-
Journal of the American College of Cardiology 10/2012; · 14.16 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cholecystokinin (CCK) is produced by discrete endocrine cells in the proximal small intestine and is released following the ingestion of food. CCK is the primary hormone responsible for gallbladder contraction and has potent effects on pancreatic secretion, gastric emptying, and satiety. In addition to fats, digested proteins and aromatic amino acids are major stimulants of CCK release. However, the cellular mechanism by which amino acids affect CCK secretion is unknown. The Ca(2+)-sensing receptor (CaSR) that was originally identified on parathyroid cells is not only sensitive to extracellular Ca(2+) but is activated by extracellular aromatic amino acids. It has been postulated that this receptor may be involved in gastrointestinal hormone secretion. Using transgenic mice expressing a CCK promoter driven/enhanced green fluorescent protein (GFP) transgene, we have been able to identify and purify viable intestinal CCK cells. Intestinal mucosal CCK cells were enriched >200-fold by fluorescence-activated cell sorting. These cells were then used for real-time PCR identification of CaSR. Immunohistochemical staining with an antibody specific for CaSR confirmed colocalization of CaSR to CCK cells. In isolated CCK cells loaded with a Ca(2+)-sensitive dye, the amino acids phenylalanine and tryptophan, but not nonaromatic amino acids, caused an increase in intracellular Ca(2+) ([Ca(2+)](i)). The increase in [Ca(2+)](i) was blocked by the CaSR inhibitor Calhex 231. Phenylalanine and tryptophan stimulated CCK release from intestinal CCK cells, and this stimulation was also blocked by CaSR inhibition. Electrophysiological recordings from isolated CCK-GFP cells revealed these cells to possess a predominant outwardly rectifying potassium current. Administration of phenylalanine inhibited basal K(+) channel activity and caused CCK cell depolarization, consistent with changes necessary for hormone secretion. These findings indicate that amino acids have a direct effect on CCK cells to stimulate CCK release by activating CaSR and suggest that CaSR is the physiological mechanism through which amino acids regulate CCK secretion.
AJP Gastrointestinal and Liver Physiology 12/2010; 300(4):G528-37. · 3.43 Impact Factor
-
Augustus O Grant
Journal of Cardiovascular Electrophysiology 07/2009; 20(9):1046-7. · 3.06 Impact Factor
-
Augustus O Grant
Circulation Arrhythmia and Electrophysiology 04/2009; 2(2):185-94. · 6.46 Impact Factor
-
Circulation 04/2007; 115(12):1659-62. · 14.74 Impact Factor
-
George A Mensah, Augustus O Grant,
Carl J Pepine,
Larry M Baddour,
Leslie T Cooper,
Sandra B Dunbar,
Erika S Froelicher,
Kurt J Greenlund,
Edward L Kaplan,
Robert A Kloner, [......],
Mark A Hlatky,
Robert C Lichtenberg,
Jonathan R Lindner,
Gerald M Pohost,
Richard S Schofield,
Samuel J Shubrooks,
James H Stein,
Cynthia M Tracy,
Robert A Vogel,
Deborah J Wesley
Circulation 04/2007; 115(12):1656-95. · 14.74 Impact Factor
-
Journal of the American College of Cardiology 03/2007; 49(12):1376-9. · 14.16 Impact Factor
-
George A Mensah, Augustus O Grant,
Carl J Pepine,
Larry M Baddour,
Leslie T Cooper,
Sandra B Dunbar,
Erika S Froelicher,
Kurt J Greenlund,
Edward L Kaplan,
Robert A Kloner, [......],
Mark A Hlatky,
Robert C Lichtenberg,
Jonathan R Lindner,
Gerald M Pohost,
Richard S Schofield,
Samuel J Shubrooks,
James H Stein,
Cynthia M Tracy,
Robert A Vogel,
Deborah J Wesley
Journal of the American College of Cardiology 03/2007; 49(12):1373-412. · 14.16 Impact Factor
-
