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Biomedical subjects

C S Thompson

Publications and source records attributed to C S Thompson.

At least 73 records · Page 4Linked to original sources
PubMed1998

Screening and confirmatory determination of ractopamine residues in calves treated with growth promoting doses of the beta-agonist.

Ractopamine (RCT) is a phenethanolamine member of the family of beta-adrenergic agonists (beta-agonists). This class of compounds have become notable for their properties of enhancing the growth rates of farm animal species but are not licensed for use in Europe. An ELISA procedure employing a polyclonal antibody raised in a goat was developed to detect RCT residues in bovine urine samples. The assay had a high sensitivity (calibration curve mid-point of 22 pg per well), allowing the analysis of urine samples without the need for sample clean-up. In addition, an LC-MS-MS confirmatory procedure was developed which was able to act as a confirmatory procedure for the ELSA results. Four calves were orally treated with RCT (0.1 mg kg-1 body mass for 17 d) and urine samples collected were assayed by both analytical procedures. It was observed that RCT residues were excreted mainly in the form of glucuronides and deconjugation could be achieved using two different sources of the enzyme beta-glucuronidase (Helix pomatia and Escherichia coli). High concentrations of RCT residues were found throughout the medication period (44-473 ng ml-1; LC-MS-MS data) and remained present for several days following removal of the drug from the diet. RCT residues were no longer detectable 2 weeks after withdrawal. Good agreement (r2 = 0.73) was achieved between the ELISA and LC-MS-MS results, especially when sample deconjugation was applied to the urine samples for sets of analyses. The results show that an effective screening and confirmatory system was devised to detect RCT residues in urine samples taken during treatment and close to withdrawal. However, alternative matrices may have to be selected to allow the illegal use of the substance to be detected following prolonged withdrawal times.

Adrenergic beta-Agonists↗
PubMed1998

Down-regulation of endothelin-B receptor sites in cavernosal tissue of hypercholesterolaemic rabbits.

OBJECTIVE: To investigate the density and distribution of endothelin-1 (ET-1) and endothelin receptor subtypes in cavernosal tissue of healthy New Zealand White (NZW) rabbits (controls) and to assess any changes in a genetic model of hypercholesterolaemia (the Watanabe rabbit). MATERIALS AND METHODS: Penises were excised from six hypercholesterolaemic (HC) rabbits 6 months after birth. Low- and high-resolution autoradiography was performed on cavernosal sections using radioligands for ET-1, endothelin A (ETA) and endothelin B (ETB) receptors, and the autoradiographs analysed densitometrically. The results were compared with those from six age-matched control rabbits. Immunohistochemical localization of ET-1-like immunoreactivity was also performed on adjacent cavernosal sections. RESULTS: ET-1, ETA and ETB receptor binding sites were primarily localized to the smooth muscle cells of the corpus cavernosum and the endothelium lining the cavernosal spaces. There was a significant decrease in ETB receptor binding sites in cavernosal tissue from HC rabbits when compared to age-matched healthy controls. CONCLUSIONS: The findings suggest that ET-1 may have a role in the pathophysiology of erectile dysfunction in HC. These effects may partly be due to enhanced vasoconstrictor actions and smooth muscle cell proliferation, consequent on a reduction in endothelial ETB receptors.

Animals↗
PubMed1998

Endothelin and erectile dysfunction: a target for pharmacological intervention?

Although erectile dysfunction (ED) is not life threatening, this common problem can significantly affect the quality of life and psychological and social well-being. The Massachusetts male ageing study (1,290 men aged 40 - 70 years) showed that 52% of men reported some degree of ED (17.1% mild, 25.2% moderate, 9.6% total). In the UK, an estimated 17 - 19% of men are thought to suffer from ED. This problem is more common with advancing age and since this proportion of the population is increasing, the prevalence of ED is expected to rise. Endothelin-1 (ET-1) belongs to a family of potent vasoconstrictor peptides consisting of 21 amino acids. We review the evidence showing that ET-1 plays a role via (ET(A) and ET(B) receptors) in the regulation of cavernosal smooth muscle tone. We also consider the various risk factors that are involved in the pathogenesis of ED and how these relate to the action of ET-1. In particular, the role of diabetes, hypertension, smoking and dyslipidaemia are discussed. The pharmaceutical industry has declared an interest in the development of ET antagonists for use in the treatment of various diseases including ED. We briefly comment on experimental ET-1 antagonists that may be of therapeutic benefit in ED.

Journal Article↗
PubMed1998

Differential alterations of prostacyclin, cyclic AMP and cyclic GMP formation in the corpus cavernosum of the diabetic rabbit.

