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Biomedical subjects

M Rudin

Publications and source records attributed to M Rudin.

At least 55 records · Page 3Linked to original sources
PubMed1997

Allo- and autotransplantation of carotid artery--a new model of chronic graft vessel disease: evaluation by magnetic resonance imaging and histology.

BACKGROUND: Graft vessel disease is a special form of accelerated arteriosclerosis. Because immunological and nonimmunological factors can contribute to graft vessel disease, we developed a model that enables the study of both factors simultaneously. METHODS: A carotid artery was allografted from DA to Lewis rats, with the excised native artery autografted on the contralateral side. Five groups of six to seven rats were treated for 8 weeks with vehicle (placebo) or cyclosporine (CsA) (0.3, 1, 3, and 10 mg x kg(-1) x day(-1)), which was administered using subcutaneous osmotic minipumps. The carotid lumen area was estimated in vivo at 2, 4, and 8 weeks by magnetic resonance imaging (MRI); CsA blood levels were determined twice. Carotid neointimal thickening and medial and luminal area were measured with histological techniques. RESULTS: MRI showed bulging of the allografts but not autografts. Bulging disappeared over time with narrowing of the allograft lumina estimated by both MRI and histology. Histologically, vehicle-treated animals developed a massive neointima, which was inhibited in a dose-dependent manner by CsA. Autografts remained normal except for minimal subintimal thickening of two of four arteries in the group given the highest dose of CsA. Cellular rejection was detected in the allografts of all but the highest-dose group. The CsA blood levels were similar to those used in man at the two lower doses and about 10-fold higher at the highest dose. CONCLUSIONS: Subintimal thickening did not correlate with in vivo lumen size, a phenomenon that we have previously described for balloon catheter-induced lesions. CsA blood concentrations similar to those used in patients suppressed neointima formation in part, and 10-fold higher concentrations almost completely suppressed neointima formation.

Animals↗
PubMed1997

Signal changes in the spinal cord of the rat after injection of formalin into the hindpaw: characterization using functional magnetic resonance imaging.

Changes in metabolism and local circulation occur in the spinal cord during peripheral noxious stimulation. Evidence is presented that this stimulation also causes signal intensity alterations in functional magnetic resonance images of the spinal cord during formalin-induced pain. These results indicate the potential of functional magnetic resonance imaging in assessing noninvasively the extent and intensity of spinal cord excitation in this well characterized pain model. Therefore, the aim of this study was to establish functional magnetic resonance imaging as a noninvasive method to characterize temporal changes in the spinal cord after a single injection of 50 microl of formalin subcutaneously into the hindpaw of the anesthetized rat. This challenge produced a biphasic licking activity in the freely moving conscious animal. Images of the spinal cord were acquired within 2 min, enabling monitoring of the site and the temporal evolution of the signal changes during the development of formalin-induced hyperalgesia without the need of any surgical procedure. The time course of changes in the spinal cord functional image in the isoflurane-anesthetized animal was similar to that obtained from behavioral experiments. Also, comparable physiological data, control experiments, and the inhibition of a response through application of the local anesthetic agent lidocaine indicate that the signal changes observed after formalin injection were specifically related to excitability changes in the relevant segments of the lumbar spinal cord. This approach could be useful to characterize different models of pain and hyperalgesia and, more importantly, to evaluate effects of analgesic drugs.

Animals↗
PubMed1997

Analysis of tracer transit in rat brain after carotid artery and femoral vein administrations using linear system theory.

Determination of tissue perfusion rates by MRI bolus tracking methods relies on the central volume principle which states that tissue blood flow is given by the tissue blood volume divided by the mean tracer transit time (MTT). Accurate determination of the MTT requires knowledge of the arterial input function which in MRI experiments is usually not known, especially when using small animals. The problem of unknown arterial input can be circumvented in animal experiments by directly injecting the contrast agent into a feeding artery of the tissue of interest. In the present article the passage of magnetite nanoparticles through the rat cerebral cortex is analyzed after injection into the internal carotid artery. The results are discussed in the framework of linear system theory using a one-compartment model for brain tissue and by using the well characterized gamma-variate function to describe the tissue concentration profile of the contrast agent. The results obtained from the intra-arterial tracer administration experiments are then compared with the commonly used intra-venous injection of the contrast agent in order to estimate the contribution of the peripheral circulation to the MTT values in the latter case. The experiments were analyzed using a two-compartment model and the gamma-variate function. As an application perfusion rates in normal and ischemic cerebral cortex of hypertensive rats were estimated in a model of focal cerebral ischemia. The results indicate that peripheral circulation has a significant influence on the MTT values and thus on the perfusion rates, which cannot be neglected.

