Search PubMed⌕ Search

Biomedical subjects

R L Moore

Publications and source records attributed to R L Moore.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1999

In situ SR function in postinfarction myocytes.

Previous studies have shown lower systolic intracellular Ca(2+) concentrations ([Ca(2+)](i)) and reduced sarcoplasmic reticulum (SR)-releasable Ca(2+) contents in myocytes isolated from rat hearts 3 wk after moderate myocardial infarction (MI). Ca(2+) entry via L-type Ca(2+) channels was normal, but that via reverse Na(+)/Ca(2+) exchange was depressed in 3-wk MI myocytes. To elucidate mechanisms of reduced SR Ca(2+) contents in MI myocytes, we measured SR Ca(2+) uptake and SR Ca(2+) leak in situ, i.e., in intact cardiac myocytes. For sham and MI myocytes, we first demonstrated that caffeine application to release SR Ca(2+) and inhibit SR Ca(2+) uptake resulted in a 10-fold prolongation of half-time (t(1/2)) of [Ca(2+)](i) transient decline compared with that measured during a normal twitch. These observations indicate that early decline of the [Ca(2+)](i) transient during a twitch in rat myocytes was primarily mediated by SR Ca(2+)-ATPase and that the t(1/2) of [Ca(2+)](i) decline is a measure of SR Ca(2+) uptake in situ. At 5.0 mM extracellular Ca(2+), systolic [Ca(2+)](i) was significantly (P </= 0.05) lower (337 +/- 11 and 416 +/- 18 nM in MI and sham, respectively) and t(1/2) of [Ca(2+)](i) decline was significantly longer (0.306 +/- 0.014 and 0.258 +/- 0.014 s in MI and sham, respectively) in MI myocytes. The 19% prolongation of t(1/2) of [Ca(2+) ](i) decline was associated with a 23% reduction in SR Ca(2+)-ATPase expression (detected by immunoblotting) in MI myocytes. SR Ca(2+) leak was measured by a novel electrophysiological technique that did not require assigning empirical constants for intracellular Ca(2+) buffering. SR Ca(2+) leak rate was not different between sham and MI myocytes: the time constants of SR Ca(2+) loss after thapsigargin were 290 and 268 s, respectively. We conclude that, independent of decreased SR filling by Ca(2+) influx, the lower SR Ca(2+) content in MI myocytes was due to reduced SR Ca(2+) uptake and SR Ca(2+)-ATPase expression, but not to enhanced SR Ca(2+) leak.

Animals↗
PubMed1999

Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy.

Multiple mutations in cardiac troponin T (cTnT) can cause familial hypertrophic cardiomyopathy (FHC). Patients with cTnT mutations generally exhibit mild or no ventricular hypertrophy, yet demonstrate a high frequency of early sudden death. To understand the functional basis of these phenotypes, we created transgenic mouse lines expressing 30%, 67%, and 92% of their total cTnT as a missense (R92Q) allele analogous to one found in FHC. Similar to a mouse FHC model expressing a truncated cTnT protein, the left ventricles of all R92Q lines are smaller than those of wild-type. In striking contrast to truncation mice, however, the R92Q hearts demonstrate significant induction of atrial natriuretic factor and beta-myosin heavy chain transcripts, interstitial fibrosis, and mitochondrial pathology. Isolated cardiac myocytes from R92Q mice have increased basal sarcomeric activation, impaired relaxation, and shorter sarcomere lengths. Isolated working heart data are consistent, showing hypercontractility and diastolic dysfunction, both of which are common findings in patients with FHC. These mice represent the first disease model to exhibit hypercontractility, as well as a unique model system for exploring the cellular pathogenesis of FHC. The distinct phenotypes of mice with different TnT alleles suggest that the clinical heterogeneity of FHC is at least partially due to allele-specific mechanisms.

Alleles↗
PubMed1999

Beta3-adrenergic regulation of leptin, food intake, and adiposity is impaired with age.

With age, there are increases in adiposity, leptin mRNA in white adipose tissue (WAT), and serum leptin levels in rats. Beta3-adrenergic agonists are anti-obesity agents in rodents, and activation of beta3-adrenergic receptors (beta3AR) mediates an acute decrease in food consumption, increased thermogenesis in brown adipose tissue (BAT), increased lipolysis in WAT, and suppression of leptin gene expression and serum leptin levels. Because beta3AR signal transduction is impaired with age in BAT and WAT, beta3AR-mediated regulation of leptin, feeding behavior, and adiposity may also be impaired with age. To test this hypothesis, we infused young (6 month) and old (24 month) F344 x BN rats with the beta3AR agonist CL316,243 (1 mg kg(-1) day(-1)) using osmotic minipumps for 7 days. Food intake, body mass, adiposity, and serum leptin, as well as leptin, uncoupling protein 1 (UCP1), and lipoprotein lipase (LPL) mRNA in BAT or WAT were determined. In young rats, CL316,243 infusion reduced body mass and adiposity, suppressed serum leptin and leptin mRNA levels in WAT, induced UCP1 in WAT, and increased UCP1 and LPL mRNA levels in BAT. Moreover, treatment with CL316,243 was associated with a marked but transient suppression of food intake. Most of the responses elicited in the old rats with CL316,243 treatment were qualitatively similar to those in the young rats, but blunted in magnitude. Beta3AR activation of adenylyl cyclase was also reduced in the aged rats. These data suggest that, although CL316,243 is an effective agent in aged rats, the maximum responses are reduced, suggesting that the impaired beta3AR signal transduction with age is a major determining factor in the reduced effectiveness of CL316,243 in older rats.

Adipose Tissue↗
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↗