Journal of Cardiovascular Electrophysiology 03/2007; 18(2):204-5. · 3.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Some mutations of the sodium channel gene Na(V1.5) are multifunctional, causing combinations of LQTS, Brugada syndrome and progressive cardiac conduction system disease (PCCD). The combination of Brugada syndrome and PCCD is uncommon, although they both result from a reduction in the sodium current. We hypothesize that slow conduction is sufficient to cause S-T segment elevation and undertook a combined experimental and theoretical study to determine whether conduction slowing alone can produce the Brugada phenotype. Deletion of lysine 1479 in one of two positively charged clusters in the III/IV inter-domain linker causes both syndromes. We have examined the functional effects of this mutation using heterologous expression of the wild-type and mutant sodium channel in HEK-293-EBNA cells. We show that DeltaK1479 shifts the potential of half-activation, V(1/2m), to more positive potentials (V(1/2m) = -36.8 +/- 0.8 and -24.5 +/- 1.3 mV for the wild-type and DeltaK1479 mutant respectively, n = 11, 10). The depolarizing shift increases the extent of depolarization required for activation. The potential of half-inactivation, V(1/2h), is also shifted to more positive potentials (V(1/2h) = -85 +/- 1.1 and -79.4 +/- 1.2 mV for wild-type and DeltaK1479 mutant respectively), increasing the fraction of channels available for activation. These shifts are quantitatively the same as a mutation that produces PCCD only, G514C. We incorporated experimentally derived parameters into a model of the cardiac action potential and its propagation in a one dimensional cable (simulating endo-, mid-myocardial and epicardial regions). The simulations show that action potential and ECG changes consistent with Brugada syndrome may result from conduction slowing alone; marked repolarization heterogeneity is not required. The findings also suggest how Brugada syndrome and PCCD which both result from loss of sodium channel function are sometimes present alone and at other times in combination.
AJP Heart and Circulatory Physiology 02/2007; 292(1):H399-407. · 3.71 Impact Factor
-
Augustus O Grant
[show abstract]
[hide abstract]
ABSTRACT: Brugada syndrome is a primary arrhythmic syndrome arising in the structurally normal heart. Any proposed mechanism should account for the major features of the syndrome: localization of the ST segment and T-wave changes to the right precordial leads, association of conduction slowing at several levels, precipitation or aggravation of the major ECG changes by sodium channel-blocking drugs and the occurrence of ventricular fibrillation. Heterogeneity of repolarization across the ventricle wall plays a major role. Any agency that shifts the net current gradient during phase I outward would exaggerate the normal heterogeneity of repolarization and result in the ST segment and T-wave changes characteristic of the syndrome. When the outward current shift is marked, premature repolarization may occur in epicardial zone and the resulting gradient may precipitate reentry. The syndrome is inherited as an autosomal dominant. However, 75% of clinically affected individuals are males. In 20% of cases, the syndrome is associated with mutations of the cardiac sodium channel gene SCN5A. The mutations result in a loss-of-function as a result of the synthesis of a non-functional protein, altered protein trafficking, or change in gating. Agencies that reduce the sodium current may precipitate the characteristic ECG changes, for example, sodium channel blockers and membrane depolarization by hyperkalemia. Sympathetic stimulation may reverse the ECG changes and reduce arrhythmia recurrence. By its nonspecific potassium channel blocking action, quinidine may also reduce arrhythmia recurrence. We still do not know the basis for defect in the majority of patients with Brugada syndrome.
