Biomedical subjects

A A Young

Publications and source records attributed to A A Young.

At least 19 recordsLinked to original sources

PubMed2006

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures.

BACKGROUND: Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents. OBJECTIVE: To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity. METHODS AND RESULTS: High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 microg/kg/day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 microg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 microg/kg/day (P<0.05). Decreased body weight gain was associated with a significant decrease in fat mass (P<0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (P<0.05). Exenatide at 10 microg/kg significantly reduced food intake (P<0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity. CONCLUSION: Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.

Animals↗

PubMed2006

Myocardial material parameter estimation-a comparative study for simple shear.

The study of ventricular mechanics-analyzing the distribution of strain and stress in myocardium throughout the cardiac cycle-is crucially dependent on the accuracy of the constitutive law chosen to represent the highly nonlinear and anisotropic properties of passive cardiac muscle. A number of such laws have been proposed and fitted to experimental measurements of stress-strain behavior. Here we examine five of these laws and compare them on the basis of (i) "goodness of fit:" How well they fit a set of six shear deformation tests, (ii) "determinability:" How well determined the objective function is at the optimal parameter fit, and (iii) "variability:" How well determined the material parameters are over the range of experiments. These criteria are utilized to discuss the advantages and disadvantages of the constitutive laws.

Animals↗

PubMed2005

Dose-response for glycaemic and metabolic changes 28 days after single injection of long-acting release exenatide in diabetic fatty Zucker rats.

AIMS/HYPOTHESIS: Exenatide (exendin-4) injected subcutaneously twice daily reduces glycaemic deterioration in diabetic fatty Zucker (ZDF) rats and reduces HbA1c in humans with type 2 diabetes. Because tachyphylaxis may develop with continuous peptide exposure, we examined the activity of a long-acting-release (LAR) formulation of exenatide on HbA1c, insulin sensitivity and beta cell secretion in ZDF rats. METHODS: Single subcutaneous injections of a poly-lactide-glycolide microsphere suspension (3% peptide) containing 0, 1, 10, 100, 1,000, 3,000 or 9,000 mug exenatide were administered to 9-week-old ZDF rats with matched initial HbA1c values (n=7 rats/group). RESULTS: In contrast to the progressive 3.22+/-0.42% increase in HbA1c in control ZDF rats observed over 28 days, single exenatide-LAR injections dose-proportionally prevented such glycaemic deterioration (median effective dose 74 microg+/-0.1 log per rat; median effective concentration 52 pmol/l+/-0.06 log). Hyperinsulinaemic-euglycaemic clamp procedures incorporating an intraclamp glucose challenge performed 28 days after treatment revealed increases in beta cell response to the glucose challenge at lower exenatide-LAR doses, and up to a 2.1-fold increase in insulin sensitivity at higher exenatide-LAR doses. CONCLUSIONS/INTERPRETATION: The finding that a single dose of exenatide-LAR enhanced glucose control for 28 days in the ZDF rat model of type 2 diabetes suggests that tachyphylaxis is unlikely to be a feature of exenatide-LAR preparations, and supports further clinical exploration.

Animals↗

PubMed2004

Effects of BDM, [Ca2+]o, and temperature on the dynamic stiffness of quiescent cardiac trabeculae from rat.

