Biomedical subjects

D A Taylor

Publications and source records attributed to D A Taylor.

At least 55 records · Page 3Linked to original sources

PubMed1998

Involvement of serotonin in the modulation of cocaine-induced locomotor activity in the rat.

The influence of serotonin (5-HT) antagonists and a selective serotonin reuptake inhibitor (SSRI) on cocaine-induced locomotor activity, rears, and head bobs was investigated in female Glaxo Wistar rats. The SSRI, fluoxetine (10 mg/kg), and the nonselective 5-HT agent, methysergide, at the dose range of 5 and 15 mg/kg enhanced the behaviors produced by cocaine (15 mg/kg) to a similar extent. Moreover, the potentiation of cocaine-induced locomotor activity, rears, and head bobs was even greater after the combined administration of methysergide ( 15 mg/kg) and fluoxetine (10 mg/kg). In order to investigate a possible involvement of 5-HT1A receptors in the observed potentiation by methysergide and fluoxetine, the potent and selective 5-HT1A antagonist, WAY 100635, was used. WAY 100635 (0.1 and 1.5 mg/kg) markedly reduced the behaviors induced by cocaine preceded by fluoxetine (10 mg/kg) and methysergide (5 and 15 mg/kg) pretreatment, respectively, suggesting an involvement of 5-HT1A receptors in the action of fluoxetine and methysergide on cocaine-induced behaviors. An attenuation of the fluoxetine-enhanced cocaine-induced behaviors was also observed after pretreatment with the 5-HT2A antagonist ketanserin (0.1 and 1.0 mg/kg). Coadministration of ketanserin (1.0 mg/kg) and WAY 100635 (1.5 mg/kg) resulted in the greatest blockade of the fluoxetine-enhanced cocaine-induced behaviors. The antagonists and the SSRI, fluoxetine, did not alter the behaviors in comparison to that of saline-treated animals. These results provide evidence for an involvement of 5-HT1A receptors in the enhancing effect of fluoxetine and methysergide on cocaine-induced locomotor activity, rears, and head bobs, and suggest a stimulatory action of methysergide at the 5-HT1A receptor. In addition, some of the actions may also be mediated by activation of the 5-HT2A receptor and/or inhibition of the 5-HT2C receptor.

Animals↗

PubMed1998

Regenerating functional myocardium: improved performance after skeletal myoblast transplantation.

The adult heart lacks reserve cardiocytes and cannot regenerate. Therefore, a large acute myocardial infarction often develops into congestive heart failure. To attempt to prevent this progression, we transplanted skeletal myoblasts into cryoinfarcted myocardium of the same rabbits (autologous transfer), monitored cardiac function in vivo for two to six weeks and examined serial sections of the hearts by light and electron microscopy. Islands of different sizes comprising elongated, striated cells that retained characteristics of both skeletal and cardiac cells were found in the cryoinfarct. In rabbits in which myoblasts were incorporated, myocardial performance was improved. The ability to regenerate functioning muscle after autologous myoblast transplantation could have a important effect on patients after acute myocardial infarction.

Animals↗

PubMed1998

Modulation of delta9-tetrahydrocannabinol-induced hypothermia by fluoxetine in the rat.

