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M Rudin

Publications and source records attributed to M Rudin.

At least 73 records · Page 4Linked to original sources
PubMed1993

Spirapril and cilazapril inhibit neointimal lesion development but cause no detectable inhibition of lumen narrowing after carotid artery balloon catheter injury in the rat.

Five groups of 12 rats were subject to balloon lesion of the left carotid artery and neointimal thickening was measured histologically 2 weeks after injury. Rat groups received either spirapril (3, 10 or 30 mg/kg/day, administered throughout the study in the food), cilazapril (10 mg/kg/day) or placebo. Spirapril caused a dose-dependent inhibition of the neointimal thickening of the rat carotid artery. The degree of inhibition with 10 mg/kg/d spirapril and cilazapril was similar (-44% and -42% respectively). The carotid lumen area was measured in vivo by nuclear magnetic resonance (NMR) imaging both before and 2 weeks after balloon injury and also postmortem by histological techniques. 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 detectably modify this stenosis process despite the use of two independent methods for assessing lumen size, even though neointimal thickening was strongly attenuated by both angiotensin converting enzyme inhibitors. This dissociation between inhibition of neointimal lesion development and decrease of lumen size provides a new view of the role of angiotensin converting enzyme inhibitors in vascular damage situations. Our results suggest that the focus, particularly in clinical studies, on lumen size, may mean that potentially beneficial effects of these drugs on other parts of the vascular wall be overlooked.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

In vivo NMR in pharmaceutical research.

In vivo NMR techniques are currently well established in pharmaceutical research and will likely become increasingly important in the future, as they procure noninvasively morphological, physiological, and biochemical information. The status of magnetic resonance imaging (MRI) and spectroscopy (MRS) in drug development is discussed on the basis of the characterization and evaluation of a rat model of ischemic stroke and the development and profiling of drugs for cerebral ischemia in this model. It can be concluded that MRI is well suited for drug screening (quantitative determination of lesion size), while dynamic MRI and MRS techniques provide relevant information on the mechanism of drug actions. The possibility to follow changes, pathological and therapeutic, in the same individual is important from two points of view. First, variations due to interindividual differences may be eliminated, increasing the statistical power of the results. Second, dose and/or time dependence of a drug can be explored in the same individual. As a result, the number of animals required for a study will be reduced, which from both ethical and economic aspects is highly desirable.

Animals↗
PubMed1992

Effect of spirapril on left ventricular hypertrophy due to volume overload in rats.

The effect of the angiotensin-converting enzyme (ACE) inhibitor spirapril on structural and functional parameters of volume-overloaded rat hearts was evaluated in a time-course study. Left ventricular hypertrophy (LVH) was induced by graded disruption of the aortic valve in male Wistar rats. Four weeks later, structural (LV mass and LV wall thickness) as well as functional parameters [LV end-systolic and end-diastolic volumes, stroke volume (SV), ejection fraction (EF)] were determined in anesthetized animals by magnetic resonance imaging (MRI). The rats were then divided into two groups, one of them receiving spirapril (10 mg/kg/day) in food. LV parameters were evaluated by MRI at 4, 18, 25, and 32 days after treatment was started. MRI analysis before the start of treatment showed that both groups had developed a similar degree of eccentric LV hypertrophy. Similarly, LV wall thickness, end-systolic and end-diastolic volumes, SV, and EF did not differ between the groups. Treatment with spirapril resulted in stable LV weight during the follow-up period of 32 days, whereas the untreated group showed a significant steady increase in heart weight. LV end-diastolic volume, LV end-systolic volume, and SV were smaller in the spirapril group when measured after 25 and 32 days, but only the difference in end-diastolic volume reached statistical significance. LV wall thickness and EF were not affected by spirapril. After the last MRI determinations, blood pressure (BP) and the response to angiotensin I (ANGI) were measured in conscious animals. Systolic BP (SBP) and mean arterial pressure (MAP) were significantly lower in spirapril-treated rats, and the dose-response curve to ANGI was shifted to the right.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Noninvasive determination of regional cerebral blood flow in rats using dynamic imaging with Gd(DTPA)

