Search PubMed⌕ Search

Biomedical subjects

J M Arnold

Publications and source records attributed to J M Arnold.

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

The effects of age on human venous responsiveness to neuropeptide Y.

AIMS: Neuropeptide Y (NPY) is a sympathetic neurotransmitter released with noradrenaline during sympathetic stimulation. Ageing has been shown to be associated with a reduction in alpha2 and beta-adrenoceptor mediated responses in veins, but it is not known whether NPY responsiveness is also altered with increasing age. METHODS: Using a dorsal hand vein technique, we examined NPY receptor responsiveness in 24 normal, healthy subjects (20-72 years; 10 males, 14 females). Graded infusions of NPY (25-2000 pmol min(-1)) were administered (5 min at each dose) into a dorsal hand vein. Venous distension at 45 mmHg was measured at 3-5 min of each infusion. Dose-response curves to NPY were constructed and the peak venoconstriction was calculated. RESULTS: Dose-dependent venoconstriction was seen in all but one subject. The peak venoconstriction observed with NPY was significantly and negatively correlated with the age of the normal subjects (r=-0.63, P<0.01). When subjects were ranked from youngest to oldest and divided into tertiles, (20-40 years, n = 8; 41-55 years, n = 8; 56-72 years, n = 8), mean dose-response curves were different with the oldest tertile being significantly less responsive (P<0.05). The peak venoconstriction observed (% of control) was 65.1+/-7.0, 46.5+/-9.4, and 24.4+/-4.8%, respectively. The oldest tertile had a significantly decreased peak venoconstriction compared with the youngest tertile (P<0.01). Infusion of NPY into a dorsal hand vein had no systemic effects on heart rate or blood pressure in any of the subjects studied. CONCLUSIONS: Hand vein responsiveness to exogenously infused NPY in normal subjects is decreased as age increases. The reduction of NPY-receptor-mediated responses with age may influence sympathetic nervous system control of the venous system with advancing age.

Adult↗
PubMed1999

Long-term changes in connexin32 gap junction protein and mRNA expression following cocaine self-administration in rats.

Considerable evidence indicates a critical role for dopamine in the reinforcing effects of cocaine. Because dopamine has been shown to be a critical modulator of gap junction communication in both eye and brain, we sought to examine whether extended intravenous cocaine self-administration would affect the expression of gap junction channel-forming proteins (connexins). Using ELISA, Western analysis, immunohistochemistry, semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR), and non-radioactive in situ hybridization, we demonstrate that withdrawal from chronic cocaine self-administration causes lasting changes in connexin32 (Cx32) expression in the nucleus accumbens and hippocampus at 2, 7 and 21 days after the last cocaine injection. A sustained decrease in Cx32 protein and mRNA levels is noted in areas that have been implicated in cocaine craving (i.e. nucleus accumbens and subfields of the hippocampal formation). A progressive increase in gap junction protein and mRNA expression is noted in areas that become hyperexcitable after chronic cocaine exposure (i.e. CA1 hippocampal neurons). We speculate that gap junction communication may be critically involved in reinforcement processes and neuroadaptive changes produced by drugs of abuse.

Animals↗
PubMed1999

Stability of solitary wave trains in Hamiltonian wave systems.

A class of Hamiltonian nonlinear wave equations possessing complex solitary waves with exponential decay is studied. It is shown that the interpulse interactions in a train of nearly identical solitary waves with large separations between the individual solitary waves are approximately described by a double Toda lattice system, with two variables at each lattice site. Under certain conditions, which are explicitly identified as Cauchy-Riemann equations, the two dynamical variables are real and imaginary parts of a single complex variable, leading to the complex Toda lattice equations, which is a discrete integrable dynamical system. This analysis generalizes to certain nonintegrable partial differential equations a recent result for the nonlinear Schrödinger equation, and is important for the study of nonlinear communications channels in optical fibers. An example, the cubic-quintic nonlinear Schrödinger equation, is worked out in detail to show that the theory can be carried through analytically. The theory is used to determine the stability of an infinite chain of nearly identical pulses separated by large time intervals. The entire theory is nonperturbative in the sense that the nonlinear wave equation need not be a weak perturbation of an integrable one.