Animals↗
PubMed1996

Magnetic resonance imaging for the evaluation of rejection of a kidney allograft in the rat.

Orthotopic DA (RT1a) into Lewis (RT1l) rat kidney allografts and control Lewis-into-Lewis grafts were assessed by magnetic resonance imaging (MRI) and perfusion measurement after intravenous injection of a superparamagnetic contrast agent. MRI anatomical scores (range 1-6) and perfusion rates were compared with graft histology (rank of rejection score 1-6). Not only acute rejection, but also chronic events were monitored after acute rejection was prevented by daily cyclosporine (Sandimmune) treatment during the first 2 weeks after transplantation. In acute allograft rejection (n = 11), MRI scores reached the maximum value of 6 and perfusion rates were severely reduced within 5 days after transplantation; histology showed severe acute rejection (histologic score 5-6). In the chronic phase (100-130 days after transplantation), allografts (n = 5) manifested rejection (in histology cellular rejection and vessel changes), accompanied by MRI scores of around 2-3 and reduced perfusion rates. Both in the acute and chronic phases, the MRI anatomical score correlated significantly with the histological score (Spearman rank correlation coefficient rs 0.89, n = 30, P < 0.01), and perfusion rates correlated significantly with the MRI score or histological score (rs values between -0.60 and -0.87, n = 23, P < 0.01). It is concluded that MRI represents an interesting tool for assessing the anatomical and hemodynamical status of a kidney allograft in the acute and chronic phases after transplantation.

Acute Disease↗
PubMed1996

Biphenyl-derivatives of 2-amino-7-phosphono-heptanoic acid, a novel class of potent competitive N-methyl-D-aspartate receptor antagonists--II. Pharmacological characterization in vivo.

A selection of biphenyl-analogues of 2-amino-7-phosphonoheptanoic acid (AP7), N-methyl-D-aspartate (NMDA) receptor antagonists with high affinity in vivo efficacy. The lead compound SDZ EAB 515 was found to inhibit L-phenylalanine uptake by the large neutral amino acid carrier in vitro and in vivo; active transport may thus confer a good bioavailability to this class of compounds. CNS effects were demonstrated by significant changes in 2-deoxyglucose-uptake in various brain regions at doses from 1 to 10 mg/kg i.p. With the most active agent, SDZ 220-581, full protection against maximal electroshock seizures (MES) was obtained at oral doses of 10 mg/kg in rats and in mice. The compound had a fast onset (< or = 1 hr) and a long duration (> or = 24 hr) of action. Motor-debilitating effects (impairment of rotarod performance) occurred at doses about 10 times higher than those required for protection against MES. Neuroprotective activity was demonstrated by the ability of the compounds to reduce the extent of quinolinic acid-induced striatal lesions in rats, in the dose range of 3-15 mg/kg (i.p.) or 10-50 mg/kg (p.o.). In the middle cerebral artery occlusion (MCAO) model of focal cerebral ischemia in rats, the test compounds reduced the infarct size by 40-50% when given i.v. before or by 20-30% when given i.v. 1 hr after MCAO. SDZ 220-581 provided 20-30% protection at > or = 2 x 10 mg/kg p.o. This compound also showed analgesic activity at low oral doses in a model of neuropathic pain, although higher doses were required in model of mechanical inflammatory hyperalgesia. Unexpectedly, SDZ 220-581 at low s.c. doses counteracted the antiparkinsonian effects of L-DOPA in MPTP-treated marmosets. (Sub)chronic administration of SDZ 220-581 did not reduce its ability to protect against quinolinic acid neurotoxicity, and no upregulation of NMDA receptors was detected using a [3H]CGP-39653 binding assay. In conclusion, from a series of biphenyl-AP7-derivatives, SDZ 220-581 is clearly the most active compound in vivo. Its pharmacological profile with a good, long-lasting oral activity might open up novel therapeutic applications for competitive NMDA receptor antagonists.