A method for the noninvasive, quantitative determination of regional cerebral blood flow (rCBF) in small laboratory animals, such as the rat, is described. The change in magnetic susceptibility in the vicinity of brain capillaries evoked by iv infusion of Gd(DTPA), a paramagnetic agent not crossing the blood-brain barrier, is detected as an attenuation of the 1H signal in T2-weighted MRI sequences. The reduction of the MR signal intensity after 1 or 2 min of Gd(DTPA) infusion correlates well (r greater than 0.95) with the rCBF values obtained using the well-established [14C]iodoantipyrine method. At a slice thickness of 3 mm, the pixel size typically is 0.15 x 0.5 mm2. The clearance rate of Gd(DTPA) from blood allows repeated measurements of CBF to be made using this technique approximately every 30 min. The experimental results obtained in normal and ischemic rat brain have been rationalized within the frame of a two-compartment model, allowing the definition of optimal experimental conditions for a given CBF: for normal and reduced CBF values (less than 150 ml/100 g/min) the reduction in MR signal intensity, measured after 1 or 2 min of Gd (DTPA) infusion, correlates closely with the CBF. However, for CBF values greater than 150 ml/100 g/min, a more reliable parameter would be the time constant of the MR signal attenuation during the infusion.

Animals↗
PubMed1991

New developments in cardiovascular magnetic resonance imaging and spectroscopy.

Methodological improvements in nuclear magnetic resonance (NMR) imaging and spectroscopy have enabled the application of these techniques to the study of functional or dynamic biological processes. Because the techniques are non-invasive, repeated measurements can be made in the same animal at different time points, allowing disease progression and regression to be followed during drug therapy. In this review, Markus Rudin, Wolfgang Zierhut, André Sauter and Nigel Cook illustrate this concept by the use of NMR to evaluate cardiovascular function in the rat in various physiological and pathological situations. The possibility of using NMR to perform similar studies in both animals and humans should lead to the design of preclinical models with an improved clinical predictability.

Animals↗
PubMed1991

Prevention of stroke and brain damage with calcium antagonists in animals.

In a rat model of embolic stroke (permanent occlusion of the left middle cerebral artery [MCAO]), various 1,4-dihydropyridine calcium antagonists have been shown to attenuate brain damage and the resultant functional impairment when administered after MCAO. Dose-response curves reveal that isradipine is one of the most potent and efficacious representatives of this class of compounds, reducing the infarct size by more than 60%. These results suggest that isradipine, when administered shortly after stroke onset, may have beneficial effects in patients suffering from brain ischemia. When isradipine is used to normalize the high blood pressure in spontaneously hypertensive rats, it will, in addition, also protect the brain from damage engendered by a subsequent stroke. This is not the case if blood pressure is controlled with a calcium antagonist which does not cross the blood-brain barrier, suggesting that the brain protection seen with isradipine is not due to blood pressure normalization. Isradipine, when used as an antihypertensive, appears to have an additional beneficial effect within the brain itself. As high blood pressure is a major risk factor for stroke, such an additional benefit with isradipine would be particularly valuable in antihypertensive therapy.

Animals↗
PubMed1990

Experimental studies with isradipine in stroke.

The effects of isradipine in a rat model of embolic stroke [permanent occlusion of the left middle cerebral artery (MCA)] are reviewed. Isradipine, when present or given up to 4 hours after the onset of stroke, reduces the infarct size, determined by magnetic resonance imaging (MRI) 24 hours, and by histology 5 days, after MCA occlusion. These cytoprotective effects seem to be permanent and are paralleled by an improvement in the neurological deficit. Isradipine has proved to be the most potent and effective calcium antagonist for reducing the infarct size compared with other representatives of this class of drugs such as nimodipine, nicardipine and flunarizine. Isradipine is cytoprotective after a stroke when used as an antihypertensive: at doses which normalise high blood pressure in spontaneously hypertensive rats, isradipine reduces by more than 60% the infarct size caused by a subsequent stroke. Since the lowering of blood pressure, e.g. by a calcium antagonist that does not cross the blood-brain barrier, is ineffective in reducing the infarct size, normalisation of blood pressure alone cannot account for the reductions in infarct size observed with isradipine. The antihypertensive drug isradipine seems rather to offer the additional benefit of attenuating the consequences of an eventual stroke. If clinically confirmed, this will be of considerable therapeutic importance. Evidence is presented that isradipine has at least 2 mechanisms within the brain that might be responsible for cytoprotection in stroke.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Calcium antagonists for reduction of brain damage in stroke.

