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Biomedical subjects

R L Moore

Publications and source records attributed to R L Moore.

At least 19 recordsLinked to original sources
PubMed1999

Effects of chronic run training on Na+-dependent Ca2+ efflux from rat left ventricular myocytes.

The effects of endurance run training on Na+-dependent Ca2+ regulation in rat left ventricular myocytes were examined. Myocytes were isolated from sedentary and trained rats and loaded with fura 2. Contractile dynamics and fluorescence ratio transients were recorded during electrical pacing at 0.5 Hz, 2 mM extracellular Ca2+ concentration, and 29 degreesC. Resting and peak cytosolic Ca2+ concentration ([Ca2+]c) did not change with exercise training. However, resting and peak [Ca2+]c increased significantly in both groups during 5 min of continuous pacing, although diastolic [Ca2+]c in the trained group was less susceptible to this elevation of intracellular Ca2+. Run training also significantly reduced the rate of [Ca2+]c decay during relaxation. Myocytes were then exposed to 10 mM caffeine in the absence of external Na+ or Ca2+ to trigger sarcoplasmic reticular Ca2+ release and to suppress cellular Ca2+ efflux. This maneuver elicited an elevated steady-state [Ca2+]c. External Na+ was then added, and the rate of [Ca2+]c clearance was determined. Run training significantly reduced the rate of Na+-dependent clearance of [Ca2+]c during the caffeine-induced contractures. These data demonstrate that the removal of cytosolic Ca2+ was depressed with exercise training under these experimental conditions and may be specifically reflective of a training-induced decrease in the rate of cytosolic Ca2+ removal via Na+/Ca2+ exchange and/or in the amount of Ca2+ moved across the sarcolemma during a contraction.

Algorithms↗
PubMed1999

Differential expression of stress proteins in rat myocardium after free wheel or treadmill run training.

High-intensity treadmill exercise increases the expression of a cardioprotective, inducible 72-kDa stress protein (SP72) in cardiac muscle. This investigation examined whether voluntary free wheel exercise training would be sufficient to confer a similar response. Male Sprague-Dawley rats were randomly assigned to either treadmill (TM-Tr) or free wheel (FW-Tr) training groups. By the end of the 8-wk training period, TM-Tr animals ran 1 h/day, 5 days/wk up a 10% grade, covering a distance of 8,282 m/wk. FW-Tr rats ran, on average, 5,300 m/wk, with one-third of the animals covering distances similar to those for the TM-Tr group. At the time of death, hearts of trained and caged sedentary control (Sed) animals were divided into left (LV) and right (RV) ventricles. Citrate synthase activity and the relative immunoblot contents of SP72, SP73 (the constitutive isoform of the SP70 family), and a 75-kDa mitochondrial chaperone (SP75) were subsequently determined. LV and RV did not differ on any measure, and SP73, SP75, and citrate synthase were not affected by training. Cardiac SP72 levels were elevated over fourfold in both ventricles of TM-Tr compared with RV of FW-Sed rats. Despite the animals having run a similar total distance, cardiac SP72 content in FW-Tr rats was not different from that in Sed animals. These data indicate that voluntary exercise training is insufficient to elicit an elevation of SP72 in rat heart and suggest that exercise intensity may be a critical factor in evoking the cardioprotective SP72 response.

Animals↗
PubMed1998

A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy.

Mutations in multiple cardiac sarcomeric proteins including myosin heavy chain (MyHC) and cardiac troponin T (cTnT) cause a dominant genetic heart disease, familial hypertrophic cardiomyopathy (FHC). Patients with mutations in these two genes have quite distinct clinical characteristics. Those with MyHC mutations demonstrate more significant and uniform cardiac hypertrophy and a variable frequency of sudden death. Patients with cTnT mutations generally exhibit mild or no hypertrophy, but a high frequency of sudden death at an early age. To understand the basis for these distinctions and to study the pathogenesis of the disease, we have created transgenic mice expressing a truncated mouse cTnT allele analogous to one found in FHC patients. Mice expressing truncated cTnT at low (< 5%) levels develop cardiomyopathy and their hearts are significantly smaller (18-27%) than wild type. These animals also exhibit significant diastolic dysfunction and milder systolic dysfunction. Animals that express higher levels of transgene protein die within 24 h of birth. Transgenic mouse hearts demonstrate myocellular disarray and have a reduced number of cardiac myocytes that are smaller in size. These studies suggest that multiple cellular mechanisms result in the human disease, which is generally characterized by mild hypertrophy, but, also, frequent sudden death.