1. It has been suggested that the dose of delta9-tetrahydrocannabinol (delta9-THC) that induces hypothermia in the rat increases the release of brain 5-hydroxytryptamine (5-HT). In light of this, we investigated the hypothermia produced by delta4-THC, and the effect the selective serotonin reuptake inhibitor fluoxetine has on this response. 2. A significant dose-dependent decrease in body temperature occurred after i.v. administration of 0.5 to 5 mg kg(-1) delta9-THC; maximum decreases being 0.8+/-0.2 degrees C to 2.9+/-0.3 degrees C. This hypothermic response was attenuated by the cannabinoid CB1 receptor antagonist SR 141716. 3. Fluoxetine (10 mg kg(-1) i.p.) alone caused a decrease in body temperature of 0.6+/-0.1 degrees C (n=32, P < 0.05) after 40 min. However, pretreatment with fluoxetine (10 mg kg(-1) i.p.) 40 min before delta9-THC significantly reduced the delta9-THC-induced hypothermia (n=7-8, P < 0.05). Contrary to this antagonist-like effect, fluoxetine administered 40 min after delta9-THC significantly potentiated the delta9-THC-induced hypothermia, producing a maximum decrease of 3.2+/-0.3 degrees C. 4. It is suggested that the effect of fluoxetine on the delta9-THC-induced hypothermic response is dependent on the time of its administration relative to that of delta9-THC. Pretreatment with fluoxetine increases extracellular 5-HT due to reuptake inhibition. Increased extracellular 5-HT can activate autoreceptors which may decrease serotonergic activity, thereby reducing the delta9-THC-induced hypothermia. Conversely, when fluoxetine is administered after delta9-THC, the reuptake block is thought to potentiate the already activated serotonergic system, hence potentiating the delta9-THC-induced hypothermia.

Animals↗

PubMed1998

Preparation and application of an isolated superior mesenteric arterial vascular preparation.

Our laboratory developed an isolated perfused superior mesenteric arterial vascular bed preparation to study and correlate vascular smooth-muscle mechanics with associated biochemical events. This preparation provides consistent dose-dependent contractile responses, contains most of the superior mesenteric artery as well as first-, second-, and third-generation arterioles, and has been used for concurrent functional and biochemical analysis of vascular smooth muscle. Preparations isolated from Sprague-Dawley rats produced rapid, dose-related vasoconstrictor responses to norepinephrine (NE) and KCl, while appearing to be unresponsive to periarterial nerve stimulation. Endothelial relaxations to bolus doses of acetylcholine (ACh) in the presence of a constant infusion of NE (10 microM) were limited, producing reductions of perfusion pressures of <25%. Receptor-binding studies conducted to evaluate alpha1-adrenoceptor subtypes revealed high- and low-affinity binding sites composing 91 and 9% of the overall population, respectively. A 60-s time course for contractile response and inositol 1,4,5-triphosphate (IP3) production revealed a significant but transient increase of IP3 that paralleled the contractile response generated by using bolus injections of NE (30 microg). This preparation offers the capacity to conduct perfusion studies investigating vasoconstrictor responses, as well as biochemical studies including receptor-binding and second-messenger assays in the same tissue.

Acetylcholine↗

PubMed1998

Effect of endogenous nitric oxide inhibition on airway responsiveness to histamine and adenosine-5'-monophosphate in asthma.

BACKGROUND: Nitric oxide (NO) may be bronchoprotective in asthma, possibly due to a direct action on airway smooth muscle or through mast cell stabilisation. To investigate this the effects of two doses of nebulised NG-nitro-L-arginine methyl ester (L-NAME), a non-selective NO synthase (NOS) inhibitor, on exhaled NO levels and airway responsiveness to histamine, a direct smooth muscle spasmogen, and adenosine-5'-monophosphate (AMP), an indirect spasmogen which activates mast cells, were evaluated in patients with mild asthma. METHODS: The study consisted of two phases each with a double blind, randomised, crossover design. In phase 1, 15 subjects inhaled either L-NAME 54 mg or 0.9% saline 30 minutes before histamine challenge. Nine of these subjects were studied in a similar fashion but were also challenged with AMP. In phase 2, 13 subjects (eight from phase 1) performed the same protocol but inhaled L-NAME in a dose of 170 mg or 0.9% saline before being challenged with histamine and AMP. RESULTS: The mean (95% CI) reduction in exhaled NO levels after L-NAME 54 mg was 78% (66 to 90) but this did not alter airway responsiveness; the geometric mean (SE) concentration provoking a fall of 20% or more in forced expiratory volume in one second (PC20) after L-NAME and saline was 0.59 (1.26) and 0.81 (1.26) mg/ml, respectively, for histamine and 20.2 (1.7) and 17.2 (1.6) mg/ml, respectively, for AMP. In contrast, L-NAME 170 mg reduced NO levels to a similar extent (81% (95% CI 76 to 87)) but increased airway responsiveness by approximately one doubling dose to both spasmogens; the geometric mean (SE) PC20 for histamine after L-NAME 170 mg and saline was 0.82 (1.29) and 1.78 (1.19) mg/ml, respectively (p < 0.001), and for AMP was 11.8 (1.5) and 24.3 (1.4) mg/ml, respectively (p < 0.001). CONCLUSIONS: These results suggest that L-NAME increases airway responsiveness in asthma. This may occur through mechanisms separate from NO inhibition or through pathways independent of those responsible for production of NO measured in exhaled air.