In a rat model of embolic stroke [permanent occlusion of the left middle cerebral artery (MCAO)], isradipine, a 1,4-dihydropyridine calcium antagonist, reduced the infarct size by more than 50%, as determined by both in vivo magnetic resonance imaging (MRI) and postmortem histology. Among several calcium antagonists tested, including nimodipine, nitrendipine, and nifedipine, isradipine was found to be the most potent and most efficacious. These results suggest that isradipine, when administered shortly after stroke onset, may have beneficial effects in patients suffering from brain ischemia. When high blood pressure in spontaneously hypertensive rats (SHR) was normalized by daily injections of isradipine, brain damage caused by a subsequent stroke (MCAO) was substantially reduced by as much as 75% in the cortex compared to controls. These results suggest that isradipine, when used as an antihypertensive drug in humans, may offer the additional benefit of reducing brain damage caused by an eventual stroke. Because high blood pressure is considered an important risk factor for stroke, this additional benefit of isradipine would be particularly valuable in antihypertensive therapy.

Animals↗
PubMed1989

Treatment of hypertension with isradipine reduces infarct size following stroke in laboratory animals.

Earlier studies have shown isradipine to reduce the size of infarct in a rat model of embolic stroke (permanent occlusion of the left middle cerebral artery) (Sauter A, Rudin M: Stroke 1986; 17: 1228-1234). The greater the delay in isradipine administration after occlusion of the left middle cerebral artery, the less these effects until no effect on infarct size was obtained when isradipine was injected six hours after occlusion of the left middle cerebral artery. Blood pressure was dose-dependently reduced in spontaneously hypertensive rats (blood pressure more than 200 mm Hg), which received injections of isradipine subcutaneously 2.5, 5, and 10 mg/kg per day for six days, to approximately 150, 135, and 120 mm Hg, respectively. Twelve hours post-injection, the left middle cerebral artery was occluded. Isradipine also dose-dependently decreased infarct size, as measured by magnetic resonance imaging at 24 hours and histology five days later, by approximately 20, 40, and 60 percent, respectively, compared with vehicle-injected controls. These results suggest that isradipine, at doses required to normalize the high blood pressure in spontaneously hypertensive rats, will substantially reduce the infarct size caused by a later stroke.

Animals↗
PubMed1989

Cerebrovascular, biochemical, and cytoprotective effects of isradipine in laboratory animals.

Dose-response curves of isradipine for blood pressure, total peripheral conductance, and regional cerebral conductances and blood flows were obtained in anesthetized cats and rabbits using the microsphere method. Cerebrovascular effects occurred at lower doses than systemic effects, and the effective duration was longer in the brain than in the periphery. In a rat model of embolic stroke (unilateral occlusion of the middle cerebral artery), isradipine has been shown to have cytoprotective efficacy (Sauter A, Rudin M: Stroke 1986; 17: 1228-1234; Rudin M, Sauter A, Wiederhold K-H: Therapie 1987; 42: 477-481; Sauter A, Rudin M, Wiederhold K-H: Neurochem Pathol 1989 [in press]). Using this model, dose-response curves for infarct size, measured by magnetic resonance imaging, and biochemical markers of infarction were obtained for various calcium antagonists. Isradipine showed the biggest improvements (50 to 60 percent at 2.5 mg/kg subcutaneously), followed by nimodipine (30 to 40 percent at 5 mg/kg subcutaneously), nitrendipine (30 to 40 percent at 10 mg/kg subcutaneously), darodipine (20 to 30 percent at 10 mg/kg subcutaneously), and nicardipine (10 percent at 10 mg/kg subcutaneously). It is concluded that isradipine differs in both efficacy and potency from the other calcium antagonists tested. The effects of isradipine, nimodipine, and darodipine on cerebral blood flow were further investigated in this model using the [14C]iodoantipyrine method. Despite systemic hypotension, cerebral blood flow was dose dependently increased in the normal and ischemic hemispheres. Isradipine elicited maximal improvements over a wider dose range than the other drugs tested (0.1 to 2.5 mg/kg), preferentially affecting cerebral blood flow in the ischemic areas, as further demonstrated using autoradiographic techniques. These effects are in good, quantitative agreement with the reductions in infarct size, observed by magnetic resonance imaging and histology, emphasizing the importance of cerebrovascular mechanisms for cytoprotection in stroke. The concurrence between cat, rabbit, and rat experiments suggests that the findings may also apply to humans.