Studies of the passive mechanical properties of cardiac tissue have traditionally been conducted at subphysiological temperatures and various concentrations of extracellular Ca(2+) ([Ca(2+)](o)). More recently, the negative inotropic agent 2,3-butanedione monoxime (BDM) has been used. However, there remains a lack of data regarding the influence of temperature, Ca(2+), and BDM on the passive mechanical properties of cardiac tissue. We have used the dynamic stiffness technique, a sensitive measurement of cross-bridge activity, in which minute (approximately 0.2% of muscle length) sinusoidal perturbations are applied at various frequencies (0.2-100 Hz) to quiescent, viable right ventricular rat trabeculae at two temperatures (20 degrees C and 26 degrees C) and at two [Ca(2+)](o) (0.5 and 1.25 mM) in the presence and absence of BDM (20 mM). The stiffness spectra (amplitude and phase) were sensitive to temperature and [Ca(2+)](o) in the absence of BDM but insensitive in the presence of BDM. From the index of cross-bridge cycling (the ratio of high- to low-frequency stiffness amplitude), we infer that BDM inhibits a small degree of spontaneous sarcomere activity, thereby allowing the true passive properties of trabeculae to be determined. In the absence of BDM, the extent of spontaneous sarcomere activity decreases with increasing temperature. We caution that the measured mechanical properties of passive cardiac tissue are critically dependent on the experimental conditions under which they are measured. Experiments must be performed at sufficiently high temperatures (>25 degrees C) to ensure a low resting concentration of intracellular Ca(2+) or in the presence of an inhibitor of cross-bridge cycling.

Animals↗

PubMed2004

Strain softening behaviour in nonviable rat right-ventricular trabeculae, in the presence and the absence of butanedione monoxime.

Strain softening is commonly reported during mechanical testing of passive whole hearts. It is typically manifested as a stiffer force-extension relationship in the first deformation cycle relative to subsequent cycles and is distinguished from viscoelasticity by a lack of recovery of stiffness, even after several hours of rest. The cause of this behaviour is presently unknown. In order to investigate its origins, we have subjected trabeculae to physiologically realistic extensions (5-15% of muscle length at 26 degrees C and 0.5 mm Ca(2+)), while measuring passive force and dynamic stiffness. While we did not observe strain softening in viable trabeculae, we found that it was readily apparent in nonviable (electrically inexcitable) trabeculae undergoing the same extensions. This result was obtained in both the presence and absence of 2,3-butanedione monoxime (BDM). Furthermore, BDM had no effect on the passive compliance of viable specimens, while its presence partly inhibited, but could not prevent, stiffening of nonviable specimens. Loss of viability was accompanied by a uniform increase of dynamic stiffness over all frequencies examined (0.2-100 Hz). The presence of strain softening during length extensions of nonviable tissue resulted in a comparable uniform decrease of dynamic stiffness. It is therefore concluded that strain softening is neither intrinsic to viable rat right ventricular trabeculae nor influenced by BDM but, rather, reflects irreversible damage of tissue in partial, or full, rigor.

Animals↗

PubMed2004

Effects of PYY[3-36] in rodent models of diabetes and obesity.

BACKGROUND: Peptide YY (PYY) is a 36 amino-acid peptide secreted from ileal L cells following meals. The cleaved subpeptide PYY[3-36] is biologically active and may constitute the majority of circulating PYY-like immunoreactivity. The peptide family that includes PYY, pancreatic peptide and neuropeptide Y is noted for its orexigenic effect following intracerebroventricular administration. OBJECTIVE: To investigate the effects of peripheral (intraperitoneal and chronic subcutaneous) infusions of PYY[3-36] on food intake, body weight and glycemic indices. DESIGN/RESULTS: Food intake was measured in normal mice and in several rodent models of obesity and type II diabetes. In marked contrast to the reported central orexigenic effects, in the present study, PYY[3-36] acutely inhibited food intake by up to 45%, with an ED(50) of 12.5 microg/kg in fasted female NIH/Swiss mice. A 4-week infusion reduced weight gain in female ob/ob mice, without affecting the cumulative food intake. In diet-induced obese male mice, PYY[3-36] infusion reduced cumulative food intake, weight gain and epididymal fat weight (as a fraction of carcass) with similar ED(50)'s (466, 297 and 201 microg/kg/day, respectively) and prevented a diet-induced increase in HbA1c. Infusion at 100 microg/kg/day for 8 weeks in male fa/fa rats reduced the weight gain (288+/-11 vs 326+/-12 g in saline-infused controls; P<0.05), similar to effects in a pair-fed group. In female ob/ob and db/db mice, there was no acute effect of PYY[3-36] on plasma glucose concentrations. In male diabetic fatty Zucker rats, PYY[3-36] infused for 4 weeks reduced HbA1c and fructosamine (ED(50)'s 30 and 44 microg/kg/day). CONCLUSION: Peripheral PYY[3-36] administration reduced the food intake, body weight gain and glycemic indices in diverse rodent models of metabolic disease of both sexes. These findings justify further exploration of the potential physiologic and therapeutic roles of PYY[3-36].