Adenosine Monophosphate↗

PubMed1998

Induction and maintenance of increased VEGF protein by chronic motor nerve stimulation in skeletal muscle.

Vascular endothelial growth factor (VEGF) causes endothelial cell proliferation in vitro and angiogenesis in vivo. Glycolytic skeletal muscles have a lower capillary density than oxidative muscles but can increase their capillary density and convert to a more oxidative phenotype when subject to chronic motor nerve stimulation (CMNS). We used Western analysis and immunohistochemical techniques to examine VEGF protein in a rabbit CMNS model of glycolytic skeletal muscle and in muscles with innate glycolytic versus oxidative phenotypes. VEGF protein per gram of total protein was increased in stimulated vs. control muscles 2.9 +/- 1.0, 3.6 +/- 1.3, 3.1 +/- 0.5, 4.4 +/- 1.6, and 2.7 +/- 0.3 times after 3 (n = 4), 5 (n = 2), 10 (n = 3), 21 (n = 3), and 56 (n = 2) days, respectively. VEGF protein was increased 3.1 +/- 0.5 times (P < 0.005) before (3, 5, and 10 days) and remained elevated 3.7 +/- 1.0 times (P < 0.05) after (21 and 56 days) the transition to an oxidative phenotype. By immunohistochemistry, VEGF protein was found primarily in the matrix between stimulated muscle fibers but not in the myocytes. In addition, VEGF protein was consistently lower in innate glycolytic compared with oxidative muscles. These findings suggest that VEGF plays a role in the alteration and maintenance of vascular density in mammalian skeletal muscles.

Animals↗

PubMed1998

A load-independent in vivo model for evaluating therapeutic interventions in injured myocardium.

Although cardiomyocyte damage is normally irreversible, gene therapy and somatic cell transfer offer potential for improving function in damaged regions of the heart. However, in ischemic models of injury, variability in depth, size, and location of damage compromises statistical evaluation of in vivo function. We have adapted cryoablation to create a reproducible, posterior, transmural lesion within rabbit myocardium in which small changes in function are measurable in vivo. Before and at 2 and 6 wk postinjury, in vivo left ventricular intracavitary pressure and myocardial segment length were measured. Regional indexes of performance, segmental stroke work (SW), and percent systolic shortening (SS) were significantly decreased (P < 0.001) postcryoinjury as was the slope (Mw) of the linear preload recruitable SW relationship between SW and end-diastolic segment length (P = 0.0001). Decreased SW, SS, and Mw correlated with wall thinning, loss of myocytes, presence of fibroblasts, and transmural scar formation. Reproducible changes in regional myocardial performance in vivo postcryoinjury suggest that this is a reasonable model for evaluating novel therapies for cardiovascular disease.

Animals↗

PubMed1998

Allergen-induced early and late asthmatic responses are not affected by inhibition of endogenous nitric oxide.