OBJECTIVE: To investigate the effect of alloxan-induced diabetes mellitus (DM, a major risk factor for erectile dysfunction and associated with impaired endothelial function) on the formation of nitric oxide (NO), prostacyclin (PGI2), cGMP and cAMP in the corpus cavernosum of rabbits. MATERIALS AND METHODS: Rabbits were rendered diabetic (hyperglycaemic, nonketotic) with alloxan; after 3 and 6 months, the penises were excised and the corpus cavernosum processed for the study of PGI2, NO, cAMP and cGMP formation, using a range of stimulators and radioimmunoassays. RESULTS: PGI2 formation in response to acetylcholine and phorbol ester, but not arachidonate, and cGMP formation in response to A23187 (NO-release dependent), was significantly diminished in diabetic rabbit corpus cavernosum compared with controls at both 3 and 6 months after the induction of DM. cAMP formation in response to forskolin and prostaglandin E1 was reduced after 6 but not 3 months, although nitroprusside-stimulated cGMP (activates guanylyl cyclase directly) was unaffected in cavernosal tissue from diabetic rabbits. CONCLUSIONS: These results show that the formation of NO and PGI2, and adenylyl cyclase activity but not guanylyl cyclase, are impaired in the corpus cavernosum of diabetic rabbits. As NO and PGI2 are produced by the endothelium, these studies consolidate the view that endothelial dysfunction is a major contributor to erectile dysfunction in diabetes mellitus.

Alloxan↗
PubMed1997

Comparison and evaluation of the specificity and binding capacity of commercial and in house affinity columns used in sample preparation for analysis of growth-promoting drugs.

Immunoaffinity chromatography (IAC) and affinity chromatography (AC) are widely used for extraction of drugs from biological samples. Fifteen column types were purchased from five different manufacturers and their ability to bind specific drugs including beta-agonists and anabolic steroids over a range of analyte concentrations in fortified bovine urine samples was assessed. The performance data obtained from these columns were compared with columns produced in this laboratory (in house columns). The in house columns gave the highest recoveries, ranging from 92 to 100% at the 1 ng spiking concentration, for five of the seven analytes assessed. Forty percent (11 of 27) of all the commercial column assessments recorded recoveries of less than 50% even when the lowest spiking concentration was applied (1 ng). For one manufacturer, only one of seven different columns purchased delivered extraction efficiencies greater than 50%. The extraction efficiencies of the clenbuterol columns were the highest with all commercially prepared columns showing at least 50% binding of radiolabelled tracer. Recoveries of alpha-nortestosterone were the lowest. The variability of these products with respect to quality control requires constant monitoring.

Adrenergic beta-Agonists↗
PubMed1997

Alterations in endothelin B receptor sites in cavernosal tissue of diabetic rabbits: potential relevance to the pathogenesis of erectile dysfunction.

PURPOSE: Diabetes Mellitus (DM) is a major risk factor for erectile dysfunction in both patients and animal models. The pathogenesis of this dysfunction has not been fully elucidated. However, alterations in the synthesis of a number of vasoactive compounds, such as nitric oxide (NO) and prostacyclin (PGI2), have been reported in various diabetic tissues. The interaction between NO, PGI2 and endothelin-1 (ET-1), a powerful vasoconstrictor and smooth muscle cell mitogen, is thought to be important in maintaining vascular tone and the erectile process. We investigated the density and distribution of ET-1 and endothelin receptor subtypes in cavernosal tissue and assessed any changes brought about by DM in a rabbit model. MATERIALS AND METHODS: DM was induced in New Zealand White rabbits using alloxan. Penises were excised from the diabetic rabbits three months (n = 6) and six months (n = 6) after the induction of DM. Low and high resolution autoradiography was performed using radioligands for ET-1, endothelin A (ETA) and endothelin B (ETB) receptors and were analyzed densitometrically. The results were compared with those from six age-matched healthy control rabbits for each group. Immunohistochemical localization of ET-1 immunoreactivity was also performed, together with ultrastructural evaluation of the corpus cavernosum. RESULTS: ET-1, ETA and ETB receptor binding sites were primarily localized to the smooth muscle cells of the corpus cavernosum and the endothelium lining the cavernosal spaces. A significant increase in ETB receptor binding sites was found only in cavernosal tissue six months after induction of DM, when compared with age-matched healthy controls. These receptor changes were accompanied by ultrastructural changes in the corpus cavernosum indicative of an early, atherosclerosis-like process. CONCLUSIONS: The autoradiographic and immunohistochemical findings in this study suggest that ET-1 may have a role in the pathophysiology of diabetic ED. This peptide may be released in an autocrine fashion causing cavernosal smooth muscle cell (CSMC) contraction and/or proliferation.