Animals↗

PubMed2003

Strain softening is not present during axial extensions of rat intact right ventricular trabeculae in the presence or absence of 2,3-butanedione monoxime.

Recent studies of passive myocardial mechanics have shown that strain softening behavior is present during both inflation of isolated whole rat hearts and shearing of tissue blocks taken from the left ventricular free wall in pigs. Strain softening is typically manifested by a stiffer force-extension relation in the first deformation cycle relative to subsequent cycles and is distinguished from viscoelasticity by a lack of recovery of stiffness, even after several hours of rest. The causes of this behaviour are unknown. We investigated whether strain softening is observed in uniaxial extensions of intact, viable, rat right ventricular (RV) cardiac trabeculae. Stretch and release cycles of 5%, 10%, and 15% muscle length were applied at a constant velocity at 26 degrees C. Muscles were tested in random order in the presence and absence of 50 mM 2,3-butanedione monoxime (BDM). Whereas strain softening was displayed by nonviable trabeculae, it was not observed in viable preparations undergoing physiologically relevant extensions whether in the presence or absence of BDM. BDM also had no effect on passive compliance. There was a reversible increase of muscle compliance between the first and subsequent cycles, with recovery after 30 s of rest, independent of the presence of BDM. We conclude that strain softening is neither intrinsic to viable rat RV trabeculae nor influenced by BDM and that passive trabeculae compliance is not altered by the addition of BDM.

Animals↗

PubMed2001

Regional heterogeneity of function in nonischemic dilated cardiomyopathy.

OBJECTIVE: To quantify regional three-dimensional (3D) motion and myocardial strain using magnetic resonance (MR) tissue tagging in patients with non-ischemic dilated cardiomyopathy (DCM). METHODS: MR grid tagged images were obtained in multiple short- and long-axis planes in thirteen DCM patients. Regional 3D displacements and strains were calculated with the aid of a finite element model. Five of the patients were also imaged after LV volume reduction by partial left ventriculectomy (PLV), combined with mitral and tricuspid valve repair. RESULTS: DCM patients showed consistent, marked regional heterogeneity. Systolic lengthening occurred in the septum in both circumferential (%S(C) -5+/-7%) and longitudinal (%S(L) -2+/-5%) shortening components (negative values indicating lengthening). In contrast, the lateral wall showed relatively normal systolic shortening (%S(C) 12+/-6% and %S(L) 6+/-5%, P<0.001 lateral vs. septal walls). A geometric estimate of regional stress was correlated with shortening on a regional basis, but could not account for the differences in shortening between regions. In the five patients imaged post-PLV, septal function recovered (%S(C) 9+/-5%,%S(L) 6+/-5%, P<0.02 pre vs. post) with normalization of wall stress, whereas lateral wall shortening was reduced (%S(C) 7+/-6%,%S(L) 3+/-3%, P<0.02 pre vs. post) around the site of surgical resection. CONCLUSIONS: A consistent pattern of regional heterogeneity of myocardial strain was seen in all patients. Reduced function may be related to increased wall stress, since recovery of septal function is possible after PLV. However, simple geometric stress determinants are not sufficient to explain the functional heterogeneity observed.

Adult↗

PubMed2001

Identification of the fascia propria by magnetic resonance imaging and its relevance to preoperative assessment of rectal cancer.