Endogenous exhaled nitric oxide (NO) is increased during the late response to inhaled allergen in patients with asthma and may be bronchoprotective in asthma or have a deleterious effect when generated in excess under inflammatory conditions. To investigate this, we evaluated the effect of inhibiting endogenous NO production with nebulized NG-nitro-L-arginine methyl ester (L-NAME), a nonselective NO synthase (NOS) inhibitor, on early and late asthmatic responses to inhaled allergen in patients with mild allergic asthma. After a screening allergen challenge (AC), 22 male patients attended two visits conducted in a double-blind, randomized, placebo-controlled, crossover manner. Twelve patients demonstrating an early asthmatic response only (single responders) inhaled either L-NAME 170 mg or 0.9% saline 20 min before AC, with exhaled NO and FEV1 measured for 3 h. Ten patients demonstrating both early and late asthmatic responses (dual responders) were studied in a similar fashion but inhaled two further doses of L-NAME or placebo 3.5 and 7 h after the initial dose, with exhaled NO and FEV1 measured for 10 h. L-NAME reduced exhaled NO levels by 77 +/- 5% (p < 0.01) and 71 +/- 7% (p < 0.01) in single and dual responders, respectively, but had no significant effect on early or late asthmatic responses. Following AC in single responders, the mean (+/- SEM) maximum fall in FEV1 after L-NAME and saline was 21.2 +/- 2.9% and 23.8 +/- 3.0%, respectively, and in dual responders, 31.2 +/- 4.5% and 31.8 +/- 5. 8% during the early asthmatic responses, and 27.4 +/- 3.9% and 30.6 +/- 4.5% during the late asthmatic responses, respectively. Area under the curve (AUC) did not significantly differ. AUC0-2 h in single responders after L-NAME and saline was 20.2 +/- 3.9 and 24.9 +/- 4.4 Delta% FEV1/h, and in dual responders, 37.6 +/- 8.4 and 36.7 +/- 8.4 Delta% FEV1/h, respectively, and 106.2 +/- 18.9 and 117.1 +/- 22.4 Delta% FEV1/h, respectively, for the AUC4-10 h. This study suggests that in mild allergic asthma, endogenous NO neither protects against nor contributes to the processes underlying airway responses to inhaled allergen.

Adult↗

PubMed1998

Regulation of carbohydrate and fatty acid utilization by L-carnitine during cardiac development and hypoxia.

This study is designed to investigate whether substrate preference in the myocardium during the neonatal period and hypoxia-induced stress is controlled intracellularly or by extracellular substrate availability. To determine this, the effect of exogenous L-carnitine on the regulation of carbohydrate and fatty acid metabolism was determined during cardiac stress (hypoxia) and during the postnatal period. The effect of L-carnitine on long chain (palmitate) and medium chain (octonoate) fatty acid oxidation was studied in cardiac myocytes isolated from less than 24 h old (new born; NB), 2 week old (2 week) and hypoxic 4 week old (HY) piglets. Palmitate oxidation was severely decreased in NB cells compared to those from 2 week animals (0.456+/-0.04 vs. 1.207+/-0.52 nmol/mg protein/30 min); surprisingly, cells from even older hypoxic animals appeared shifted toward the new born state (0.695+/-0.038 nmol/mg protein/30 min). Addition of L-carnitine to the incubation medium, which stimulates carnitine palmitoyl-transferase I (CPTI) accelerated palmitate oxidation 3 fold in NB and approximately 2 fold in HY and 2 week cells. In contrast, octanoate oxidation which was greater in new born myocytes than in 2 week cells, was decreased by L-carnitine suggesting a compensatory response. Furthermore, oxidation of carbohydrates (glucose, pyruvate, and lactate) was greatly increased in new born myocytes compared to 2 week and HY cells and was accompanied by a parallel increase in pyruvate dehydrogenase (PDH) activity. The concentration of malonyl-CoA, a potent inhibitor of CPTI was significantly higher in new born heart than at 2 weeks. These metabolic data taken together suggest that intracellular metabolic signals interact to shift from carbohydrate to fatty acid utilization during development of the myocardium. The decreased oxidation of palmitate in NB hearts probably reflects decreased intracellular L-carnitine and increased malonyl-CoA concentrations. Interestingly, these data further suggest that the cells remain compliant so that under stressful conditions, such as hypoxia, they can revert toward the neonatal state of increased glucose utilization.