Animals↗
PubMed1997

Elevation of neuronal expression of NAIP reduces ischemic damage in the rat hippocampus.

We show here that transient forebrain ischemia selectively elevates levels of neuronal apoptosis inhibitory protein (NAIP) in rat neurons that are resistant to the injurious effects of this treatment. This observation suggests that increasing NAIP levels may confer protection against ischemic cell death. Consistent with this proposal, we demonstrate that two other treatments that increase neuronal NAIP levels, systemic administration of the bacterial alkaloid K252a and intracerebral injection of an adenovirus vector capable of overexpressing NAIP in vivo, reduce ischemic damage in the rat hippocampus. Taken together, these findings suggest that NAIP may play a key role in conferring resistance to ischemic damage and that treatments that elevate neuronal levels of this antiapoptotic protein may have utility in the treatment of stroke.

Adenoviridae↗
PubMed1996

Hydrolysis of cyclic guanosine monophosphate and cyclic adenosine monophosphate by the penis and aorta of the diabetic rat.

OBJECTIVE: To investigate the hydrolysis of adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) by specific phosphodies-terases (PDEs) in the penis and aorta of diabetic rats. MATERIALS AND METHODS: Non-ketonuric diabetes mellitus was induced in 10 Sprague-Dawley rats with streptozotocin. After 2 months, the rats were killed and their penises and aortae excised. The tissues were incubated with [3H]-cAMP and [3H]-cGMP and the degree of hydrolysis was assessed by separating [3H]-cAMP and [3H]-cGMP from [3H]-AMP and [3H]-GMP, respectively, in the incubation supernatants using thin layer chromatography (polyethyleneimine cellulose developed in 50 mmol/L KCl). RESULTS: The hydrolysis of cAMP and cGMP was significantly reduced in penile and aortic tissue from diabetic rats compared to that of seven age-matched controls. CONCLUSIONS: Such a reduction of PDE activity would result in increased intracellular cyclic nucleotide levels (and thus corporeal smooth muscle relaxation and erection). Consequently, the altered activity of PDE enzyme systems is not related aetiologically to the pathogenesis of diabetic erectile dysfunction. Furthermore, these data consolidate the concept that enhanced cyclic nucleotide synthesis and decreased degradation constitute an adaptive response to counteract the deleterious effects of diabetes mellitus on erectogenic mechanisms. The pathophysiology and therapeutic implications of these findings warrant further investigation.

Animals↗
PubMed1996

Calcium reverses octreotide inhibition of insulin and glucagon levels in patients with insulinoma and glucagonoma.

Excessive secretion of peptides causes the clinical syndromes associated with functional gastro-intestinal tumours. The somatostatin analogue octreotide acetate inhibits peptide release from a variety of tumours. This study investigated the interactions of calcium and somatostatin analogues on peptide release in two patients, one with a glucagonoma (patient A) and one with an insulinoma (patient B). Peptide responses were evaluated before (fasting levels) and after provocative tests (a 4-hour calcium infusion, an intravenous tolbutamide infusion, a secretin bolus and a standard test meal) in the absence and presence of octreotide acetate treatment (100 micrograms subcutaneously every 8 h). Patients A and B had elevated fasting plasma levels of glucagon and insulin, respectively, which were reduced by octreotide therapy by 73 and 50%, respectively. The peak provoked levels and calculated values for peptide synthesis were lower after octreotide therapy. In both patients, tolbutamide provoked most peptide release, and calcium infusion was the least susceptible to the effects of octreotide therapy. Calcium appears to inhibit octreotide suppression of glucagon and insulin secretion in patients with glucagonoma and insulinoma, respectively. Calcium may stimulate peptide release from endocrine tumours by suppressing the inhibitory effects of endogenous somatostatin. Normalisation of serum calcium, either surgically or pharmacologically, may improve the effectiveness of somatostatin analogue therapy.

Antineoplastic Agents, Hormonal↗
PubMed1996

Autoradiographic localization of nitric oxide synthase binding sites in normal and diabetic rat corpus cavernosum.