Journal Article↗
PubMed1999

Orally administered NHE1 inhibitor cariporide reduces acute responses to coronary occlusion and reperfusion.

Na+/H+ exchange (NHE) mediates myocardial ischemic and reperfusion injury. We examined the effects of dietary administration of the potent and selective NHE1 inhibitor cariporide on acute responses to coronary artery ligation and reperfusion in the anesthetized rat. Male Sprague-Dawley rats received control rat chow or an identical diet containing 3 parts per million of cariporide for 1 wk before 225 min of occlusion of the left main coronary artery or 45 min of occlusion followed by 180 min of reperfusion. Hearts were excised and divided into left ventricle, right ventricle, and interventricular septum for analysis of NHE1 mRNA expression and apoptosis by staining with terminal deoxynucleotidyl transferase-mediated nick end labeling. Ischemia and reperfusion were associated with a threefold elevation in NHE1 mRNA expression in control animals that was significantly reduced in cariporide-fed rats. Cariporide reduced mortality from 26% of animals to 0%. The incidence of all arrhythmias was significantly reduced, including ventricular fibrillation (from 42 to 0%) and ventricular tachycardia (from 81 to 15%), as well as the number of ventricular premature beats (from 70 +/- 12 to 17 +/- 6). Cariporide moderately reduced apoptosis only in the reperfused left ventricle to values not significantly greater than those in sham-operated animals, and this was associated with a significantly higher ratio of Bcl-2 to Bax. This study suggests that NHE inhibition with dietary cariporide represents an effective management of acute postinfarction responses.

Administration, Oral↗
PubMed1999

Hemps, a novel EGF-like protein, plays a central role in ascidian metamorphosis.

All chordates share several characteristic features including a dorsal hollow neural tube, a notochord, a pharynx and an endostyle. Unlike other chordate taxa, ascidians have a biphasic life-history with two distinct body plans. During metamorphosis, the larval nerve cord and notochord degenerate and the pharyngeal gill slits and endostyle form. While ascidians, like other marine invertebrates, metamorphose in response to specific environmental cues, it remains unclear how these cues trigger metamorphosis. We have identified a novel gene (Hemps) which encodes a protein with a putative secretion signal sequence and four epidermal growth factor (EGF)-like repeats which is a key regulator of metamorphosis in the ascidian Herdmania curvata. Expression of Hemps increases markedly when the swimming tadpole larva becomes competent to undergo metamorphosis and then during the first 24 hours of metamorphosis. The Hemps protein is localised to the larval papillae and anterior epidermis of the larva in the region known to be required for metamorphosis. When the larva contacts an inductive cue the protein is released, spreading posteriorly and into the tunic as metamorphosis progresses. Metamorphosis is blocked by incubating larvae in anti-Hemps antibodies prior to the addition of the cue. Addition of recombinant Hemps protein to competent larvae induces metamorphosis in a concentration-dependent manner. A subgroup of genes are specifically induced during this process. These results demonstrate that the Hemps protein is a key regulator of ascidian metamorphosis and is distinct from previously described inducers of this process in terrestrial arthropods and aquatic vertebrates.

Animals↗
PubMed1998

Clusterin biogenesis is altered during apoptosis in the regressing rat ventral prostate.

Clusterin was first characterized as an apoptosis-associated transcript after it was identified as testosterone-repressed prostate message (TRPM-2) that is expressed in the epithelial cells of the regressing rat ventral prostate. Increases in clusterin mRNA and protein have been consistently detected in apoptotic cell death paradigms, establishing clusterin gene expression as a prominent marker of apoptotic cell loss. However, enhanced protein expression has also been reported in surviving cells. This ambiguity makes it difficult to define the contribution of clusterin to apoptosis. To address this problem, a panel of polyclonal and monoclonal antibodies were raised against the clusterin alpha-chain, beta-chain, and mixed alpha/beta epitopes. These antibodies detect changes in the biogenesis of clusterin during apoptosis by Western analysis and immunohistochemistry. A 42-kDa glyco/isoform of clusterin appears to be up-regulated in dying epithelial cells. This glyco/isoform is apparently generated as a result of apoptosis-induced stimulation of a normal but under-utilized, synthetic pathway. These data demonstrate that clusterin synthesized by apoptotic cells can be immunologically distinguished from clusterin synthesized by surviving cells in damaged tissue.

