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PubMed1992

Comparison of amplitude of human soleus H-reflex during sitting and standing.

The modulation of the H-reflex in the human soleus muscle under conditions of different length or of background EMG activity was compared in 7 healthy subjects under three conditions: sitting, standing with support, and standing without support. The amplitude of the H-reflex increased when the muscle was shortened in both the sitting and standing conditions. The degree of increase in H-reflex was smaller during standing than sitting for the same change in muscle length. The H-reflex was augmented according to the increase of the background EMG. The "reflex gain", the ratio of the increase in amplitude of the H-reflex to soleus muscle EMG activity, decreased on sitting, standing with support and standing without support, ranked in that order. From these observations, it is concluded that the H-reflex is modulated by both muscle length and the degree of postural stability. The modulation of the reflex could be interpreted in terms of gain compensation and would serve to stabilize posture. A decrease in reflex gain may be appropriate in stabilizing the spinal reflex feedback loop during standing, especially without support.

Adult↗

PubMed1996

A collaborative project in Connecticut to improve the care of patients with acute myocardial infarction.

BACKGROUND: State-based peer review organizations (PROs) and individual hospitals are challenged to achieve their quality improvement (QI) goals with shrinking resources. In 1993-1994 the Connecticut PRO and 15 local hospitals generated a comparative QI database on acute myocardial infarction (AMI) care for 1,202 Medicare and non-Medicare patients discharged in 1992 and 1993. METHODS: A steering committee composed of hospital and PRO representatives was assembled to provide oversight. PRO staff developed a chart abstraction tool and trained hospital abstractors who collected and submitted data to the PRO for comparative analyses. Written feedback was provided to all hospitals and supplemented with onsite presentations when requested. Each hospital prepared a written QI plan based on its unique data profile. RESULTS: Opportunities for improvement were identified at all hospitals. The most commonly targeted areas for improvement included the use of thrombolytics at presentation, aspirin at presentation and at discharge, and beta blockers at discharge. Improvement interventions included staff education sessions, development of AMI critical paths and standing orders, and storage of appropriate medications in emergency departments. Self-report data from the hospitals indicate improvements in care. DISCUSSION: PROs and hospitals can augment their individual QI activities by working together to share data, resources, and lessons learned. Twenty-three hospitals are now collaborating with the Connecticut PRO on a similarly designed QI project aimed at improving the care of patients hospitalized with atrial fibrillation. This project includes a more formal means of communicating QI interventions.

Aged↗

PubMed1999

Photothermal effects of laser tissue soldering.

Low-strength anastomoses and thermal damage of tissue are major concerns in laser tissue welding techniques where laser energy is used to induce thermal changes in the molecular structure of the tissues being joined, hence allowing them to bond together. Laser tissue soldering, on the other hand, is a bonding technique in which a protein solder is applied to the tissue surfaces to be joined, and laser energy is used to bond the solder to the tissue surfaces. The addition of protein solders to augment tissue repair procedures significantly reduces the problems of low strength and thermal damage associated with laser tissue welding techniques. Investigations were conducted to determine optimal solder and laser parameters for tissue repair in terms of tensile strength, temperature rise and damage and the microscopic nature of the bonds formed. An in vitro study was performed using an 808 nm diode laser in conjunction with indocyanine green (ICG)-doped albumin protein solders to repair bovine aorta specimens. Liquid and solid protein solders prepared from 25% and 60% bovine serum albumin (BSA), respectively, were compared. The efficacy of temperature feedback control in enhancing the soldering process was also investigated. Increasing the BSA concentration from 25% to 60% greatly increased the tensile strength of the repairs. A reduction in dye concentration from 2.5 mg ml(-1) to 0.25 mg ml(-1) was also found to result in an increase in tensile strength. Increasing the laser irradiance and thus surface temperature resulted in an increased severity of histological injury. Thermal denaturation of tissue collagen and necrosis of the intimal layer smooth muscle cells increased laterally and in depth with higher temperatures. The strongest repairs were produced with an irradiance of 6.4 W cm(-2) using a solid protein solder composed of 60% BSA and 0.25 mg ml(-1) ICG. Using this combination of laser and solder parameters, surface temperatures were observed to reach 85+/-5 degrees C with a maximum temperature difference through the 150 microm thick solder strips of about 15 degrees C. Histological examination of the repairs formed using these parameters showed negligible evidence of collateral thermal damage to the underlying tissue. Scanning electron microscopy suggested albumin intertwining within the tissue collagen matrix and subsequent fusion with the collagen as the mechanism for laser tissue soldering. The laser tissue soldering technique is shown to be an effective method for producing repairs with improved tensile strength and minimal collateral thermal damage over conventional laser tissue welding techniques.