Animals↗
PubMed1998

Endurance exercise alters the contractile responsiveness of rat heart to extracellular Na+ and Ca2+.

PURPOSE AND METHODS: The isovolumic contractile responsiveness of left ventricular (LV) myocardium to altered extracellular [Ca2+], [Na+], and pacing frequency was examined using perfused hearts (37 degrees C) isolated from sedentary (SED) and treadmill-trained (TR) adult female rats. RESULTS: The suppressive effect of reducing perfusate free [Ca2+] to 0.7 mM on LV developed pressure (delta LVP) was greater in the TR hearts compared with SED hearts (P < 0.05). When perfusate [Na+] was reduced to 120 mM ([Ca2+] = 0.7 mM), delta LVP augmentation was greatest in the TR hearts (P < 0.05). The negative force-frequency relationship observed at physiologic [Ca2+] and [Na+] was progressively altered toward a positive force-frequency relationship with each subsequent change in perfusate [Ca2+] and [Na+] although the effect was greatest in TR hearts (P < 0.05). CONCLUSIONS: Training elicited a small but significant (P < 0.05) prolongation in the pressure development phase of contraction. Under the physiological [Ca2+], [Na+] perfusion condition, training produced an increase in the magnitude of extrasystolic potentiation of LV pressure, whereas the time constant of mechanical restitution was unaffected. Training affected neither the Ca(2+)-dependence nor the maximal capacity of [3H] ryanodine binding to LV myocardial homogenates. The simplest interpretation of [Na+] and [Ca2+] reduction experiments is that myocardial Ca2+ efflux was augmented by exercise training.

Adaptation, Physiological↗
PubMed1998

Sprint training attenuates myocyte hypertrophy and improves Ca2+ homeostasis in postinfarction myocytes.

Myocytes isolated from rat hearts 3 wk after myocardial infarction (MI) had decreased Na+/Ca2+ exchange currents (I Na/Ca; 3 Na+ out:1 Ca2+ in) and sarcoplasmic reticulum (SR)-releasable Ca2+ contents. These defects in Ca2+ regulation may contribute to abnormal contractility in MI myocytes. Because exercise training elicits positive adaptations in cardiac contractile function and myocardial Ca2+ regulation, the present study examined whether 6-8 wk of high-intensity sprint training (HIST) would ameliorate some of the cellular maladaptations observed in post-MI rats with limited exercise activity (Sed). In MI rats, HIST did not affect citrate synthase activities of plantaris muscles but significantly increased the percentage of cardiac alpha-myosin heavy chain (MHC) isoforms (57.2 +/- 1.9 vs. 49.3 +/- 3.5 in MI-HIST vs. MI-Sed, respectively; P < or = 0.05). At the single myocyte level, HIST attenuated cellular hypertrophy observed post-MI, as evidenced by reductions in cell lengths (112 +/- 4 vs. 130 +/- 5 micrograms in MI-HIST vs. MI-Sed, respectively; P < or = 0.005) and cell capacitances (212 +/- 8 vs. 242 +/- 9 pF in MI-HIST vs. MI-Sed, respectively; P < or = 0.015). Reverse I Na/Ca was significantly lower (P < or = 0.0001) in myocytes from MI-Sed rats compared with those from rats that were sham operated and sedentary. HIST significantly increased reverse I Na/Ca (P < or = 0.05) without affecting the amount of Na+/Ca2+ exchangers (detected by immunoblotting) in MI myocytes. SR-releasable Ca2+ content, as estimated by integrating forward I Na/Ca during caffeine-induced SR Ca2+ release, was also significantly increased (P < or = 0.02) by HIST in MI myocytes. We conclude that the enhanced cardiac output and stroke volume in post-MI rats subjected to HIST are mediated, at least in part, by reversal of cellular maladaptations post-MI.

Animals↗
PubMed1998

Shortening and [Ca2+] dynamics of left ventricular myocytes isolated from exercise-trained rats.