UNLABELLED: If rectal cancer does not penetrate the fascia propria of the rectum and the rectum is removed with the fascial envelope intact (extrafascial excision), then local recurrence of the cancer will be minimal. Modern imaging techniques have identified a fascial plane surrounding the rectum and mesorectum, and it has been suggested that this is the fascia propria. The aim of this study was to identify whether this plane is the rectal fascia propria and whether tumor invasion through this fascia can be identified preoperatively. METHODS: Two separate experiments were performed: 1) pelvic magnetic resonance imaging was performed before and after dissection and marking of the plane of extrafascial dissection of the rectum of a cadaver; and 2) magnetic resonance imaging was performed in 43 rectal cancer patients preoperatively. Two radiologists independently reported the depth of tumor invasion in relation to the fascia propria. The tumors were resected by extrafascial excision, and a pathologist independently reported the relation of the tumor to the fascia propria. RESULTS: The marker inserted in the extrafascial plane showed that the plane visualized on pelvic magnetic resonance imaging was the fascia propria dissected in extrafascial excision of the rectum. The magnetic resonance imaging detected tumor penetration through the fascia propria with a sensitivity of 67 percent, a specificity of 100 percent, and an accuracy of 95 percent. CONCLUSION: The surgical fascia propria can be identified on preoperative magnetic resonance imaging in patients with rectal cancer. Tumor invasion through this fascia can be detected on magnetic resonance imaging. This method of assessment offers a new way to select those patients who require preoperative radiotherapy.

Cadaver↗

PubMed2001

Nitrification of high strength ammonia wastewaters: comparative study of immobilisation media.

Due to legislative pressures, sludge production and processing in the UK will increase substantially in the future resulting in a supernatant liquid high in ammonia (500-1000 mg l-1) and "hard" COD (approximately 500 mg l-1). A small footprint reactor is required to effectively nitrify this effluent, and the aim of this work was to compare a number of immobilisation media under a variety of conditions in order to determine which media held the most promise for future development. Laboratory-scale continuously stirred tank reactors containing freely suspended and immobilised biomass were operated with a high-strength synthetic ammonia wastewater (500 mg N l-1) to determine the nitrification rates at various temperatures, and ammonia and COD loadings. COD:NH3 ratios in sludge liquors vary widely depending on the treatment processes employed, and therefore ratios of 1:1 and 2:1 were tested as being fairly typical. The freely suspended nitrifiers were washed out of the reactors at a 1 d hydraulic retention time (HRT), whereas the reactors containing adsorption particles (Linpor and Kaldnes) and PVA-encapsulated nitrifiers continued partially nitrifying down to 12 h, and oxygen addition enhanced nitrification. A decrease in temperature from 25 to 16 degrees C only caused a small (10%) decrease in nitrification in the immobilised cell reactors, demonstrating that nitrification was mass transfer rather than kinetically controlled. A reduction in nitrification occurred when glucose (500 mg l-1) was added to the feed due to the growth of a heterotrophic population. The adsorbed biomass reactors lost 35% of nitrification compared to only 7% with PVA, and it appears that the colonisation of PVA by heterotrophs is more difficult than for Linpor and Kaldnes. Respiration rates for all particles increased with time in the reactors, and nitrifiers immobilised in PVA retained approximately 40% of their viability after immobilisation. Volumetric nitrification rates were generally higher for the PVA reactor than for Linpor and Kaldnes, and were: suspended biomass reactor: 0.36; Linpor: 0.57; Kaldnes: 0.53 and PVA: 0.70 kg N m-3-reactor d-1 for a 25% reactor fill. These equate to 2.28, 4.24 and 3.97 g N m-2-media d-1 for Linpor, Kaldnes and PVA respectively, hence other reactor fill rates for Kaldnes warrant further investigation. However, the PVA particles with the highest nitrification rates under all conditions showed promise as an immobilisation medium, and are amenable to further optimisation for the nitrification of high-strength ammonia wastewaters.