Amino Acids↗
PubMed1995

Noninvasive 3D MR microscopy as a tool in pharmacological research: application to a model of rheumatoid arthritis.

Magnetic resonance microscopy (MRM) was applied to noninvasively image skeletal structures in the hindpaw of the live rat to characterize the progression of a heterologous type II collagen-induced arthritic process. Using a resonator, with optimized filling factor, three-dimensional (3D) gradient-echo images with voxel dimensions of 94 x 81 x 60 micron3 were acquired in 54.6 min. Three-dimensional MRM reduces the slice positioning problem, which is critical in longitudinal studies. Moreover, due to the much smaller slice thickness of images derived from 3D data sets, partial volume effects are less pronounced than in corresponding 2D images. Distinct pathomorphological changes associated with the collagen-induced arthritic process (e.g., increase of metatarsophalangeal joint space, and bone and cartilage erosion) could thus be analyzed under in vivo conditions.

Animals↗
PubMed1995

Strain-dependent drug effects in rat middle cerebral artery occlusion model of stroke.

In the rat middle cerebral artery occlusion (MCAO) model of embolic stroke, calcium antagonists, as well as competitive and noncompetitive N-methyl-D-aspartate (NMDA) antagonists have been studied extensively by various groups. However, there are divergent conclusions concerning their efficiencies. These discrepancies may be due to the different experimental conditions and/or rat strains used. In this study we have assessed in five commonly used rat strains, under identical experimental conditions, the ability of one representative of each of these drug classes to reduce the infarct size in this model. Drugs or corresponding vehicle were injected immediately after permanent unilateral MCAO and the infarct volume was determined 48 hr later by magnetic resonance imaging. In vehicle-treated controls, the total infarct volume was strain-dependent (range, 70-200 microliters), primarily due to variations in the cortex. The extent of total infarct volume reduction (up to 65%) elicited by the three drugs also was strain-dependent, the main effect and variation being observed in the cortex (range, 0-83% reduction). No difference in efficiency was seen between the competitive and noncompetitive NMDA antagonist, whereas the calcium antagonist showed better results in all five strains. The potential to reduce the infarct size in the rat MCAO model with calcium or NMDA antagonists depends upon the strain used. The exact reasons and mechanisms are presently not understood. Such knowledge would certainly add to the confidence in this model and would allow more accurate predictions concerning the clinical efficacy of drugs in stroke trials.

Animals↗
PubMed1995

Quantification of optic nerve blood flow changes using magnetic resonance imaging.

PURPOSE: To evaluate the possibilities of magnetic resonance imaging (MRI) for quantification of pharmacologically induced changes in optic nerve microcirculation. METHOD: T2-weighted MRI sequences were used to image the eye, optic nerve, and frontal cortex in rats. Two sets of control images before and one set during Gd (DTPA) infusion were recorded. Blood flow values for two regions of the optic nerve (an anterior part, including the optic nerve head, and a more posterior part) and the frontal cortex were calculated by image analysis from the change in signal intensity, as already reported for cerebral blood flow. For each rat, a control experiment before drug administration and a second experiment 30 minutes after subcutaneous injection of either placebo (n = 7), timolol (n = 7), or SDZ GLC-756, a dopamine D-1 antagonist and D-2 agonist (n = 7), were carried out in a double-blind fashion. RESULTS: Mean basal blood flow values were found between 29.4 and 45.6 ml/100 g per minute in the anterior part of the optic nerve, 38.3 and 42.9 ml/100 g per minute in the posterior part of the optic nerve, and 68.0 and 75.0 ml/100 g per minute in the frontal cortex. Placebo and timolol did not cause significant changes. SDZ GLC-756 significantly increased blood flow by 238% +/- 65% in the anterior part and by 87% +/- 40% in the posterior part of the optic nerve. CONCLUSIONS: These results suggest that MRI provides quantification of optic nerve blood flow and that dopaminergic substances increase optic nerve blood flow.

Animals↗
PubMed1994

[13C]NMR studies of the effect of the somatostatin analogue octreotide on hepatic glycogenesis and glycogenolysis.