Animals↗

PubMed1998

Myocardial infarction complicated by ventricular septal rupture in a patient with polycythemia vera and minimal coronary ectasia.

Although it is known that patients with polycythemia vera (PV) are at increased risk of myocardial infarction (MI) secondary to thrombosis, ventricular septal rupture in this setting has never been reported. Ventricular septal rupture complicating a small anteroseptal MI is reported in a patient with PV and with only minimal ectasia of the left anterior descending coronary artery. Despite small infarct size these patients may be predisposed to myocardial hemorrhage, increasing the likelihood of myocardial rupture.

Aged↗

PubMed1998

Surgical resection for hepatocellular carcinoma in Cape Town--a clinical and histopathological study.

OBJECTIVE: Review of surgical resections performed for hepatocellular carcinoma (HCC) at our institution between 1990 and 1996, histology of resected specimens, and clinical outcome. DESIGN: Retrospective and prospective study of 14 patients who underwent resection for HCC. SETTING: The Hepatobiliary Unit and Liver Clinic, Groote Schuur Hospital, Cape Town. PATIENTS: Fourteen patients who underwent liver resections for HCC. INTERVENTIONS: Hepatic resections using prolonged vascular inflow occlusion. OUTCOME MEASURES: Clinical outcome and disease-free survival following resection. RESULTS: Fourteen patients (5.6% of the total number presenting with HCC) underwent liver resection for HCC at our institution between 1990 and 1996. There were 7 men, median age 40 years (range 18-74 years). Only 2 patients were black, and only 1 of these patients had evidence of hepatitis B virus (HBV) infection in the liver. Extensive liver resections were often required. The mean (SD) ischaemic time was 81 (26) minutes and mean estimated blood loss was 938 (649) ml. During hospital admission, 1 patient developed a minor bile leak that settled spontaneously, and 1 patient suffered a stroke and died. The mean hospital stay following operation was 12 days (range 7-21 days). Disease-free patient survival at 1, 2 and 3 years was 85%, 75%, and 62%, respectively. Histopathology of the resected specimens showed that 10 of 14 tumours had arisen in non-cirrhotic livers. Mean tumour size was 10.6 (4.6) cm. Only 1 specimen showed the fibrolamellar variant of HCC. CONCLUSIONS: Only a small proportion of patients with HCC seen at Groote Schuur Hospital were eligible for resection, and only a minority of these had HBV-associated 'African' HCC. The results of hepatic resection at our institution compare favourably with literature reports, despite the relatively large size of the tumours. It is of interest that most tumours arose in non-cirrhotic livers. There was no evidence of proliferation of 'oval-like' cells in non-neoplastic liver tissue.

Adolescent↗

PubMed1997

A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma.