Journal of Cardiovascular Electrophysiology 10/2005; 16 Suppl 1:S3-7. · 3.06 Impact Factor
-
Journal of the American College of Cardiology 05/2005; 45(8):1354-63. · 14.16 Impact Factor
-
Circulation 04/2005; 111(10):1205-7. · 14.74 Impact Factor
-
Richard J Popp,
Sidney C Smith,
Rober J Adams,
Elliot M Antman,
Rae Ellen W Kavey,
Anthony N DeMaria,
Erik Magnus Ohman,
Bertram Pitt,
James T Willerson,
Buce J Bellande, [......],
Eric D Peterson,
Eric N Prystowsky,
Jeffrey L Anderson,
Melvin D Cheitlin,
Larry B Goldstein, Augustus O Grant,
George A Beller,
Edward F Hines,
David Wm Livingston,
Christine W McEntree
Circulation 11/2004; 110(16):2506-49. · 14.74 Impact Factor
-
Journal of the American College of Cardiology 11/2004; 44(8):1747-9. · 14.16 Impact Factor
-
Circulation 07/2004; 109(25):3062-6063. · 14.74 Impact Factor
-
Circulation 03/2004; 109(5):561. · 14.74 Impact Factor
-
Augustus O Grant
[show abstract]
[hide abstract]
ABSTRACT: Advances in endocardial mapping techniques and ablation have greatly increased the indications for catheter-ablation of supraventricular arrhythmias. Rate or rhythm control is a valid treatment option for patients with atrial fibrillation; however, all patients with one or more risk factors should be treated with oral anticoagulants. The early success rate and long-term cure of atrial fibrillation by radiofrequency catheter ablation continues to increase. The number of centers offering this treatment option has increased substantially. Implantable defibrillator-cardioverters are the primary treatment modality for patients with ventricular tachycardia and their role in primary prevention is also being defined. Future advances in arrhythmia management will include improvements in catheter design and energy sources for ablation, and greater monitoring capacity of implantable devices.
Circulation Journal 09/2003; 67(8):651-5. · 3.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The vulnerable period (VP) defines an interval during which premature impulses can trigger reentrant arrhythmias leading to ventricular fibrillation and sudden death. The mechanistic basis of the success or failure of impulse propagation during the VP remains unclear. Recent clinical reports of gene mutations, drugs and cardiac disease link a variety of often lethal conditions with loss of cardiac Na channel function (NaLOF) and reentrant proarrhythmia. We hypothesized that during the VP, the Na conductance at the stimulus site is graded and that NaLOF would favor reentry specifically by flattening this gradient, which would destabilize antegrade front formation.
Using numerical studies of propagation in a one-dimensional cable of ventricular cells, we identified the boundaries of the VP using paired (s1-s2) stimulation. We explored VP alterations associated with different NaLOF scenarios including reduced channel density, accelerated rate of inactivation, and prolonged recovery from inactivation.
Following the passage of a wave over the s2 site, a gradient in the restoration of Na channel conductance was demonstrated to exist during the VP. The VP boundaries coincided with different thresholds for stable retrograde and antegrade impulse propagation. Reducing channel density, accelerating inactivation and slowing the recovery from inactivation flattened the restoration gradient and extended the VP. VP extension was directly proportional to the time constant of Na channel recovery.
Mutations that accelerate inactivation, slow recovery from inactivation, or reduce Na channel density flatten the restoration gradient within the VP which prolongs the VP and increases the probability that a premature impulse will initiate reentry. These studies define a new mechanism that links alterations in Na channel function with conditions that enable premature excitation to generate proarrhythmia and sudden death.
Cardiovascular Research 02/2003; 57(1):82-91. · 6.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The function of the 12 positive charges in the 53-residue III/IV interdomain linker of the cardiac Na(+) channel is unclear. We have identified a four-generation family, including 17 gene carriers with long QT syndrome, Brugada syndrome, and conduction system disease with deletion of lysine 1500 (DeltaK1500) within the linker. Three family members died suddenly. We have examined the functional consequences of this mutation by measuring whole-cell and single-channel currents in 293-EBNA cells expressing the wild-type and DeltaK1500 mutant channel. The mutation shifted V(1/2)h( infinity ) to more negative membrane potentials and increased k(h) consistent with a reduction of inactivation valence of 1. The shift in h( infinity ) was the result of an increase in closed-state inactivation rate (11-fold at -100 mV). V(1/2)m was shifted to more positive potentials, and k(m) was doubled in the DeltaK1500 mutant. To determine whether the positive charge deletion was the basis for the gating changes, we performed the mutations K1500Q and K1500E (change in charge, -1 and -2, respectively). For both mutations, V(1/2)h was shifted back toward control; however, V(1/2)m shifted progressively to more positive potentials. The late component of Na(+) current was increased in the DeltaK1500 mutant channel. These changes can account for the complex phenotype in this kindred and point to an important role of the III/IV linker in channel activation.
Journal of Clinical Investigation 11/2002; 110(8):1201-9. · 15.39 Impact Factor