Ammonia↗

PubMed2001

Selective amylin inhibition of the glucagon response to arginine is extrinsic to the pancreas.

Amylin, a peptide hormone from pancreatic beta-cells, is reported to inhibit insulin secretion in vitro and in vivo and to inhibit nutrient-stimulated glucagon secretion in vivo. However, it has been reported not to affect arginine-stimulated glucagon secretion in vitro. To resolve if the latter resulted from inactive peptide (a problem in the early literature), those experiments were repeated here with well-characterized peptide and found to be valid. In isolated perfused rat pancreas preparations, coperfusion with 1 nM amylin had no effect on arginine-, carbachol-, or vasoactive intestinal peptide-stimulated glucagon secretion. Amylin also had no effect on glucagon output stimulated by decreasing glucose concentration from 11 to 3.2 mM or on glucagon suppression caused by increasing glucose from 3.2 to 7 mM. Amylin at 100 nM had no effect in isolated islets in which glucagon secretion was stimulated by exposure to 10 mM arginine, even though glucagon secretion in the same preparation was inhibited by somatostatin. In anesthetized rats, amylin coinfusion had no effect on glucagon secretion stimulated by insulin-induced hypoglycemia. To reconcile reports of glucagon inhibition with the absence of effect in the experiments just described, anesthetized rats coinfused with rat amylin or with saline were exposed sequentially to intravenous L-arginine (during a euglycemic clamp) and then to hypoglycemia. Amylin inhibited arginine-induced, but not hypoglycemia-induced, glucagon secretion in the same animal. In conclusion, we newly identify a selective glucagonostatic effect of amylin that appears to be extrinsic to the isolated pancreas and may be centrally mediated.

Amyloid↗

PubMed2001

Amylin replacement with pramlintide as an adjunct to insulin therapy in type 1 and type 2 diabetes mellitus: a physiological approach toward improved metabolic control.

Destruction and dysfunction of pancreatic beta-cells, resulting in absolute and relative insulin deficiency, represent key abnormalities in the pathogenesis of type 1 and type 2 diabetes, respectively. Following the discovery of amylin, a second beta-cell hormone that is co-secreted with insulin in response to nutrient stimuli, it was realized that diabetes represents a state of bihormonal beta cell deficiency and that lack of amylin action may contribute to abnormal glucose homeostasis. Experimental studies show that amylin acts as a neuroendocrine hormone that complements the effects of insulin in postprandial glucose regulation through several centrally mediated effects. These include a suppression of postprandial glucagon secretion and a vagus-mediated regulation of gastric emptying, thereby helping to control the influx of endogenous and exogenous glucose, respectively. In animal studies, amylin has also been shown to reduce food intake and body weight, consistent with an additional satiety effect. Pramlintide is a soluble, non-aggregating, injectable, synthetic analog of human amylin currently under development for the treatment of type 1 and insulin-using type 2 diabetes. Long-term clinical studies have consistently demonstrated that pre-prandial s.c. injections of pramlintide, in addition to the current insulin regimen, reduce HbA(1c) and body weight in type 1 and type 2 diabetic patients, without an increase in insulin use or in the event rate of severe hypoglycemia. The most commonly observed side effects were gastrointestinal-related, mainly mild nausea, which typically occurred upon initiation of treatment and resolved within days or weeks. Amylin replacement with pramlintide as an adjunct to insulin therapy is a novel physiological approach toward improved long-term glycemic and weight control in patients with type 1 and type 2 diabetes.

Amyloid↗

PubMed2000

The effect of synthetic patch repair of coarctation on regional deformation of the aortic wall.