OBJECTIVES: To investigate density and distribution of nitric oxide synthase (NOS) binding sites in rat cavernosal tissue, and to assess any changes brought about by the onset of diabetes mellitus. METHODS: Hyperglycaemic non-ketonuric diabetes mellitus was induced in 5 rats using streptozotocin. The penises were excised from these rats 2 months after the administration of streptozotocin and stored at -70 degrees C. Longitudinal serial sections (6 microns) were cut in a cryostat and thaw mounted onto gelantinized microscope slides. Low- and high-resolution autoradiography was performed using a radioligand for NOS. Densitometric analysis was performed on the autoradiographs and the results compared with those obtained from 5 age-matched no-diabetic rats. RESULTS: NOS binding was primarily localized to the endothelium lining the cavernosal lacunar spaces. Significantly increased binding of NOS was seen in the diabetic cavernosal tissue 2 months after induction of diabetes mellitus. CONCLUSIONS: NOS binding is present on the endothelium of the rat corpus cavernosum and is increased in diabetic rats 2 months after streptozotocin administration. This increase in NOS binding may be part of the endothelial dysfunction which is reported in the corpus cavernosum of diabetic patients or rats.

Animals↗
PubMed1995

Effects of papaverine and vasointestinal polypeptide on penile and vascular cAMP and cGMP in control and diabetic animals: an in vitro study.

Adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) mediate penile erection. We have previously established that adenylate and guanylate cyclase activity is elevated in the diabetic rat penis and aorta. This study investigates the action of papaverine and vasoactive intestinal polypeptide (VIP) on these cyclases. The aortae and penes of Sprague Dawley rats (n = 7) were stimulated with VIP and papaverine. Diabetes mellitus (DM) was induced in Sprague Dawley rats (n = 7) with streptozotocin and the penile and aortic tissues were treated with VIP. The penes, aortae and carotid arteries of New Zealand White rabbits were similarly processed. cAMP and cGMP generation was measured by radioimmunoassay. In all tissues: VIP stimulated cAMP synthesis; VIP did not increase cGMP levels; papaverine was without effect on either cAMP or cGMP synthesis. VIP-stimulated cAMP was significantly enhanced in the diabetic rat penis and aorta; there was also a significant elevation in the basal levels of cGMP in these tissues. These data: (1) consolidate that cAMP is a mediator of penile erection, (2) indicate that papaverine and VIP elicit erection by different mechanisms, (3) suggest that an enhanced penile capacity to generate cAMP in DM may constitute an adaptive response to counteract the previously reported reduction in VIP content and VIP receptors, and (4) indicate that the penile and vascular tissues of the rabbit respond in a similar manner to VIP and papaverine.

Animals↗
PubMed1994

2,3,7,8-Tetrachlorodibenzo-p-dioxin induced alterations of pyruvate carboxylase levels and lactate dehydrogenase isozyme shifts in C57BL/6J male mice.

A dose-dependent reduction of hepatic pyruvate carboxylase levels and activity occurs in C57BL/6J male mice given 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) i.p. in a corn oil carrier. The dose range was from 1 to 75 micrograms/kg body weight and the analysis was done 8 days postinjection. At the maximum TCDD level investigated, we found a 10-fold reduction in pyruvate carboxylase activity. Furthermore, TCDD at a dose of 1 microgram/kg body weight blocks corn oil induction of an increase in the amount of pyruvate carboxylase in liver protein extracts. At doses beyond those required to initiate a reduction in pyruvate carboxylase, lactate dehydrogenase isozyme patterns shift. This is accompanied by an increase in blood lactic acid levels. We propose that TCDD-mediated reduction in pyruvate carboxylase and lactate dehydrogenase isozyme shifts may represent a major component in TCDD toxicity.

Animals↗
PubMed1994

Improvement of ketoacidosis in the diabetic rat after the administration of the oral antilipolytic agent GR 79236.

1. We assessed the effect of a novel oral antilipolytic agent, N-[(1S, trans)-2-hydroxycyclopentyl]adenosine (GR 79236), in experimental diabetic ketoacidosis. Ketotic rats were gavaged with GR 79236 (1 mg/kg) or water (vehicle) and their blood/plasma/serum biochemistry and haematological profile was determined. 2. We found that GR 79236 reduced the plasma non-esterified fatty acid concentration. This effect was associated with the correction of blood/plasma/serum biochemical variables (beta-hydroxybutyrate, acetoacetate, triacylglycerol) directly related to diabetic ketoacidosis, and of others (cholesterol, creatinine, creatine kinase and aspartate transaminase) which are not directly related to this metabolic abnormality. 3. There was, however, no evidence of GR 79236 lowering blood glucose in this model. One possible explanation for this observation is that GR 79236 stimulated gastric emptying leading to enhanced absorption of stomach contents when compared with untreated animals.

Adenosine↗