Efficacy of isradipine in middle cerebral artery-occluded rats.
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Animals↗
Biomedical subjects
A Sauter
Publications and source records attributed to A Sauter.
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↗
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↗
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↗
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↗
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↗
Adaptive cytoprotection of gastric surface epithelial cells against injury by physiologic concentrations of bile acid.
The purpose of this study was to determine whether adaptive cytoprotection of gastric mucosa could be demonstrated with concentrations of bile acid, which is normally found in the human stomach, and whether cyclooxygenase inhibition, in turn, could blunt the response. Surface epithelial cell exfoliation and ion fluxes were used as end points. A transduodenal gastric cannula was placed, and the pylorus/gastroesophageal junction was ligated in adult male Sprague-Dawley rats that had been anesthetized. In experiment 1 (N = 30), rat stomachs were exposed for 15 minutes to 5 ml of either a neutral test solution (160 mmol/L NaCl, pH 7) or 1 mmol/L acidified taurocholate (ATC) (100 mmol/L HCl, 60 mmol/L NaCl, 1 mmol/L taurocholic acid; pH 1.2). All rats were subsequently exposed for 15 minutes to 5 mmol/L ATC during which time mucosal injury was assessed by measuring net flux of H+, Na+, and K+, volume, and DNA efflux. In experiment 2 (N = 35), all stomachs were pretreated for 15 minutes with 1 mmol/L ATC before mucosal injury with 5 mmol/L ATC (15 minutes). Eighteen rats were pretreated with indomethacin (5 mg/kg) subcutaneously 75 minutes before the experiment was begun, and the same parameters were measured. Pretreatment of rat gastric mucosa with 1 mmol/L ATC significantly attenuated the mucosal injury that was seen with subsequent exposure to 5 mmol/L ATC, resulting in significantly (p less than 0.05) less luminal H+ loss (-16 +/- 4 vs -32 +/- 4 mEq/15 min) and DNA efflux (181 +/- 21 vs 270 +/- 25 micrograms/15 min) than the nonadapted group. Indomethacin pretreatment significantly attenuated the adaptive protective response, resulting in greater loss of H+ (-29 +/- 4 vs -18 +/- 3) and DNA efflux (190 +/- 35 vs 110 +/- 18, both p less than 0.05) after exposure to 5 mmol/L ATC. These studies demonstrate that adaptive cytoprotection of gastric mucosa occurs with physiologic concentrations of an irritant that is normally present in the stomach. Indomethacin blunts this effect, which suggests that adaptive cytoprotection in this setting may be mediated by production of endogenous prostaglandins.
Acids↗
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↗
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↗
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↗
Postnatal evolution of the gamma-aminobutyric acid/benzodiazepine receptor complex in a model of inherited epilepsy: the quaking mouse.
Binding assays of [3H]muscimol and [3H]-flunitrazepam have been performed on brain homogenates of brainstem, cerebellum, and forebrain of genetically epileptic quaking (qk) mutant mice 20, 40, 70, and 90 days old and their corresponding controls of the same strain (C57BL/6J). The endogenous gamma-aminobutyric acid (GABA) content has been determined in various brain regions of 70-day-old qk and control mice. Finally, the behavioral effects of diazepam, of the mixed GABAA/GABAB receptor agonist progabide, and of the selective GABAB receptor agonist baclofen have been assessed in adult qk mutants. Our results strongly suggest a lack of involvement of GABAergic neurotransmission in the inherited epilepsy of the qk mutant mouse.
Aging↗
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↗
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↗
Application of NMR imaging and spectroscopy to the pharmacology of cerebro-vascular disorders.
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Animals↗
High-performance liquid chromatographic determination of adenine nucleotides in biological materials. Improvements and adaptations to routine analysis.
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Adenine Nucleotides↗
Determination of neuropeptides in discrete regions of the rat brain by high-performance liquid chromatography with electrochemical detection.
High-performance liquid chromatography (HPLC) in combination with electrochemical detection (ED) is suitable for measuring accurately the levels of oxidizable neuropeptides in small samples of brain tissue. We have determined by HPLC-ED and a two-column-switching technique the levels of leucine- and methione-enkephalin in rat brain. By a sequential two-column HPLC-ED method we have also determined the levels of cholecystokinin tetrapeptide and octapeptide sulphate in various regions of the rat brain. The values found are in good agreement with those reported previously based on radioimmunoassay. We conclude that, due to its simplicity, HPLC-ED is an attractive alternative to existing methods for the determination of some neuropeptides in biological material.
Animals↗
Classification of drugs according to receptor binding profiles.
The affinity for eight different neurotransmitter receptors of about forty drugs, used for the treatment of various central nervous system disorders, was determined following in vitro receptor binding assays. Our findings indicate that, in spite of widely varying chemical structures and often poorly understood mechanisms of action, the similarities in the "affinity profiles" permit a clinically meaningful classification of these drugs. Such an approach would thus be useful in the assessment of newly synthesized compounds at an early stage of drug development.
Animals↗
Effect of insulin on central catecholamines.
The effects of insulin on levels and turnover of catecholamines in the hypothalamus and medulla oblongata were investigated. Systemic or intraventricular administration of insulin had no effect on catecholamine levels, but increased the turnover rate of norepinephrine and epinephrine. Insulin induced a dose-related increased release of norepinephrine, epinephrine and dopamine from hypothalamic slices. These results indicate that the effects of insulin on central catecholamines are elicited by its action in the brain.
Animals↗