BACKGROUND: Inhaled glucosteroids and oral theophylline are widely used to treat asthma. We compared the benefits of adding theophylline to inhaled glucosteroid with those of doubling the dose of inhaled glucosteroid in patients with persistent symptoms despite the use of inhaled glucosteroid. METHODS: In a double-blind, placebo-controlled trial, we randomly assigned 62 patients to receive either 400 microg of inhaled budesonide (low-dose budesonide) with 250 or 375 mg of theophylline (depending on body weight) or 800 microg of inhaled budesonide (high-dose budesonide). All doses were given twice daily for three months. Lung function was measured serially, and patients kept records of peak expiratory flow, symptoms, and albuterol use. The effects of treatment on endogenous cortisol levels were also assessed. RESULTS: Both treatments resulted in improvements in lung function that were sustained throughout the study. As compared with treatment with high-dose budesonide, treatment with low-dose budesonide plus theophylline resulted in greater improvements in forced vital capacity (P=0.03) and forced expiratory volume in one second (P= 0.03). There were significant and similar reductions in beta2-agonist use and the variability of peak expiratory flow, a correlate of bronchial hyperresponsiveness and the severity of asthma. Serum cortisol concentrations were significantly reduced in the group given high-dose budesonide (from a mean [+/-SE] of 18.4+/-2.4 microg per deciliter to 15.9+/-2.1 microg per deciliter, P=0.02) but were unchanged in the other group. The median serum theophylline concentration was 8.7 microg per milliliter (therapeutic range, 10 to 20) among those who received theophylline. Both treatments were well tolerated. CONCLUSIONS: For patients with moderate asthma and persistent symptoms, low-dose inhaled budesonide with theophylline and high-dose inhaled budesonide produced similar benefits. Effects were achieved at theophylline concentrations below the recommended therapeutic range. The addition of low-dose theophylline to inhaled glucosteroid may be preferable to and cheaper than increasing the dose of inhaled glucosteroid.

Administration, Inhalation↗

PubMed1997

Calretinin expression in the chick brainstem auditory nuclei develops and is maintained independently of cochlear nerve input.

The expression of the calcium-binding protein calretinin (CR) in the chick brainstem auditory nuclei angularis (NA), laminaris (NL), and magnocelularis (NM) was studied during normal development and after deafening by surgical removal of the otocyst (embryonic precursor of the inner ear) or columella (middle ear ossicle). CR mRNA was localized by in situ hybridization by using a radiolabeled oligonucleotide chick CR probe. CR immunoreactivity (CR-IR) was localized on adjacent tissue sections. CR mRNA signal in the auditory nuclei was expressed at comparable levels at embryonic day (E)9 and E11 and increased thereafter to reach the highest levels in posthatch chicks. CR-IR neurons were apparent in NM and NA at E11 and in NL by E13, and CR-IR increased in all three auditory nuclei thereafter. Neither unilateral nor bilateral otocyst removal caused detectable changes in the intensity of CR mRNA expression or CR-IR in the auditory nuclei at any of the several ages examined. Similarly, columella removal at posthatching day 2 or 3 failed to significantly affect CR mRNA or CR-IR levels at 3 hours, 1 day, or 3-4 days survival times. We conclude that cochlear nerve input is not necessary for expression of either calretinin mRNA or protein and that the profound decrease in sound-evoked activity caused by columella removal does not affect the maintenance of CR expression after hatching.

Acoustic Stimulation↗

PubMed1997

The structure of a calmodulin mutant with a deletion in the central helix: implications for molecular recognition and protein binding.

BACKGROUND: Calmodulin (CaM) is the major calcium-dependent regulator of a large variety of important intracellular processes in eukaryotes. The structure of CaM consists of two globular calcium-binding domains joined by a central 28-residue alpha helix. This linker helix has been hypothesized to act as a flexible tether and is crucial for the binding and activation of numerous target proteins. Although the way in which alterations of the central helix modulate the molecular recognition mechanism is not known exactly, the relative orientation of the globular domains seems to be of great importance. The structural analysis of central helix mutants may contribute to a better understanding of how changes in the conformation of CaM effect its function. RESULTS: We have determined the crystal structure of a calcium-saturated mutant of chicken CaM (mut-2) that lacks two residues in the central helix, Thr79 and Asp80, at 1.8 A resolution. The mutated shorter central helix is straight, relative to that of the wild-type structure. The loss of a partial turn of the central alpha helix causes the C-terminal domain to rotate 220 degrees around the helix axis, with respect to the N-terminal domain. This rotation places the two domains on the same side of the central helix, in a cis orientation, rather than in the trans orientation found in wild-type structures. CONCLUSIONS: The deletion of two residues in the central helix of CaM does not distort or cause a bending of the linker alpha helix. The main consequence of the mutation is a change in the relative orientation of the two globular calcium-binding domains, causing the hydrophobic patches in these domains to be closer and much less accessible to interact with the target enzymes. This may explain why this mutant of CaM shows a marked decrease in its ability to activate some enzymes while the mutation has little or no effect on its ability to activate others.