Animals↗

PubMed2004

Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension.

Hypertension is the most prevalent risk factor for cardiovascular diseases, present in almost 30% of adults. A key element in the control of vascular tone is the large-conductance, Ca(2+)-dependent K(+) (BK) channel. The BK channel in vascular smooth muscle is formed by an ion-conducting alpha subunit and a regulatory beta(1) subunit, which couples local increases in intracellular Ca(2+) to augmented channel activity and vascular relaxation. Our large population-based genetic epidemiological study has identified a new single-nucleotide substitution (G352A) in the beta(1) gene (KCNMB1), corresponding to an E65K mutation in the protein. This mutation results in a gain of function of the channel and is associated with low prevalence of moderate and severe diastolic hypertension. BK-beta(1E65K) channels showed increased Ca(2+) sensitivity, compared with wild-type channels, without changes in channel kinetics. In conclusion, the BK-beta(1E65K) channel might offer a more efficient negative-feedback effect on vascular smooth muscle contractility, consistent with a protective effect of the K allele against the severity of diastolic hypertension.

Adult↗

PubMed1985

Host defenses: development and maternal contributions.

During the intrauterine period, the human immunologic system develops through a complex but orderly series of events. The functional capacity of the system remains incomplete, not only during prenatal life but also through much of infancy. Many of the factors not produced by the fetus or infant are provided by the mother. Systemic immunity is augmented by specific IgG antibodies from the placenta and mucosal immunity by a wide array of defense agents from human milk including sIgA antibodies, lactoferrin, lysozyme, other soluble factors with antimicrobial properties, and specifically adapted leukocytes. It appears that the defense of the infant and the maternal contribution to that defense are geared to protect principally by noninflammatory mechanisms. Although much has been discovered about the ontogeny of the human immunologic system and the maternal contributions to this immunity, much remains to be learned about the molecular controls of the system, the fate of the transported maternal factors, feedback mechanisms between the immunologic systems of the mother and infant and the precise effects of maternal factors upon the infant. Answers to these questions may lead to the development of immunizing agents which are better suited to the infant, mucosal immunogens fashioned to stimulate the production of protective SIgA antibodies in human milk, the provision of defense factors for serious infections in young infants, and ways to enhance the maturation of the immunologic system of the infant when that is desirable.

Antibody Formation↗

PubMed1997

A collaborative project in Connecticut to improve the care of patients with acute myocardial infarction.

BACKGROUND: State-based peer review organizations (PROs) and individual hospitals are challenged to achieve their quality improvement (QI) goals with shrinking resources. In 1993-1994 the Connecticut PRO and 15 local hospitals generated a comparative QI database on acute myocardial infarction (AMI) care for 1,202 Medicare and non-Medicare patients discharged in 1992 and 1993. METHODS: A steering committee composed of hospital and PRO representatives was assembled to provide oversight. PRO staff developed a chart abstraction tool and trained hospital abstracters who collected and submitted data to the PRO for comparative analyses. Written feedback was provided to all hospitals and supplemented with onsite presentations when requested. Each hospital prepared a written QI plan based on its unique data profile. RESULTS: Opportunities for improvement were identified at all hospitals. The most commonly targeted areas for improvement included the use of thrombolytics at presentation, aspirin at presentation and at discharge, and beta blockers at discharge. Improvement interventions included staff education sessions, development of AMI critical paths and standing orders, and storage of appropriate medications in emergency departments. Self-report data from the hospitals indicate improvements in care. DISCUSSION: PROs and hospitals can augment their individual QI activities by working together to share data, resources, and lessons learned. Twenty-three hospitals are now collaborating with the Connecticut PRO on a similarly designed QI project aimed at improving the care of patients hospitalized with atrial fibrillation. This project includes a more formal means of communicating QI interventions.

Aged↗

PubMed1990

An augmented escape of beta-endorphins to suppression by dexamethasone in severely depressed patients.