Animals↗
PubMed1989

Non-invasive determination of cerebral blood flow changes by 19F NMR spectroscopy.

The build-up and clearance of halothane in rat brain have been measured non-invasively by 19F NMR spectroscopy using a surface coil placed on the intact scalp. When the halothane supply (3% in O2/N2O, 33/66%) was turned off, the 19F signal decreased exponentially to approximately 50% of the initial value, with a time constant, in normal rats, of 8.6 +/- 0.7 min (mean +/- SEM, n = 16), followed by a decay slower by at least one order of magnitude. The time constant of the rapid decay (tau), which was found to be specific for brain, was reduced in hypoxic/hypercapnic (5% O2/5% CO2) rats to 2.9 +/- 0.2 min (p = 0.001, n = 4), in rats infused with physostigmine (20 micrograms/kg/min i.v.) to 5.7 +/- 0.3 min (p = 0.005, n = 6) and increased in rats injected with pentothal (40 mg/kg i.p.) to 10.7 +/- 1.6 min (p = 0.2, n = 5). Based on the theory of exchange of inert gas at the lungs and tissues developed by Kety, the rapid exponential decay of the 19F signal was used to calculate relative cerebral blood flow (CBF). Assuming the cortical CBF in a normal rat to be about 130 mL min-1 100 g-1, the following CBF values (means +/- SEM) were obtained: controls 130 +/- 10, hypoxia/hypercapnia 390 +/- 59, hypercapnia 220 +/- 25, physostigmine 195 +/- 26, pentothal 105 +/- 23 mL min-1 100 g-1. These values are in good agreement with published values obtained with established methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Dihydropyridine calcium antagonists reduce the consumption of high-energy phosphates in the rat brain. A study using combined 31P/1H magnetic resonance spectroscopy and 31P saturation transfer.

The disappearance of high-energy phosphates (HEPs) in the rat brain during global ischemia induced by cardiac arrest is slowed down significantly by dihydropyridine Ca antagonists (DCAs) compared to controls. Two mechanisms might account for this effect: increased HEP production via anaerobic glycolysis or decreased HEP consumption. In order to obtain more insight into the underlying mechanisms of ATP preservation we have studied in the rat the effect of the DCAs isradipine, darodipine and nimodipine on the cerebral steady-state levels of HEPs and lactate as well as the intracellular pH value during global ischemia using combined 31P/1H magnetic resonance spectroscopy. We have found that the ATP preservation in DCA-treated animals is not associated with significantly higher postischemic lactate levels (lactate/N-acetylaspartate 0.97 +/- 0.08 for isradipine at a dose of 2.5 mg/kg i.p.) or lower pH values (6.40 +/- 0.03) as compared to control rats (lactate/N-acetylaspartate 0.94 +/- 0.13, pH = 6.49 +/- 0.03). This is in contrast to hyperglycemic rats, in which similar preservation of ATP levels during ischemia was observed; however, at the expense of a larger drop in brain pH (6.22 +/- 0.09) and a concomitant increase in cerebral lactate (lactate/N-acetylaspartate = 1.40 +/- 0.09). These results strongly favor reduced ATP consumption to be the cause for the protective effect of DCAs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1988

Partial inhibition of the growth of transplanted dunning rat prostate tumors with the long-acting somatostatin analogue sandostatin (SMS 201-995).