Amino Acid Sequence↗
PubMed1998

Promoter trapping identifies real genes in C. elegans.

Promoter trapping involved screening uncharacterized fragments of C. elegans genomic DNA for C. elegans promoter activity. By sequencing the ends of these DNA fragments and locating their genomic origin using the available genome sequence data, promoter trapping has now been shown to identify real promoters of real genes, exactly as anticipated. Developmental expression patterns have thereby been linked to gene sequence, allowing further inferences on gene function to be drawn. Some expression patterns generated by promoter trapping include subcellular details. Localization to the surface of particular cells or even particular aspects of the cell surface was found to be consistent with the genes, now associated with these patterns, encoding membrane-spanning proteins. Data on gene expression patterns are easier to generate and characterize than mutant phenotypes and may provide the best means of interpreting the large quantity of sequence data currently being generated in genome projects.

Animals↗
PubMed1998

Elevation of an endogenous inhibitor of nitric oxide synthesis in experimental congestive heart failure.

OBJECTIVE: NG,NG-dimethylarginine (asymmetric dimethylarginine, ADMA) is an important endogenous substance with potent inhibitory actions on nitric oxide (NO) synthesis. The present study was designed to determine circulating ADMA levels and endothelium-dependent, NO mediated vasodilation in a rat model of congestive heart failure (CHF). METHODS: CHF was induced in rats by coronary artery ligation. Sham-operated rats served as normal controls. Plasma ADMA was determined by high performance liquid chromatography with fluorescence detection. Glomerular filtration rate (GFR) and renal blood flow (RBF) were measured by the clearance of inulin and p-aminohippuric acid, respectively. Endothelial function of the aorta was assessed in an organ bath. RESULTS: Plasma levels of ADMA in rats with CHF (0.94 +/- 0.05 mumol/l) were significantly increased compared with sham-operated controls (0.75 +/- 0.06 mumol/l, p < 0.05). Plasma levels of ADMA was negatively correlated with GFR (r = -0.65, p < 0.05). Decreased endothelium-dependent relaxation to acetylcholine in the aorta of CHF was completely restored by L-arginine (300 microM) (p < 0.01) while endothelium-independent relaxation to nitroprusside was not altered. ADMA potently inhibited endothelium-dependent relaxation in thoracic aorta of normal and CHF rats. The effect of ADMA was completely antagonized by L-arginine in both groups (p < 0.01). Moreover, L-arginine improved endothelium-dependent relaxation in CHF rats in the presence of ADMA. CONCLUSIONS: An endogenous NO synthesis inhibitor ADMA is increased in the circulation of rats with CHF. The increased plasma levels of ADMA may contribute to the decreased endothelium-dependent relaxation in CHF, which is restored by L-arginine, possibly by competitive antagonism of ADMA.

Acetylcholine↗
PubMed1998

Enhanced in vivo alpha1- and alpha2-adrenoceptor-mediated venoconstriction with indomethacin in humans.