The effects of run endurance training and fura 2 loading on the contractile function and Ca2+ regulation of rat left ventricular myocytes were examined. In myocytes not loaded with fura 2, the maximal extent of myocyte shortening was reduced with training under our pacing conditions [0.5 Hz at 2.0 and 0.75 mM external Ca2+ concentration ([Ca2+]o)], although training had no effect on the temporal characteristics. The "light" loading of myocytes with fura 2 markedly suppressed (approximately 50%) maximal shortening in the sedentary and trained groups, although the temporal characteristics of myocyte shortening were significantly prolonged in the trained group. No discernible differences in the dynamic characteristics of the intracellular Ca2+ concentration ([Ca2+]) transient were detected at 2.0 mM [Ca2+]o, although peak [Ca2+] and rate of [Ca2+] rise during caffeine contracture were greater in the trained state at 0.75 mM [Ca2+]o. We conclude that training induced a diminished myocyte contractile function under the conditions studied here and a more effective coupling of inward Ca2+ current to sarcoplasmic reticulum Ca2+ release at low [Ca2+]o, and that fura 2 and its loading vehicle DMSO significantly alter the intrinsic characteristics of myocyte contractile function and Ca2+ regulation.

Animals↗
PubMed1998

Cellular adaptations of the heart muscle to exercise training.

Exercise training is unique in that it represents a stress that elicits positive adaptations in the heart. Hallmark adaptations of the heart to training include resting and submaximal exercise bradycardia, increases in end-diastolic dimension, improved ventricular function, and an increase in the resistance of the heart to ischaemic insult. Endurance exercise training has also been shown to be effective in the treatment and/or prevention of the cardiac functional deficits that are known to occur in settings of chronic hypertension, advanced age, and myocardial infarction. Over the last 20-25 years, considerable effort has been directed towards identifying the cellular basis for the global adaptations of the normal and pathologically involved heart to endurance exercise training. It is the intent of this brief review to identify some of the known and hypothetical cellular adaptations that underlie the positive effects of endurance exercise training on the heart.

Adaptation, Physiological↗
PubMed1997

Hypertension alters rapid cooling contractures in single rat cardiocytes.

Previous work has demonstrated that, in single, paced left ventricular (LV) myocytes isolated from rats with hypertension, the extent of myocyte shortening and the amplitude of the cytosolic Ca2+ concentration transient are decreased relative to normal myocytes. These findings suggest that reduced sarcoplasmic reticular (SR) Ca2+ release could be responsible for hypertension-induced attenuation of the myocyte contractile response. Hypertension-induced reductions in SR Ca2+ release could be due to 1) a decrease in releasable SR Ca2+ content relative to the sarcoplasmic volume into which it is released or 2) alterations in the SR Ca2+ release mechanism such that the fractional release of SR Ca2+ is reduced. Using rapid cooling contractures (RCCs) to provide an index of SR Ca2+ content, we conducted a series of experiments designed to test the former hypothesis. Single LV myocytes were isolated from normotensive control rats and from rats with hypertension, which was induced by abdominal aortic banding (for approximately 4 mo). The extent of myocyte shortening during an RCC is taken to be directly proportional to SR Ca2+ content. As expected, the amplitudes of both twitches and RCCs decreased as pacing frequency increased from 0.2 to 1.0 Hz across both control and hypertensive groups, although the effect was greatest in control myocytes. A significant finding of this study was that, at both pacing frequencies, RCC magnitude was attenuated in hypertensive relative to control myocytes. These results suggest that in hypertension cellular Ca2+ homeostasis is altered and there is a mismatch between releasable SR Ca2+ content and the sarcoplasmic volume into which it is released.

Animals↗
PubMed1997

Endurance training does not affect intrinsic calcium current characteristics in rat myocardium.