Baseline beta-endorphin and cortisol levels and their responses to 1 mg dexamethasone were measured in 11 healthy controls and in 35 depressed patients, categorized according to the DSM-III. Dexamethasone significantly suppressed beta-endorphin levels. Depressed patients with melancholia/psychotic features exhibited significantly increased post-dexamethasone beta-endorphin levels compared with healthy controls, minor and simple major depressives; the baseline beta-endorphin levels did not differ between those study samples. Post-dexamethasone beta-endorphin and cortisol values were found to be significantly and positively correlated. Accordingly, cortisol non-suppressors showed significantly higher post-dexamethasone beta-endorphin levels. Post-dexamethasone beta-endorphin may be the most sensitive and specific reflection of the disorder in negative feedback exerted by dexamethasone in depression.

Adult↗

PubMed1986

Products of polymorphonuclear cell injury inhibit IgG enhancement of monosodium urate-induced superoxide production.

The generation of polymorphonuclear cell (PMN) superoxide ion (O2-) by monosodium urate (MSU) crystals may be important in the pathogenesis of acute gout. Coating MSU crystals with IgG prior to exposure to PMN markedly augmented O2- generation. This augmentation was inhibited by supernates, termed cell lysate, derived from sonicated PMN or PMN exposed to MSU crystals for 5 hours at 37 degrees C. Lysate was effective in inhibiting O2- production when incubated with MSU crystals prior to, during, or after MSU crystals were exposed to IgG. No IgG could be eluted from crystals exposed to both lysate and IgG. Immunoelectron microscopy showed virtually no IgG on crystal surfaces after incubation of crystals with lysate and IgG. These data suggest that products of PMN injury can modulate further PMN responses to MSU crystals. This phenomenon provides a negative feedback loop and is one possible mechanism for the self-limitation of acute gouty attacks.

Animals↗

PubMedDate not supplied

Development and evaluation of the Families, Cultures and Augmentative and Alternative Communication (AAC) multimedia program.

PURPOSE: The Families, Cultures and AAC Project was designed to provide professionals and families with accurate, culturally sensitive information about augmentative communication technologies and decision-making strategies through an innovative, user-friendly format. METHODS: The project resulted in the development of the first interactive bilingual CD-ROM designed to be used by professionals at the pre- or in-service level, and family members from diverse cultures to develop AAC decision-making competencies. RESULTS: The Interactive Health Communication (IHC) model provided an effective structure for conceptualizing, developing and evaluating the program. The program also incorporated universal access design concepts. The program was evaluated in the following 10 categories: usability, visual appearance, consistency, error tolerance, navigation, feedback, user control, redundant formats, content accuracy, and engaging styles. CONCLUSION: Reviewers of the program indicated that it was well designed and would be useful for the intended purpose.

Adult↗

PubMed1990

The Mikamo lecture. Role of higher nervous activity in sudden cardiac death.

The brain receives and catalogues myriads of information from within and without the organism. These inputs promote neural integration of bodily function through a multiplicity of cybernetic feedback loops. Higher nervous activity shapes the contours of perceived well-being and determines the course and progress of disease. Behavioral and neural factors play an important role in cardiovascular function and are especially relevant to the problem of sudden cardiac death (SCD). Clinical data attesting to the role of biobehavioral factors in SCD derive from a diversity of sources. It has long been known that bereavement increases the prevalence of cardiac fatality. Business failure rates are strongly related to increased mortality among persons aged 55 and over. Recession in economic activity, with increasing unemployment, is associated with augmented death rates from ischemic heart disease. In extensive surveys conducted among London civil servants, Rose and Marmot found not only the level but the type of employment to be a factor determining coronary heart disease mortality. Blue collar workers had a 3.6 times greater chance of dying from heart disease than an age-matched population in the higher ranks of civil service. A man's employment status was a stronger predictor of risk for dying from coronary heart disease than any of the usual risk factors, such as smoking, blood pressure, height-weight ratio, leisure time activities, glucose tolerance, or plasma cholesterol. Operation of behavioral factors is also suggested by the time of occurrence of sudden death. Among 3,983 men followed for more than 30 years, Rabkin and co-workers observed an excess proportion of fatalities on Mondays. No such pattern was noted for cancer mortality. Not only the day of the week but the time of day appears to be a factor. Muller and co-workers found a significant preponderance in the occurrence of myocardial infarction and sudden death from 6:00 AM to noon. They could not implicate operation of circadian rhythm, but suggested a role for augmented autonomic neural discharge associated with early morning activities following waking from sleep. The longitudinal epidemiologic studies of the Health Insurance Plan of New York (HIP) have indicated an important association between behavioral and psychologic factors and the prevalence of sudden cardiac death.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1976

Suppression of ethanol-induced locomotor stimulation by GABA-like drugs.

