizing potentials in the developing rat hippocampus by exerting a negative control on glutamatergic inputs.

Adenosine is a widespread neuromodulator that can be directly released in the extracellular space during sustained network activity or can be generated as the breakdown product of adenosine triphosphate (ATP). Whole cell patch-clamp recordings were performed from CA3 principal cells and interneurons in hippocampal slices obtained from P2-P7 neonatal rats to study the modulatory effects of adenosine on giant depolarizing potentials (GDPs) that constitute the hallmark of developmental networks. We found that GDPs were extremely sensitive to the inhibitory action of adenosine (IC(50) = 0.52 microM). Adenosine also contributed to the depressant effect of ATP as indicated by DPCPX-sensitive changes of ATP-induced reduction of GDP frequency. Similarly, adenosine exerted a strong inhibitory action on spontaneous glutamatergic synaptic events recorded from GABAergic interneurons and on interictal bursts that developed in CA3 principal cells after blockade of gamma-aminobutyric acid type A (GABA(A)) receptors with bicuculline. All these effects were prevented by DPCPX, indicating the involvement of inhibitory A1 receptors. In contrast, GABAergic synaptic events were not changed by adenosine. Consistent with the endogenous role of adenosine on network activity, DPCPX per se increased the frequency of GDPs, interictal bursts, and spontaneous glutamatergic synaptic events recorded from GABAergic interneurons. Moreover, the adenosine transport inhibitor NBTI and the adenosine deaminase blocker EHNA decreased the frequency of GDPs, thus providing further evidence that endogenous adenosine exerts a powerful control on GDP generation. We conclude that, in the neonatal rat hippocampus, the inhibitory action of adenosine on GDPs arises from the negative control of glutamatergic, but not GABAergic, inputs.

Action Potentials↗
PubMed1988

Androgens exert selective effects on protein kinase C induced LH and FSH release in rat anterior pituitary cells in culture.

This study compares the selective effect of androgens on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release induced either by LH-releasing hormone (LH-RH) or by protein kinase C activation in rat anterior pituitary cells in culture. In control cells, phorbol-12-myristate-13-acetate (PMA) stimulated the release of radioimmunoassayable LH and FSH in a dose-dependent manner at an ED50 value of 5.95 +/- 1.45 nM. The maximal release of gonadotropins induced during a 3-hour incubation with PMA was 40-60% of that induced by LH-RH. Preincubation of the cells for 2-4 days with 10 nM 5 alpha-dihydrotestosterone (DHT) decreased by approximately 60% the subsequent release of LH induced by 100 nM LH-RH or by 500 nM PMA during a subsequent 3-hour incubation. The inhibitory effect of DHT was completely suppressed by coincubation with the antiandrogen hydroxyflutamide. DHT exerted a similar inhibitory effect on LH release induced by another stimulator of protein kinase C activity, namely 1-oleoyl-2-acetylglycerol. The potent inhibitory action of DHT on LH-RH- or PMA-induced LH release was exerted at an ED50 value of approximately 10 pM. Contrary to the effect on LH, the FSH response to LH-RH or to PMA was increased by preincubation with 2 nM DHT, the stimulatory effect of the androgen being completely antagonized by hydroxyflutamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗
PubMed2003

Insulin-like growth factor-1 exerts Ca2+-dependent positive inotropic effects in failing human myocardium.

Myocardial generation of insulin-like growth factor-1 (IGF-1) is altered in hypertrophy and heart failure, but there are no reports on acute functional effects of IGF-1 in human cardiac muscle. We examined inotropic responses and signal transduction mechanisms of IGF-1 in human myocardium. Experiments were performed in isolated trabeculae or cardiomyocytes from 46 end-stage failing hearts. The effect of IGF-1 (0.001 to 0.2 micromol/L) on isometric twitch force (37 degrees C, 1 Hz), intracellular Ca2+ transients (aequorin method), sarcoplasmic reticulum (SR) Ca2+ content (rapid cooling contractures), L-type Ca2+ current (whole-cell voltage clamp), and cAMP concentrations was assessed. In addition, the effects of blocking IGF-1 receptors, phosphoinositide 3-kinase (PI3-kinase), protein kinase C (PKC), or transsarcolemmal Ca2+ entry were tested. IGF-1 exerted concentration-dependent positive inotropic effects (twitch force increased to maximally 133+/-4% of baseline values at 0.1 micromol/L; P<0.05). The IGF-1 receptor antibody alphaIR3 or the PI3-kinase inhibitor wortmannin prevented the functional effects. The inotropic response was paralleled by increases in Ca2+ transients and SR Ca2+ content. IGF-1 (0.1 micromol/L) increased L-type Ca2+ current amplitude by 24+/-7% (P<0.05). Blockade of SR function did not affect the inotropic response to IGF-1. In contrast, L-type Ca2+ channel blockade with diltiazem partially prevented ( approximately 50%) the inotropic response to IGF-1. Inhibition of PKC (GF109203X), Na+-H+ exchange (HOE642), or reverse-mode Na+-Ca2+ exchange (KB-R7943) reduced the response to IGF-1 by approximately 60% to 70%. IGF-1 exerts Ca2+-dependent positive inotropic effects through activation of IGF-1 receptors and a PI3-kinase-dependent pathway in failing human myocardium. The increased [Ca2+]i with IGF-1 originates from both enhanced L-type Ca2+ currents and enhanced Na+-H+ exchange-dependent reverse-mode Na+-Ca2+ exchange. These nongenomic functional effects of IGF-1 may be of clinical relevance.

Calcium↗