Vasodilator prostaglandins are released in vitro from endothelium during adrenergic stimulation. We hypothesized that indomethacin would block this production in vivo and increase venoconstriction to alpha1- and alpha2-stimulation but not to the nonadrenergic agonist PGF2alpha. Hand vein distension was measured in 24 normal subjects (23.0 +/- 0.5 yr) during local infusions of phenylephrine (8-12,000 ng/min), clonidine (3-7,000 ng/min), or PGF2alpha (1-2,048 ng/min) plus indomethacin (3 microg/min) versus saline on two separate days. Dose-dependent venoconstriction to phenylephrine occurred in all subjects, with a parallel shift to the left with indomethacin (P = 0. 003) and a decrease in the phenylephrine 50% effective dose (1,009 vs. 241 ng/min, geometric means, P = 0.012). Venoconstriction to clonidine was more variable, with most subjects eliciting a biphasic response (initial venoconstriction followed by attenuation). With indomethacin, the dose-response curve was displaced up and to the left (P = 0.005), and peak venoconstriction was increased (51.1 +/- 6.8 vs. 27.2 +/- 5.3% of control, P = 0.018) without a biphasic response. In all subjects, PGF2alpha elicited dose-dependent venoconstriction that was not altered by indomethacin. Thus venous alpha1- and alpha2-stimulation results in release of vasodilator prostaglandins that antagonize the venoconstrictor response. This modulates the sympathetic response of venous smooth muscle and may be important in diseases with endothelial dysfunction.

Adrenergic alpha-Agonists↗
PubMed1997

Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. HEART Study Investigators.

BACKGROUND: The long-term administration of ACE inhibitors to selected patients with left ventricular dysfunction appears to reduce the incidence of recurrent myocardial infarction (MI) and unstable angina pectoris. The mechanisms responsible for the reduction in ischemic events are unknown, but likely candidates include effects on the atherosclerotic process, thrombosis, and/or vascular tone. METHODS AND RESULTS: The effects of ACE inhibitor therapy with ramipril on plasma fibrinolytic variables were assessed in 120 subjects participating in the Healing and Early Afterload Reduction Therapy (HEART) study, a double-blind, placebo-controlled trial of acute anterior MI patients who were randomly assigned within 24 hours of the onset of symptoms to receive low-dose ramipril (0.625 mg daily), full-dose ramipril (1.25 mg titrated to 10 mg/d), or placebo for 14 days. Plasma levels of plasminogen activator inhibitor-1 (PAI-1) activity and PAI-1 antigen and tissue plasminogen activator (TPA) antigen were measured before randomization and on day 14. Clinical characteristics of the three study groups were similar, as were the prerandomization plasma levels of PAI-1 antigen, PAI-1 activity, and TPA antigen. Compared with the placebo group, PAI-1 antigen levels were 44% lower (P=.004) at day 14 in the ramipril-treated patients, and PAI-1 activity levels were 22% lower (P=.02). In contrast, plasma TPA levels were not significantly different between the placebo-treated and ramipril-treated groups. CONCLUSIONS: Treatment with ramipril has a significant impact on plasma fibrinolytic variables during the recovery phase after acute MI. The renin-angiotensin system appears to play an important role in the regulation of vascular fibrinolysis, and interruption of this regulatory pathway may contribute to the clinical benefits of ACE inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Early versus delayed angiotensin-converting enzyme inhibition therapy in acute myocardial infarction. The healing and early afterload reducing therapy trial.

BACKGROUND: Although ACE inhibitor therapy has been shown to reduce mortality in patients with acute myocardial infarction (MI), the optimal dose and the timing of its initiation have not been determined. METHODS AND RESULTS: In a double-blind trial of 352 patients with anterior MI, we compared the safety and effectiveness of early (day 1) versus delayed (day 14) initiation of the ACE inhibitor ramipril (10 mg) on echocardiographic measures of left ventricular (LV) area and ejection fraction (EF). An early, low-dose ramipril (0.625 mg) arm was also evaluated. Clinical events did not differ. During the first 14 days, the risk of manifesting a systolic arterial pressure of < or = 90 mm Hg was increased in both ramipril groups. LVEF increased in all groups during this period, but the early, full-dose ramipril group had the greatest improvement in EF (increase: full, 4.9 +/- 10.0; low, 3.9 +/- 8.2%; delayed, 2.4 +/- 8.8%; P for trend < .05) and was the only group that did not demonstrate a significant increase in LV diastolic area. CONCLUSIONS: The results of the present study demonstrated that in patients with anterior MI, the early use of ramipril (titrated to 10 mg) attenuated LV remodeling and was associated with a prompter recovery of LVEF. The use of low-dose regimen did not prevent hypotension and had only intermediate benefits on LV size and function. The more favorable effects on LV topography of the early use of full-dose ramipril support the results of the major clinical trials, which have demonstrated an early survival benefit of ACE inhibition.