Animals↗

PubMed1997

Mechanisms of adaptive supersensitivity: correlation of guinea pig atrial supersensitivity with modifications in adenylyl cyclase activity.

The possibility that the cellular mechanism underlying adaptive supersensitivity in right and left atria of the guinea pig may involve either adenylyl cyclase or components of that transduction process was examined in left and right atria obtained from controls or guinea pigs chronically treated with reserpine. Adenylyl cyclase activity and the abundance of alpha-subunits of several G-proteins (i.e. Gs, Gi, and Go) were quantified using standard techniques. Functional concentrations of Gs and Gi were compared in tissues from control and treated animals using pertussis- or cholera toxin-induced protein ribosylation. Chronic treatment with reserpine did not alter basal levels of adenylyl cyclase activity in left or right atrium but did increase significantly the ability of isoproterenol, 5'-guanylylimido diphosphate, and forskolin to activate adenylyl cyclase in the left atrium compared with the control. In contrast, treatment with reserpine increased the ability of only isoproterenol to active adenylyl cyclase in the right atrium. The increases in enzyme activation were not correlated with any detectable change in the concentrations of G-proteins or beta-adrenoceptors. The correlation between the specificity of changes in responsiveness and increased activation of adenylyl cyclase suggests that the cellular mechanism that underlies the development of adaptive supersensitivity in the guinea pig myocardium may involve a modification of adenylyl cyclase. The data also support the idea that the development of enhanced responsiveness in cardiac muscle may not only involve more than one cellular mechanism but may even differ between right and left atrium and ventricles of the same species.

Adaptation, Physiological↗

PubMed1997

Acute and chronic effects of adriamycin on fatty acid oxidation in isolated cardiac myocytes.

This study was designed to determine if acute (in vitro) or chronic (in vivo) adriamycin inhibits cardiac fatty acid oxidation and if so at what sites in the fatty acid oxidation pathway. In addition, the role of L-carnitine in reversing or preventing this effect was examined. We determined the effects of adriamycin in the presence or absence of L-carnitine on the oxidation of the metabolic substrates [1-14C]palmitate. [1(-14)C] octanoate. [1(-14)C]butyrate, [U-14C]glucose, and [2(-14)C]pyruvate in isolated cardiac myocytes. Acute exposure to adriamycin caused a concentration- and time-dependent inhibition of carnitine palmitoyl transferase 1 (CPT 1) dependent long-chain fatty acid, palmitate, oxidation. Chronic exposure to (18 mg/kg) adriamycin inhibited palmitate oxidation 40% to a similar extent seen in vitro with 0.5 mM adriamycin. Acute or chronic administration of L-carnitine completely abolished the adriamycin-induced inhibition of palmitate oxidation. Interestingly, medium- and short-chain fatty acid oxidation, which are independent of CPT 1, were also inhibited acutely by adriamycin and could be reversed by L-carnitine. In isolated rat heart mitochondria, adriamycin significantly decreased oxidation of the CPT 1 dependent substrate palmitoyl-CoA by 50%. However, the oxidation of a non-CPT 1 dependent substrate palmitoylcarnitine was unaffected by adriamycin except at concentrations greater than 1 mM. These data suggest that after in vitro or in vivo administration, adriamycin, inhibits fatty acid oxidation in part secondary to inhibition of CPT 1 and/or depletion of its substrate, L-carnitine, in cardiac tissue. However, these findings also suggest that L-carnitine plays an additional role in fatty acid oxidation independent of CPT 1 or fatty acid chain length.