BACKGROUND: A long-term complication of synthetic patch repair of coarctation is true aneurysm formation. AIM: An in vitro study was undertaken to determine the effects of patch angioplasty on aortic geometry and strain adjacent to the patch. METHODS: Segments of human descending thoracic aorta were subject to 10 pressure loading cycles (10-120 mm Hg; 1.36-16.32 kPa) before and after simulated coarctation repair with a synthetic patch. Local curvature and strain were estimated by fitting a geometric model to reconstructed three-dimensional surface marker points. RESULTS: In the control aortas, when pressure increased from 11 +/- 1.0 to 124 +/- 4.0 mm Hg (1.5 +/- 0.14 to 16.86 +/- 0.54 kPa), average circumferential curvature decreased from 0.1543 +/- 0.03 to 0.1065 +/- 0.03 mm(-1). The average major extension reached a maximum of 1.43 +/- 0.08. After patch implantation, the average circumferential curvature was reduced relative to control at all pressures. Average major extensions were significantly greater than paired control values and reached a maximum of 1.55 +/- 0.08 at 122 +/- 4.0 mm Hg (16.59 +/- 0. 54 kPa). Substantial strain inhomogeneity was observed and major extensions were greatest immediately adjacent to the patch. INFERENCE: Synthetic patch repair of coarctation of the aorta increases wall strain and produces significant regional gradients in strain. With control aortic material properties there may be a substantial increase in wall stress immediately adjacent to the aorta, which could lead to true aneurysm formation.

Adolescent↗

PubMed2000

A triaxial-measurement shear-test device for soft biological tissues.

A novel shear-test device for soft biological tissue, capable of applying simple shear deformations simultaneously in two orthogonal directions while measuring the resulting forces generated in three axes, is described. We validated the device using a synthetic gel, the properties of which were ascertained from independent tensile and rotational shear tests. Material parameters for the gel were fitted using neo-Hookean analytical solutions to the independent test data, and these matched the results from the device. Preliminary results obtained with rat septal myocardium are also presented to demonstrate the feasibility of the apparatus in determining the shear characteristics of living tissue.

Animals↗

PubMed2000

Left ventricular mass and volume: fast calculation with guide-point modeling on MR images.

The authors describe a fast method for calculating left ventricle (LV) mass and volumes from multiplanar magnetic resonance (MR) images. Mathematic models were fitted to a small number of user-selected guide points in 15 healthy volunteers, 13 patients after myocardial infarction, and a canine model of mitral regurgitation in eight dogs. Errors between model and manual contours were small (LV mass, 1.8 g +/- 4.9 [mean +/- SD]; end-diastolic volume, 2.2 mL +/- 4.6; end-systolic volume, 2.3 mL +/- 3.8). Estimates of global function could be obtained in 6 minutes, a time saving of 5-10 times over estimates with manual contouring.

Adolescent↗

PubMed2000

Amylin inhibits ovariectomy-induced bone loss in rats.

Amylin (AMY), a peptide co-secreted with insulin by pancreatic beta-cells, inhibits bone resorption and stimulates osteoblastic activity. The ovariectomized (OVX) rat is an established animal model for human osteoporosis. Thus, the present experiment was performed to study the effects of AMY on estrogen deficiency-induced bone loss in rats. Thirty-one 6-month-old Wistar rats were randomized by body weight (BW) into two groups. The first underwent surgical OVX (n=21). The second was sham-operated (SH; n=10). Sixty days after surgery, 11 OVX rats were s.c. injected with rat AMY (3 microg/100 g BW/day, for 30 days; OVX+AMY), and 10 with solvent alone in the same way (0.15 ml/100 g BW; OVX). Each rat, housed in an individual cage, was fed daily the mean quantity of diet consumed the day before by SH rats. This diet contained 0.24% calcium and 0. 16% phosphorus. The 31 animals were killed on day 90. No difference in daily weight gain and BW was observed between groups. Neither AMY treatment nor OVX had any significant effect upon femoral morphology, femoral failure load, diaphyseal femoral density (representative of cortical bone) and total femoral calcium content. Nevertheless, both distal metaphyseal (representative of cancellous bone) and total femoral bone densities were higher in SH and OVX+AMY than in OVX rats. The highest plasma osteocalcin concentration was measured in OVX+AMY rats. Simultaneously, urinary deoxypyridinoline excretion was lower in OVX+AMY than in OVX rats. These results indicate that in OVX rats, AMY treatment inhibited trabecular bone loss both by inhibiting resorption and by stimulating osteoblastic activity.