Ethanol (2.4 g/kg) was given intraperitoneally to mice and was found to cause a marked increase in spontaneous locomotor activity. When mice were pretreated with low doses of agents which mimic or augment the action of GABA (gamma-hydroxybutyric acid, baclophen, or aminooxyacetic acid) the ethanol-induced locomotor stimulation was completely eliminated; Baclophen (10 mg/kg) was found to cause an initial increase followed by a later decrease in synthesis of catecholamines, as measured by the accumulation of dopa after inhibition of central aromatic L-amino acid decarboxylase, in dopamine-rich areas of rat brain. These data are consistent with previous findings that baclophen, as well as other agents which enhance the activity of GABA systems, reduce the firing of dopamine neurons, thus causing enhanced synthesis of dopamine via feedback mechanisms. These findings also indicate a potential interaction between GABA-like drugs and alcohol in man, and may be of heuristic value in the treatment of chronic alcoholism. The possibility that the mechanism of the inhibition of ethanol-induced locomotor stimulation by GABA-like drugs may be due to a selective interference with ethanol-induced dopamine release is discussed.

Aminobutyrates↗

PubMed2002

Integration-differentiation and gating of carotid afferent traffic that shapes the respiratory pattern.

The phase-dependent plasticity of carotid chemoafferent signaling was studied with electrical stimulation of a carotid sinus nerve during either inspiration or expiration in anesthetized, glomectomized, vagotomized, paralyzed, and ventilated rats. Stroboscopic and interferometric analyses of the resulting phase-contrast disturbances of the respiratory rhythm revealed that carotid chemoafferent traffic was dynamically filtered centrally by a parallel bank of leaky integrators and differentiators, each being logically gated to the inspiratory or expiratory phase in a stop-and-go manner as follows: 1) carotid short-term potentiation of inspiratory drive was mediated by dual integrators that both shortened inspiration and augmented phrenic motor output cooperatively in long and short timescales; 2) carotid short-term depression of respiratory frequency was mediated by a (possibly pontine) integrator that lengthened expiration with a relatively long memory; and 3) carotid "chemoreflex" shortening of expiration was mediated by an occult fast integrator, which, together with carotid short-term depression, formed a differentiator. These effects were modulated anteriorly by integrators in the nucleus tractus solitarius that were "auto-gated" to, or recruited by, the carotid sinus nerve input. Such phase-selective and activity-dependent time-frequency filtering of carotid chemoafferent feedback in parallel neurological-neurodynamic central pathways may profoundly affect respiratory stability during hypoxia and sleep and could contribute to the dynamic optimization of the respiratory pattern and maintenance of homeostasis in health and in disease states.

Afferent Pathways↗

PubMed1996

Clamped Corticosterone (B) Reveals the Effect of Endogenous B on Both Facilitated Responsivity to Acute Restraint and Metabolic Responses to Chronic Stress.

To determine the effects of both corticosterone (B) and chronic stressors on acute ACTH responses to restraint, young male rats were exposed to streptozotocin-induced diabetes, cold (5-7 degreesC) or intracerebroventricular (icv) neuropeptide Y (NPY) for 5 d and then exposed to restraint within 2 h after lights on. Two groups of rats were studied: intact and adrenalectomized replaced with B pellets that maintained plasma B in the normal mean 24-h range of intact rats. In addition to ACTH and B responses to restraint on d 5, body weight, food intake, fat depots, glucose and other hormones were measured to determine the role of stress-induced elevations in B on energy balance. ACTH responses to restraint were normal in intact rats subjected to diabetes or cold. By contrast, there was no ACTH or B response to restraint in NPY-infused intact rats. All 3 groups of chronically stimulated adrenalectomized rats with clamped B had facilitated ACTH responses to restraint compared to their treatment controls. Overall food intake increased in all groups of stressed rats; however, augmented intake occurred only during the light in intact rats and equally in the light and dark in B-clamped rats. White adipose depot weights were decreased by both diabetes and cold and increased by NPY in intact rats; the decreases with cold and increases with NPY were both blunted and changes in fat stores were not significant in adrenalectomized, B-clamped rats. We conclude that: 1. diabetes- and cold-induced facilitation of restraint-induced afferent input to hypothalamic control of the hypothalamo-pituitary-adrenal (HPA) axis is opposed in intact rats by the elevated feedback signal of B secretion; 2. NPY does not induce facilitation of afferent stress pathways; 3. chronic stimulation of the HPA axis induces acute hyperresponsiveness of hypothalamic neurons to restraint provided that the afferent input of this acute stimulus is not prevented by B feedback; 4. stimulus-induced elevations in B secretion result in day-time feeding; 5. insensitivity of both caloric efficiency and white fat stores to chronic stress in adrenalectomized, B-clamped rats results from loss of normally variable B levels.