Aged↗
PubMed1997

Novel gene containing multiple epidermal growth factor-like motifs transiently expressed in the papillae of the ascidian tadpole larvae.

We have investigated molecular mechanisms of the embryonic development of an ascidian, a primitive chordate which shares features of both invertebrates and vertebrates, with a view to identifying genes involved in development and metamorphosis. We isolated 12 partial cDNA sequences which were expressed in a stage-specific manner using differential display. We report here the isolation of a full-length cDNA sequence for one of these genes which was specifically expressed during the tailbud and larval stages of ascidian development. This cDNA, 1213 bp in length, is predicted to encode a protein of 337 amino acids containing four epidermal growth factor (EGF)-like repeats and three novel cysteine-rich repeats. Characterization of its spatial expression pattern by in situ hybridisation in late tailbud and larval embryos demonstrated strong expression localised throughout the papillae and anteriormost trunk and weaker expression in the epidermis of the remainder of the embryo. As recent evidence indicates that the signal for metamorphosis originates in the anterior trunk region, these results suggest that this gene may have a role in signalling the initiation of metamorphosis.

Amino Acid Sequence↗
PubMed1997

A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement.

This paper is a critique of fixed and progressive ratio schedules used to examine the neural substrates of cocaine reinforcement. The discussion focuses on problems encountered while examining the effects of neurotoxic lesions and pharmacological pretreatments on cocaine reinforcement. We review the theoretical and interpretational problems associated with the use of the fixed ratio (FR) schedules that have been used in the majority of studies, and we conclude that rate of drug intake cannot directly address the issue of increased or decreased reinforcer efficacy. The progressive ratio (PR) schedule offers some advantages over FR schedules, although it is now clear that the same implementation cannot be applied across all drug classes. It is likely that the motivation to self-administer psychostimulant vs. opiate drugs is qualitatively different. We conclude that there is no single schedule that can quantify all aspects of drug reinforcement and that behavioral paradigms will need to be adapted according to the particular question under study.

Animals↗
PubMed1997

Additive beneficial effects of beta-blockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. SAVE Investigators.

OBJECTIVES: This study assessed whether treatment with a beta-adrenergic blocking agent in addition to the use of the angiotensin-converting enzyme (ACE) inhibitor captopril decreases cardiovascular mortality and morbidity in patients with asymptomatic left ventricular dysfunction after myocardial infarction (MI) and whether the presence of neurohumoral activation at the time of hospital discharge predicts the effects of beta-blocker treatment in these patients. BACKGROUND: Both beta-blockers and ACE inhibitors have been shown to have beneficial effects in patients with left ventricular dysfunction but no overt heart failure after MI. These patients often have persistent neurohumoral activation at the time of hospital discharge, and one would expect that patients with activation of the sympathetic nervous system derive the most benefit from treatment with beta-blockers. However, beta-blockers are underutilized in this high risk group of patients, and it is unknown whether their beneficial effects are additive to those of ACE inhibitors. METHODS: We performed a retrospective analysis of data from the Survival and Ventricular Enlargement (SAVE) study and its neurohumoral substudy. The relations between beta-blocker use at the time of randomization and neurohumoral activation and the subsequent development of cardiovascular events were analyzed by use of Cox proportional hazards models controlling for covariates. RESULTS: After adjustment for baseline imbalances, beta-blocker use was associated with a significant reduction in risk of cardiovascular death (30%, 95% confidence interval [CI] 12% to 44%) and development of heart failure (21%, 95% CI 3% to 36%), but the reduction in recurrent MI (11%, 95% CI 13% to 31%) was not significant. These reductions were independent of the use of captopril. Beta-blockers were not found to have a greater effect in patients with neurohumoral activation at the time of hospital discharge. CONCLUSIONS: The beneficial effects of beta-blocker use at the time of hospital discharge in patients with asymptomatic left ventricular dysfunction after MI appear to be additive to those of captopril and other interventions known to improve prognosis. Neurohumoral activation at the time of hospital discharge fails to identify those patients who will derive the greatest benefit from treatment with beta-blockers.