Amino Acids↗

PubMed1999

Pharmacological characterisation of amylin-related peptides activating subfornical organ neurones.

Amylin, calcitonin gene-related peptide (CGRP) and calcitonin are structurally related peptides with overlapping peripheral and central actions. Amylin and calcitonin excite the majority of neurones in the subfornical organ (SFO), where high densities of so-called C-type G-protein-coupled receptors have been detected. Subcutaneous injection of these hormones stimulates drinking similar to angiotensin II (ANGII), a dipsogen acting via the SFO. We now show that in addition to amylin and rat calcitonin (rCT), CGRP and salmon calcitonin (sCT) also excite SFO neurones. In extracellular recordings of an in vitro slice preparation of the SFO, 78% of all neurones (n=31) superfused with CGRP (10(-6) M) were excited. The excitatory effect was dose-dependent and reversible with an average threshold concentration of 5x10(-7) M, which is approximately 15-fold higher than reported for amylin-induced excitations. sCT (10(-7) M), which behaves as a non-competitive agonist at amylin as well as calcitonin receptors, caused irreversible excitatory responses in 96% of all recordings (n=26). Amylin-, CRGP- and rCT-induced excitations could be blocked by the selective amylin receptor antagonist AC187 (10(-5) to 10(-6) M), whereas sCT-induced excitations were not inhibited. The receptor antagonist human CGRP(8-37) (10(-6) M) partly caused agonistic responses, but did not block CGRP-induced excitations. The pharmacological profile observed in the present work, and in a recent publication using the same preparation, indicating (1) that CGRP is a weaker agonist in the SFO than amylin, (2) that sCT excites SFO neurones, and (3) that responses are blocked by AC187 but not by CGRP(8-37), is inconsistent with activation via CGRP receptors, but is instead consistent with involvement of amylin (C3) and calcitonin (C1) receptors, which are co-localized to a high degree on the same subset of SFO-neurones. We propose that it is unlikely that blood-borne CGRP has a significant effect on neurones in the SFO.

Amyloid↗

PubMed1999

3-Dimensional configuration of perimysial collagen fibres in rat cardiac muscle at resting and extended sarcomere lengths.

1. We have used fluorescence confocal laser scanning microscopy to attain the three-dimensional (3-D) microstructure of perimysial collagen fibres over the range of sarcomere lengths (1.9-2.3 micrometers) in which passive force of cardiac muscle increases steeply. 2. A uniaxial muscle preparation (right ventricular trabecula of rat) was used so that the 3-D collagen configuration could be readily related to sarcomere length. Transmission electron microscopy showed that these preparations were structurally homologous to ventricular wall muscle. 3. Trabeculae were mounted on the stage of an inverted microscope and fixed at various sarcomere lengths. After a trabecula was stained with the fluorophore Sirius Red F3BA and embedded in resin, sequential optical sectioning enabled 3-D reconstruction of its perimysial collagen fibres. The area fraction of these fibres, determined from the cross-sections of seven trabeculae, was 10.5 +/- 3.9 % (means +/- s.d.). 4. The reconstructed 3-D images show that perimysial collagen fibres are wavy (as distinct from coiled) cords which straighten considerably as the sarcomere length is increased from 1.85 +/- 0.06 micrometer (near-resting length) to 2.3 +/- 0.04 micrometer (means +/- s.d., n = 4). These observations are consistent with the notion that the straightening of these fibres is responsible for limiting extension of the cardiac sarcomere to a length of approximately 2.3 micrometers.

Analysis of Variance↗