Journal Article↗

PubMed1995

[From obesity to diabetes].

The frequent development of Type 2 diabetes in the obese suggests a relationship between obesity and diabetes. This study presents evidence for a continuum form obesity to diabetes via glucose intolerance and hyperinsulinemic diabetes. The defect which seems to be at the origin of this development resides in the increase in lipid oxidation already present in the early stages of obesity. It reflects the increased utilisation of fatty acids for energy purpose in the obese, at the expenses of glucose. In non-diabetic obese subjects, insulin resistance can be demonstrated by the inhibition of glucose storage during a euglycemic, hyperinsulinemic, clamp. This defect in glucose storage is not observed during a oral glucose tolerance test (OGTT), as it is compensated by hyperinsulinemia and hyperglycemia during glucose tolerance. Glucose tolerance appears with the inhibition of glucose oxidation by the augmented lipid oxidation. This decreased glucose utilization causes a slowdown of the utilization of glycogen stores which leads, as a consequence, to the inhibition of glycogen synthase by its product, glycogen. Diabetes appears when the increase in glycemia and insulinemia does not compensate any more for the inhibition of glucose storage. The rise in basal glycemia simultaneously with the fall in glucose storage corresponds to the transition to diabetes. The decreased glucose mobilization together with the inhibition of glycogen phosphorylase are such in the diabetic patient that glycogen stores tend to remain full and glycogen synthase is inhibited by negative feedback. The retrograde inhibition of glycogen stores on glycogen synthase activity brings up incapacity to store glucose and leads to a rise in glycemia. Finally, the evolution of obesity to diabetes leads to a decrease in insulin secretion with increase in hepatic glucose production through gluconeogenesis and decreased capacity to store glucose. Therapeutic implications are discussed in this review.

Adult↗

PubMed1991

Folate-deficient human lymphoblasts: changes in de novo purine and pyrimidine synthesis and phosphoribosylpyrophosphate.

Peripheral blood lymphocytes from healthy volunteers cultured with phytohaemagglutinin in a folate-deficient medium exhibit megaloblastic maturation and reduced cellular folate content. For these cells, changes in de novo purine and pyrimidine synthesis and cellular phosphoribosylpyrophosphate (PRPP) have been determined. Mitogen-stimulated cells cultured with undialyzed pooled human serum (PHS) exhibit undetectable de novo purine synthesis, a three-fold increase in PRPP content and augmented de novo pyrimidine synthesis; these changes are independent of cellular folate status. Folate-replete cells cultured with PHS which was dialyzed to reduce purine compounds concentrations show markedly increased de novo purine synthesis. The PRPP content and pyrimidine synthesis rates of these cells are similar to those of folate-replete cells cultured with undialyzed PHS. Folate-deficient cells cultured in dialyzed PHS show a 10-fold reduction in purine synthesis and a corresponding increase in PRPP levels. Pyrimidine synthesis was moderately reduced. The purine bases hypoxanthine and adenine markedly reduced the augmented purine synthesis of folate-replete cells or the increased PRPP content of folate-deficient cells cultured with dialyzed PHS. These findings suggest that cellular folate status is critical for de novo purine synthesis only when coupled with purine bases restriction and that the latter are efficient regulators of de novo purine synthesis.

Cells, Cultured↗

PubMed2004

Vagal nerve stimulation technique: enhancing its efficacy and acceptability by augmentation with auto activation and deactivation mode of operation.

The purpose of this article is to search for an additional modus operandi to improve the functioning of currently deployed vagal nerve stimulation (VNS) technique that is being used as an adjunctive therapy for intractable epilepsy, mainly complex partial seizures (partial onset with secondary generalization). The efficacy and success of current VNS technique is variable and limited, which can be attributed (to a considerable extent) to its present modi operandi. The mechanism of anti-epileptic action of VNS that has been hypothesized in the article is found to conform to observations and results in a large number of studies including those on VNS itself. Based on this mechanism in controlling seizures, the author proposes an additional mode of operation of the VNS device, (an auto activation and deactivation mode), designed to work on a feedback mechanism, which would deliver VNS as and when the brain requires it to abort/arrest the impending focal attack and/or its generalization, thus eliminating the limitations associated with the current VNS device. This mode should enhance its acceptability, efficacy and success.