The voltage-dependent Ca2+ channel (L-type channel) controls an inward Ca2+ current (ICa) that is centrally involved in the regulation of myocardial excitation-contraction (EC) coupling. A significant body of evidence exists to support the idea that exercise training elicits alterations in myocardial Ca2+ regulation, and the L-type channel has been implicated as a possible site of adaptation. The purpose of this study was to determine whether training elicits adaptations at the level of the L-type Ca2+ channel, as reflected by alterations in whole cell ICa characteristics in single myocytes isolated from rat left ventricle (LV). Female rats were treadmill trained at a moderately high intensity for a minimum of 20 wk. Body weight was unaffected by the training protocol, whereas there was a trend (P = 0.06) for a modest increase in LV weight (approximately 8%). Training produced significant (P < 0.05) increases in mean myocyte capacitance (approximately 9%) and myocyte length (approximately 6%), thus providing electrophysiological and morphological evidence that training elicited LV cardiocyte hypertrophy. Whole cell ICa vs. voltage and ICa density vs. voltage relationships as well as ICa inactivation and recovery characteristics were unaffected by our training paradigm. These findings do not support the hypothesis that training elicits adaptations in L-type Ca2+ channel number or intrinsic function in a model exhibiting classical exercise training-induced myocardial hypertrophy. Our results do not, however, preclude the possibility that training-induced adaptations at sites other than the L-type Ca2+ channel could affect ICa and myocardial EC coupling.

Animals↗
PubMed1997

Placebo-controlled trial of sucralfate for inhibiting radiation-induced esophagitis.

PURPOSE: To determine whether a sucralfate oral solution can prevent/alleviate radiation-induced esophagitis. PATIENTS AND METHODS: Patients included on this clinical trial were beginning thoracic radiation therapy to the mediastinum. Following stratification, they were randomized, in a double-blind manner, to receive a sucralfate solution or an identical-appearing placebo solution. Esophagitis was measured by physicians who used standard criteria and also by patients who used short questionnaires completed weekly during the course of the trial. RESULTS: A total of 97 assessable patients were entered onto this clinical trial. During the first 2 weeks of the study, two placebo patients (4%) stopped their study medication, compared with 20 sucralfate patients (40%). This was related to substantially increased incidences of gastrointestinal toxicity (58% of sucralfate patients v 14% of placebo patients; P > .0001). There was no substantial benefit from the sucralfate in terms of esophagitis scores. CONCLUSION: This oral sucralfate solution does not appear to inhibit radiation-induced esophagitis and is associated with disagreeable gastrointestinal side effects in this patient population.

Administration, Oral↗
PubMed1996

Phase III double-blind evaluation of an aloe vera gel as a prophylactic agent for radiation-induced skin toxicity.

PURPOSE: Considerable pilot data and clinical experience suggested that an aloe vera gel might help to prevent radiation therapy-induced dermatitis. METHODS AND MATERIALS: Two Phase III randomized trials were conducted. The first one was double blinded, utilized a placebo gel, and involved 194 women receiving breast or chest wall irradiation. The second trial randomized 108 such patients to aloe vera gel vs. no treatment. Skin dermatitis was scored weekly during both trials both by patients and by health care providers. RESULTS: Skin dermatitis scores were virtually identical on both treatment arms during both of the trials. The only toxicity from the gel was rare contact dermatitis. CONCLUSIONS: This dose and schedule of an aloe vera gel does not protect against radiation therapy-induced dermatitis.

Adult↗
PubMed1996

Olsalazine is contraindicated during pelvic radiation therapy: results of a double-blind, randomized clinical trial.

PURPOSE: A randomized clinical trial from Great Britain suggested a possible beneficial effect of acetylsalicylate in the prevention of radiation-induced bowel toxicity. Olsalazine is an orally administered drug designed to deliver 5-aminosalicylate to the large bowel with minimal systemic absorption. A randomized clinical trial was undertaken to assess the effectiveness of olsalazine in preventing acute diarrhea in patients receiving pelvic radiation therapy. METHODS AND MATERIALS: Patients receiving pelvic radiation therapy were randomized, in double-blind fashion, to olsalazine 250 mg, two capsules twice daily, or an identical appearing placebo, two capsules twice daily. Patients were then evaluated weekly during radiation therapy for the primary study endpoint, diarrhea, as well as rectal bleeding, abdominal cramping, and tenesmus. RESULTS: The study was closed early, after entry of 58 evaluable patients, when a preliminary analysis showed excessive diarrhea in patients randomized to olsalazine. The incidence and severity of diarrhea were worse in patients randomized to olsalazine (p = 0.0036). Sixty percent of the patients randomized to olsalazine experienced Grade 3 or 4 diarrhea compared to only 14% randomized to placebo. There was also a trend toward higher incidence and greater severity of abdominal cramping in patients who were randomized to olsalazine (p = 0.084). CONCLUSION: Administration of olsalazine during pelvic radiation therapy resulted in an increased incidence and severity of diarrhea. Olsalazine is contraindicated in patients receiving pelvic radiation therapy.