Animals↗

PubMed1997

Involvement of mu- and delta-opioid receptors in the effects of systemic and locally perfused morphine on extracellular levels of dopamine, DOPAC and HVA in the nucleus accumbens of the halothane-anaesthetized rat.

The effects of systemic and intra-accumbens infusion of morphine on the extracellular level of dopamine (DA) and its metabolites, DOPAC and HVA, were investigated in the nucleus accumbens (NAcc) of halothane-anaesthetized rats using in vivo microdialysis. Morphine in a dose of 1 or 5 mg/kg i.v. produced a significant increase (60-100% of baseline levels) in the extracellular level of DA for at least 3 h. Morphine at 5, but not 1 mg/kg, produced a small (10-15%) but significant reduction in the level of DOPAC when compared with saline in the first h following injection. Pretreatment with the preferential mu-opioid receptor antagonist naloxone in a dose of 1 or 3 mg/kg i.p. significantly blocked the morphine-induced changes in the extracellular levels of DA and DOPAC. Pretreatment with the selective delta-opioid receptor antagonist, naltrindole, at 1 mg/kg i.p. blocked only the morphine-induced decrease in DA metabolism. Furthermore, in the presence of naltrindole, systemic morphine induced a large and long-lasting increase in the level of DOPAC and HVA, which was significantly higher than in rats receiving combinations of saline/water + saline, saline/water + morphine and naltrindole + saline. When applied directly into the NAcc, morphine at concentrations of 125, 250 and 500 ng infused over 10 min produced a dose-related increase in the extracellular level of accumbens DA with either no effect or a small reduction in the level of DOPAC and HVA. The effects of intra-accumbens morphine on DA levels were significantly blocked by pretreatment with i.p. naltrindole but not naloxone. These results indicate that, while systemic morphine probably increases DA via activation of mu-opioid receptors, local perfusion of morphine increases DA in the NAcc via activation of delta-opioid receptors located in the NAcc. Furthermore, under the conditions of the study, it appears that activation of mu- and delta-opioid receptors by morphine respectively increases and decreases DA metabolism.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1997

Examination by radioligand binding of the alpha1 adrenoceptors in the mesenteric arterial vasculature during the development of salt-sensitive hypertension.

Previous experiments have suggested that the vascular smooth muscle of Dahl salt-sensitive (DS) rats may possess a difference in the alpha1-adrenoceptor population or its transduction processes compared to Dahl salt-resistant (DR) rats. The purpose of the current research is to study the role of alpha1-adrenoceptors in the specific supersensitivity to norepinephrine (NE) seen prior to and early in the development of hypertension in the DS rat. Experiments in isolated perfused superior mesenteric arterial vasculature from DS rats chronically fed a high (7%) salt diet for 5 days or 3 weeks, in the absence or presence of an elevation in systolic blood pressure, respectively, demonstrated a specific supersensitivity to NE relative to DR rats. The enhanced responsiveness was specific to NE after 5 days of high salt since no differences in sensitivity of these preparations was observed to either KCl or 5-HT. A small but significant elevation in sensitivity to KCl following 3 weeks of treatment suggests that multiple factors may contribute to tissue responsiveness at this time. Radioligand binding experiments were performed using [125I]-HEAT to study the alpha1-adrenoceptor population and its subtypes. Saturation experiments using membranes prepared from the superior mesenteric arterial vasculature or mesenteric arterial branches showed no significant differences in overall alpha1-adrenoceptor population between DS and DR rats fed a high-salt diet for 5 days or 3 weeks. Competition experiments using membranes prepared from the superior mesenteric arterial branches in the presence of the alpha1A-subtype selective antagonist 5-methylurapidil showed two binding sites (high and low affinity) in these resistance vessels but no significant differences in nature or ratio of these sites between the DS and DR groups. These results suggest that changes in the alpha1-adrenoceptor population are not responsible for the specific supersensitivity to NE, which may be an early event in the induction and development of hypertension.

Adrenergic alpha-Agonists↗