Brain↗

PubMed1999

Fish oil augments macrophage cyclooxygenase II (COX-2) gene expression induced by endotoxin.

BACKGROUND: Fish oil-supplemented diets have anti-inflammatory and immunomodulating effects. Although fish oil is readily incorporated into the cell membrane and influences the production of eicosanoids, the exact mechanism is not clear. This study was designed to investigate the effects of eicosapentaenoic acid (EPA), a major component of fish oil, on macrophage (Mphi) cyclooxygenase (COX) gene expression induced by LPS. METHODS: RAW 264.7 cells, a mouse Mphi cell line, were grown in EPA-rich media for 24 h. Mphi were washed and exposed to Escherichia coli LPS (10 microg/ml). Membrane lipid profile was determined by gas chromatographic analysis. COX-1 and COX-2 mRNA expressions were determined by Northern blot assays with mouse-specific cDNA probes. PGE(2) production of Mphi was measured by ELISA. Mphi production of COX-2 protein was determined by Western blot assays with an anti-COX-2 antibody. RESULTS: Incubation in EPA-rich media increased membrane EPA and decreased arachidonic acid (AA) composition. COX-2 mRNA expression was induced by EPA and further augmented by LPS stimulation. EPA also augmented Mphi production of COX-2 protein. In comparison, COX-1 mRNA expression was not affected by either LPS stimulation or EPA incubation. EPA reduced PGE(2) production by LPS-stimulated Mphi. To further support that COX-2 mRNA was regulated by COX product, exogenous PGE(2) was added to Mphi prior to LPS stimulation. PGE(2) reduced COX-2 mRNA of LPS-stimulated Mphi. CONCLUSION: EPA displaces AA and reduces PGE(2) production by LPS-stimulated Mphi. Fish oil inhibition of Mphi PGE(2) production induces COX-2 mRNA expression through a COX-2 product-mediated feedback mechanism.

Animals↗

PubMed2005

Crosstalk between membrane potential and cytosolic Ca2+ concentration in beta cells from Sur1-/- mice.

AIMS/HYPOTHESIS: Islets or beta cells from Sur1(-/-) mice were used to determine whether changes in plasma membrane potential (V(m)) remain coupled to changes in cytosolic Ca(2+) ([Ca(2+)](i)) in the absence of K(ATP) channels and thus provide a triggering signal for insulin secretion. The study also sought to elucidate whether [Ca(2+)](i) influences oscillations in V(m) in sur1(-/-) beta cells. METHODS: Plasma membrane potential and ion currents were measured with microelectrodes and the patch-clamp technique. [Ca(2+)](i) was monitored with the fluorescent dye fura-2. Insulin secretion from isolated islets was determined by static incubations. RESULTS: Membrane depolarisation of Sur1(-/-) islets by arginine or increased extracellular K(+), elevated [Ca(2+)](i) and augmented insulin secretion. Oligomycin completely abolished glucose-stimulated insulin release from Sur1(-/-) islets. Oscillations in V(m) were influenced by [Ca(2+)](i) as follows: (1) elevation of extracellular Ca(2+) lengthened phases of membrane hyperpolarisation; (2) simulating a burst of action potentials induced a Ca(2+)-dependent outward current that was augmented by increased Ca(2+) influx through L-type Ca(2+) channels; (3) Ca(2+) depletion of intracellular stores by cyclopiazonic acid increased the burst frequency in Sur1(-/-) islets, elevating [Ca(2+)](i) and insulin secretion; (4) store depletion activated a Ca(2+) influx that was not inhibitable by the L-type Ca(2+) channel blocker D600. CONCLUSIONS/INTERPRETATION: Although V(m) is largely uncoupled from glucose metabolism in the absence of K(ATP) channels, increased electrical activity leads to elevations of [Ca(2+)](i) that are sufficient to stimulate insulin secretion. In Sur1(-/-) beta cells, [Ca(2+)](i) exerts feedback mechanisms on V(m) by activating a hyperpolarising outward current and by depolarising V(m) via store-operated ion channels.

ATP-Binding Cassette Transporters↗