Aged↗
PubMed1996

Na+/Ca2+ exchange currents and SR Ca2+ contents in postinfarction myocytes.

Myocytes isolated from rat hearts 3 wk after myocardial infarction (MI) had lower peak cytosolic free Ca2+ concentration ([Ca2+]i) and reduced maximal extent of cell shortening during contraction, but Ca2+ entry via L-type Ca2+ channels was normal. In the current study using whole cell patch-clamp technique, reverse Na+/Ca2+ exchange current (INa/Ca; 3 Na+ out:1 Ca2+ in) was measured in myocytes in which Na+, K+, and Ca2+ currents were blocked or minimized. Steady-state outward currents measured under these conditions increased with depolarization or with elevation of extracellular Ca2+ concentration ([Ca2+]o) from 1.8 to 5.0 mM, but were inhibited by 5 mM Ni2+ or by reduction of [Ca2+]i to near zero. In addition, reduction of cytosolic free Na+ concentration or of [Ca2+]i also decreased the amplitude of the outward current. These characteristics indicate the outward current was INa/Ca operating in reverse mode. Reverse INa/Ca was significantly lower in MI myocytes, especially at more positive voltages. In addition, sarcoplasmic reticulum (SR)-releasable Ca2+ content as estimated by integrating forward INa/Ca during caffeine-induced SR Ca2+ release was also significantly lower in MI myocytes. Depressed Na+/Ca2+ exchange activity may contribute to abnormal [Ca2+]i dynamics in MI myocytes.

Animals↗
PubMed1996

Chronic exercise enhances cardiac alpha 1-adrenergic inotropic responsiveness in rats with mild hypertension.

The singular and combined effects of mild renovascular hypertension (HTN) and chronic exercise on the contractile responsiveness of the heart to alpha 1-adrenergic receptor (alpha 1-AR) stimulation were determined. Age-matched normotensive and HTN male Fischer-344 rats were assigned to sedentary control or treadmill training groups. Left ventricular (LV) contractile performance was assessed by utilizing a modified isovolumic heart preparation at varying concentrations of phenylephrine (PE). Groups studied were normotensive sedentary (NSD), hypertensive sedentary (HSD), normotensive trained (NTR), and hypertensive trained (HTR). PE elicited increases in LV developed pressure (delta P), LV maximal rate of pressure development (dP/dt(max)), and LV dP/dt(max)/delta P in all experimental groups in a dose-dependent fashion. These PE-induced effects were representative of alpha 1-AR-mediated responses because they were observed in the presence of beta-adrenoceptor blockade with propranolol. Relative to NSD, the effects of PE on contractile function were attenuated in HSD and augmented in NTR and HTR hearts. The strength of extrasystolic contractions elicited by the delivery of a 300-ms extrasystolic interval at each of three different pacing frequencies (240, 270, and 300 beats/min) was greater in NTR and HTR and significantly reduced in HSD compared with NSD. Scatchard analysis of [3H]prazosin binding was used to assess alpha 1-AR number in myocardium isolated from each experimental group. Across all groups, a significant correlation was found between alpha 1-AR number and the inotropic responsiveness of the heart to PE stimulation. Collectively, these data provide evidence that mild HTN diminishes while training augments the inotropic responsiveness of the heart to alpha 1-AR stimulation. In addition, training appears to attenuate the adverse effects of mild HTN on the alpha 1-AR contractile responsiveness of the myocardium.

Adrenergic alpha-Agonists↗
PubMed1995

Molecular analysis of the same HIV peptide functionally binding to both a class I and a class II MHC molecule.