Adrenergic beta-Antagonists↗
PubMed1996

The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.

BACKGROUND: In patients with high cholesterol levels, lowering the cholesterol level reduces the risk of coronary events, but the effect of lowering cholesterol levels in the majority of patients with coronary disease, who have average levels, is less clear. METHODS: In a double-blind trial lasting five years we administered either 40 mg of pravastatin per day or placebo to 4159 patients (3583 men and 576 women) with myocardial infarction who had plasma total cholesterol levels below 240 mg per deciliter (mean, 209) and low-density lipoprotein (LDL) cholesterol levels of 115 to 174 mg per deciliter (mean, 139). The primary end point was a fatal coronary event or a nonfatal myocardial infarction. RESULTS: The frequency of the primary end point was 10.2 percent in the pravastatin group and 13.2 percent in the placebo group, an absolute difference of 3 percentage points and a 24 percent reduction in risk (95 percent confidence interval, 9 to 36 percent; P = 0.003). Coronary bypass surgery was needed in 7.5 percent of the patients in the pravastatin group and 10 percent of those in the placebo group, a 26 percent reduction (P=0.005), and coronary angioplasty was needed in 8.3 percent of the pravastatin group and 10.5 percent of the placebo group, a 23 percent reduction (P=0.01). The frequency of stroke was reduced by 31 percent (P=0.03). There were no significant differences in overall mortality or mortality from noncardiovascular causes. Pravastatin lowered the rate of coronary events more among women than among men. The reduction in coronary events was also greater in patients with higher pretreatment levels of LDL cholesterol. CONCLUSIONS: These results demonstrate that the benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levels.

Adult↗
PubMed1996

Erythromycin-felodipine interaction: magnitude, mechanism, and comparison with grapefruit juice.

OBJECTIVE: To investigate a potentially marked effect by erythromycin on felodipine pharmacokinetics, to characterize the mechanism, and to compare the interaction with that between grapefruit juice and felodipine. METHODS: Felodipine, 10 mg extended release, was administered with 250 ml water, 250 mg erythromycin, or 250 ml grapefruit juice in a randomized crossover study of 12 healthy men. Erythromycin base, 250 mg four times a day, was started the day before and continued on that study day. Pharmacokinetic values of felodipine, the primary metabolite dehydrofelodipine, and the major secondary derivative M3 metabolite were studied. RESULTS: Compared with water, erythromycin produced severalfold higher felodipine area under the plasma drug concentration-time profile (AUC), plasma peak drug concentration (Cmax), and apparent elimination half-life (t1/2); however, the effect was variable among individuals. Erythromycin augmented dehydrofelodipine AUC, Cmax, and t1/2 but decreased dehydrofelodipine/felodipine ratios. The AUC of the M3 metabolite and the M3 metabolite/dehydrofelodipine ratios were reduced. These findings support inhibition of both metabolic pathways likely mediated by CYP3A4. Grapefruit juice produced similar mean effects but did not prolong felodipine or dehydrofelodipine t1/2. Individually, felodipine AUC with erythromycin was greater than or similar to that with grapefruit juice. Relative felodipine AUC (erythromycin compared with grapefruit juice) correlated with relative felodipine Cmax but not with relative felodipine t1/2, suggesting felodipine AUC differed between these treatments, mainly from factors affecting presystemic drug elimination. CONCLUSIONS: Erythromycin produced an important pharmacokinetic interaction with felodipine by inhibition of drug metabolism. Although erythromycin and grapefruit juice shared a common mechanism, erythromycin likely reduced felodipine biotransformation at the gut wall and liver, whereas single-dose grapefruit juice had an effect mainly at the gut wall.

Adolescent↗