NMR spectroscopy is a useful tool for monitoring multiple intermediate metabolic pathways in different organs in intact animals and humans. We report the effect of the somatostatin analogue octreotide on the fate of 13C-labeled glucose administered to fasted and well-fed rats as determined by NMR spectroscopy. The production of 13C-labeled glycogen and its subsequent breakdown after the end of infusion was identified with a time resolution of 7 min. Hepatic glycogen synthesis was not different between control and octreotide-treated animals but persisted for 15 min after the end of the infusion only in control animals. Glycogenolysis, however, was initiated immediately after the end of infusion in octreotide-treated animals where the half-life of glycogen was 40 min compared with 68 min in control animals. However, once initiated, the rate of glycogenolysis was not significantly altered by octreotide. Although octreotide had no effect on glucose signal intensities in fasted animals, 13C glucose signals were more intense in octreotide compared with control well-fed animals. In conclusion, octreotide alters rat hepatic metabolism by accelerating the onset of glycogenolysis and stimulating glucose accumulation without significantly interfering with glycogen synthesis.

Animals↗
PubMed1994

Decreased lumen size after balloon injury despite inhibition of neointimal thickening and antivasospastic treatment.

OBJECTIVE: Both calcium antagonists and angiotensin converting enzyme (ACE) inhibitors are known to diminish the development of intimal thickening after a balloon catheter lesion. It was previously shown that narrowing of carotid artery lumen induced by balloon injury was not influenced by treatment, even though the two ACE inhibitors used inhibited neointimal thickening. The aim of the present study was to include a calcium antagonist as well, in order to investigate whether vasospasm contributes to the persistence of lumen narrowing in ACE inhibitor treated rats after a balloon lesion. METHODS: Six groups of 10 rats were subject to balloon lesion of the left carotid artery. They received spirapril (10 mg.kg-1 x d-1) or isradipine (30 or 100 mg.kg-1 x d-1) or both, given throughout the study in the food. Controls received no drug. Neointimal thickening was measured histologically two weeks after injury. The cross sectional carotid lumen area was measured in vivo by nuclear magnetic resonance imaging, both before and two weeks after balloon injury, and also postmortem by histological techniques. RESULTS: Two weeks after injury, the lumen area of the left carotid artery was significantly reduced following balloon injury, as measured by both techniques. Treatment did not modify the stenosis process as assessed by either method for measuring lumen size. Neointimal thickening, however, was inhibited by between 4% (low dose isradipine) and 59% (combined spirapril + high dose isradipine) in the various treatment groups. CONCLUSIONS: Since calcium antagonist treatment was not able to influence the reduction of lumen size, it is unlikely that the narrowing is due to reversible spasm of the carotid artery in the first two weeks after inducing a balloon lesion. Alternatively, chronic vasospasm of neointimal smooth muscle might not be very sensitive to calcium antagonists.

Angioplasty, Balloon, Coronary↗
PubMed1993

Determination of creatine kinase kinetic parameters in rat brain by NMR magnetization transfer. Correlation with brain function.

The pseudo first-order rate constant kf of the creatine kinase (CK) forward reaction as well as the CK forward flux FCK,f have been shown to correlate better with cardiac performance than the steady-state levels of ATP and PCr (Bittl, J. A., and Ingwall, J. S. (1985) J. Biol. Chem. 260, 3512-3517). In order to elucidate the relationship between the CK kinetic parameters and brain activity, we have determined, using the non-invasive NMR technique of magnetization transfer, kf and FCK,f in rats, in which brain activity was experimentally varied by administration of either thiopental sodium or bicuculline to decrease or increase electro-encephalogram (EEG) intensity, respectively. The steady-state levels of ATP and PCr, as well as the accumulation of deoxyglucose 6-phosphate (DG-6P) in brain following intraperitoneal administration of deoxyglucose, were determined simultaneously by the NMR technique, whereas the cortical EEG was recorded in a separate experiment. The EEG intensity (range, 1-20 Hz), taken as a measure for brain performance, as well as the amount of DG-6P formed in brain, reflecting the synthesis rate of high energy phosphates (ATP and PCr), linearly correlated with kf. Despite large changes in both EEG intensity (50-250%) and kf (0.12-0.69 s-1) between thiopental sodium- and bicuculline-treated rats, the ATP levels remained constant, whereas the PCr levels decreased with high EEG activity. In contrast to the expectation based on model calculations of CK kinetics, the PCr levels did not increase above control values at reduced EEG intensity (50% of controls). At EEG intensities exceeding control values (bicuculline-treated rats) FCK,f increased as predicted by CK equilibrium. In conclusion, we have shown that in the rat brain, like in the heart, the CK forward rate constant kf, in contrast to ATP and PCr levels, is a sensitive reliable indicator of both increased and reduced function.