Although several peptides have been found to bind to both class I and class II molecules, the basis for this binding of the same peptide to two classes of MHC molecules has not been compared previously. We have analyzed one such peptide, P18 from the V3 loop of HIV-1 gp160, which we have previously shown to be recognized by CD8+ CTL with the class I molecule H-2Dd, and by CD4+ Th cells with the class II molecule I-Ad. With the use of truncated and substituted peptides, we found that the minimal core peptides are very similar, that the residues required for class I binding precisely fit the recently identified consensus motif for peptides binding to Dd (XGPX[R/K/H]XXX(X) [L/I/F]), and that at least three of the same residues are involved in binding to class II I-Ad. In addition, several of the same residues are involved in TCR interaction when the peptide is presented by class I and class II molecules. Modeling shows results to be consistent with the crystal structure of a peptide-class II MHC complex. Thus, the recognition of this versatile peptide by CD4+ Th cells with class II MHC molecules and by CD8+ cytotoxic T cells with class I MHC molecules is remarkably similar in both the core peptide used and the role of different residues in the ternary complex.

Amino Acid Sequence↗
PubMed1995

[Ca2+]i transients in hypertensive and postinfarction myocytes.

Changes in intracellular calcium concentration ([Ca2+]i) in paced fura 2-loaded myocytes isolated from Sham, renovascular hypertensive (Hyp), and myocardial-infarcted (MI) rats were examined. Compared with controls, Hyp myocytes paced at physiological rates had similar systolic but elevated diastolic [Ca2+]i. By contrast, systolic [Ca2+]i was significantly lower and diastolic [Ca2+]i higher in MI myocytes. The different patterns of alterations in [Ca2+]i dynamics in Hyp and MI myocytes may partly explain predominantly diastolic dysfunction in hypertensive hearts and systolic dysfunction in hearts surviving MI. In the presence of 1 microM isoproterenol, both Hyp and MI myocytes had much lower systolic [Ca2+]i when compared with their respective controls. Isoproterenol restored the elevated diastolic [Ca2+]i in Hyp myocytes toward normal but had no effect on the intrinsic differences in diastolic [Ca2+]i between Sham and MI myocytes. The observation that isoproterenol lowers diastolic [Ca2+]i in Hyp myocytes toward normal may provide a cellular mechanism for the lack of efficacy of beta-adrenergic blockers to improve diastolic compliance in patients with hypertensive hypertrophic cardiomyopathy.

Adrenergic beta-Agonists↗
PubMed1995

Calcium currents in postinfarction rat cardiac myocytes.

Myocytes isolated from rat hearts that have suffered 35% myocardial infarction (MI) 3 wk prior have lower peak cytosolic Ca2+ concentration ([Ca2+]i) during contraction compared with Sham myocytes, a difference that is amplified by isoproterenol or high extracellular Ca2+ concentration ([Ca2+]o). To evaluate whether reduced [Ca2+]i in MI myocytes is due to decreased Ca2+ entry, we measured [3H]PN-200-110 [dihydropyridine (DHP)] binding and whole cell Ca2+ current (ICa). DHP binding decreased in both sarcolemmal vesicles and intact myocytes from hearts 3 wk after MI. In contrast, ICa was not different between Sham and MI myocytes incubated at 1.8 mM [Ca2+]o. At 5.0 mM [Ca2+]o, ICa increased similarly in Sham and MI myocytes. Steady-state voltage dependence of activation and inactivation were similar between Sham and MI myocytes, as were the fast- and slow-inactivation time constants. Isoproterenol (1 microM) significantly increased ICa in Sham but not in MI myocytes. Forskolin (10 microM) dibutyryl adenosine 3',5'-cyclic monophosphate (5 mM) significantly increased ICa in MI myocytes; the magnitude of ICa increase was similar to that observed in Sham myocytes. We conclude that 1) decreased systolic [Ca2+]i in MI myocytes was not due to reduced Ca2+ entry via L-type Ca2+ channels; 2) discrepancy between DHP binding (decrease) and ICa (no change) results may be explained by higher channel availability and/or increased long-opening modes (mode 2) in MI myocytes; 3) reduction in isoproterenol-induced [Ca2+]i increase in MI myocytes was partly due to decreased ICa, resulting in less Ca2+ release from sarcoplasmic reticulum; 4) the adenylate cyclase-protein kinase A signal-transduction pathway functioned normally in MI myocytes; and 5) decreased beta-adrenergic responsiveness in MI myocytes was likely due to altered coupling by G proteins.

Animals↗