The growth-inhibiting effects of the long-acting somatostatin analogue Sandostatin on the transplanted Dunning R3327-H androgen-sensitive rat prostate tumor were investigated. Recipient animals were male Copenhagen x Fischer F1 rats (N = 36). When mean tumor volume reached 700 mm3 (20 weeks following transplantation), the rats were divided into four groups: control; Sandostatin (100 micrograms/kg s.c. twice a day); castrate; castrate/Sandostatin. Tumor size was assessed by magnetic resonance imaging 21, 42, 63, 105, and 138 days subsequently. Administration of Sandostatin was interrupted between days 43 and 62. As assessed by transplant volume, Sandostatin caused a moderate (up to 50%) but highly significant (P less than 0.001) suppression of tumor growth in the intact rats; the effect was reversed when drug administration was stopped. In the castrates, in which tumor growth was markedly less than in intact rats, no significant effect of Sandostatin was seen. Analysis of the tumor growth rate demonstrated that Sandostatin led to a 19% reduction (P less than 0.05) in growth rate in intact rats and a 9% decrease (not significant) in castrates. These findings extend previous reports of partial suppression of various types of tumors in vivo with Sandostatin and other somatostatin analogues. Their relevance with regard to the possible use of Sandostatin in the treatment of prostatic carcinoma in humans is discussed.

Animals↗
PubMed1988

Quantitative magnetic resonance imaging of estradiol-induced pituitary hyperplasia in rats.

Magnetic resonance imaging (MRI) has been used for the determination in vivo of rat pituitary size. In midsagittal T2-weighted sections the pituitary, having a lower T2 value than the surrounding tissue, was visible with pronounced contrast. The size has been estimated by pixel counting. A close correlation (r = 0.96) with the pituitary weights determined postmortem has been obtained, demonstrating the reliability of the in vivo method. Using MRI the effects of Sandostatin, a somatostatin analog, on the pituitary size have been monitored in a rat model of prolactinoma (estradiol-induced hyperplasia of the pituitary). Treatment with Sandostatin over 4 weeks resulted in a 40% reduction of the hyperplastic pituitaries. These results have been confirmed by determination of pituitary weights postmortem. However, due to a large interindividual variation in size of hyperplastic pituitaries, more animals are required to reach statistical significance when only endpoints of treatment can be measured. In contrast, MRI allows one to monitor individually the drug effects over a long period of time, eliminating interindividual variations.

Adenoma↗
PubMed1988

Visualization and quantification of transplanted Dunning prostate tumors in rats using magnetic resonance imaging.

Quantitative magnetic resonance imaging (MRI) has been used for the in vivo size determination of subcutaneously implanted Dunning R3327-H tumors in male Copenhagen-Fisher rats (N = 18). Images have been recorded using a multislice spin-echo sequence SE(1000/36) with a resolution of 0.2 x 0.2 mm2 in the imaging plane and a slice thickness of 2 mm. The reliability in the MRI size determination was of the order of 10%. The MRI results were compared with caliper measurements. Five months after tumor implantation nine rats were castrated. Orchiectomy led to a marked and statistically significant reduction in tumor growth rate as determined by both methods of quantification. Qualitative MRI information regarding the tumor morphology was compared with that for histological specimens.

Adenocarcinoma↗
PubMed1987

Effects of calcium antagonists on high-energy phosphates in ischemic rat brain measured by 31P NMR spectroscopy.

The effects of various calcium antagonists on the ATP, PCr, and Pi levels as well as intracellular pH in normal and ischemic rat brain were examined by 31P NMR spectroscopy using a surface coil. None of the calcium antagonists tested showed any effect in the nonischemic rat brain. However, when global ischemia was induced by cardiac arrest, the ensuring rapid decrease of ATP and PCr and concomitant increase of Pi were significantly retarded by dihydropyridine calcium antagonists, but not by verapamil. The fall in pH caused by ischemia was not affected by either drug. Barbiturates showed effects similar to calcium antagonists, whereas calcium agonists showed the opposite. These results suggest that dihydropyridine calcium antagonists, similar to barbiturates, decrease the high-energy phosphate consumption of the brain, which might be beneficial in instances where their production is severely hampered, e.g., during ischemia.

Adenosine Triphosphate↗