Adenosine Triphosphate↗
PubMed1993

SDZ ENS 163 a novel pilocarpine like drug: pharmacological in vitro and in vivo profile.

The thiolactone analogue of pilocarpine, SDZ ENS 163, acts in vitro and in vivo as a partial agonist at M1/M3 and as an antagonist at M2 muscarinic receptors. In vitro, the properties of SDZ ENS 163 have been investigated in several functional models for muscarinic receptors: it is a full agonist at M1 (rat superior cervical ganglion, carbachol = 100%) and a partial agonist at M3 receptors (guinea pig ileum). However, the drug shows antagonistic properties at M2 receptors (rat atria). Radioligand binding studies with 3H-N-methylscopolamine (3H-NMS) using CHO cells expressing m1 or m3 receptors indicate that SDZ ENS 163 does not discriminate between m1 and m3 receptors (Ki 1.5 and 2.4 microM respectively). Regarding phosphoinositide (PI) turnover in A9L cells, SDZ ENS 163 is a partial agonist at m1 receptors. In ex vivo neurochemical studies in rats SDZ ENS 163 displays effects characteristic of muscarinic antagonists regarding the turnover of ACh which is increased in the brain. At a similar dose-range SDZ ENS 163 accelerates PI metabolism in the rat brain in vivo and increases the energy of the low frequency band (2-5 Hz) in the rat hippocampal EEG. These effects observed in vivo are consistent with postsynaptic M1 agonistic and presynaptic M2 antagonistic activities. Since SDZ ENS 163 at centrally active doses exerts no peripheral cholinergic effects, it may be useful for the symptomatic treatment of Alzheimer's disease.

Acetylcholine↗
PubMed1993

Time course of spirapril-induced structural and functional changes after myocardial infarction in rats followed with magnetic resonance imaging.

Structural alterations after myocardial infarction (MI) in rats are usually examined only after death of the experimental animal. Magnetic resonance imaging (MRI) allows repeated and noninvasive measurements of important structural [left ventricular (LV) mass, LV wall thickness, LV chamber radius] as well as function [LV end-systolic and LV end-diastolic volume, stroke volume (SV), ejection fraction (EF)] parameters for a prolonged period. We describe our experience in a series of experiments in rats. Three weeks after MI, infarct size (IS) was determined by MRI and the rats were divided into two groups with equal IS. Three weeks later, treatment with the angiotensin-converting enzyme (ACE) inhibitor spirapril (10 mg/kg in food) or placebo was started. In both groups, the first MRI scan taken before the treatment showed moderately dilated left ventricles and signs of impaired LV function, i.e., an increase in LV end-systolic and end-diastolic volume and decreased EF. After 3-week treatment, no significant differences with respect to heart structure and function were detected as compared with those of untreated animals. Prolonged treatment for 10 weeks with spirapril resulted in significant reduction of LV dilatation, LV mass, and LV end-systolic and end-diastolic volume, which was accompanied by improved EF. Hemodynamic examinations after treatment for 6 months showed, in contrast to control animals, no increase in right ventricular systolic pressure in animals receiving spirapril. Furthermore, histologic examination of perfusion-fixed hearts at the end of the study demonstrated more pronounced LV dilatation in control animals, thus confirming the in vivo MRI data. Delayed treatment with spirapril proved to have beneficial effects on structure and function of infarcted hearts within 10 weeks. Spirapril limited LV dilatation, reduced LV weight and LV end-systolic and end-diastolic volumes, and improved EF.

Angiotensin-Converting Enzyme Inhibitors↗