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 effectiv...
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Published in | The American journal of medicine Vol. 86; no. 4; pp. 134 - 146 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
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Elsevier Inc
17.04.1989
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Abstract | 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 hypertension, 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. |
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AbstractList | 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. 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 hypertension, 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. |
Author | Sauter, André Hof, Robert P. Wiederhold, Karl-Heinz Rudin, Markus |
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Cites_doi | 10.1111/j.1476-5381.1985.tb08833.x 10.1093/bja/57.1.47 10.1038/jcbfm.1981.6 10.1007/BF01959909 10.1038/jcbfm.1983.51 10.1002/ana.410160212 10.1161/01.RES.21.2.163 10.1016/0010-468X(79)90014-X 10.1097/00005344-198501000-00030 10.1161/01.RES.48.5.650 10.1111/j.1476-5381.1983.tb09403.x 10.1016/0006-291X(82)91339-0 10.1016/0002-9149(87)90081-6 10.1007/BF01910452 10.1016/0002-9149(87)90079-8 10.1161/01.STR.17.6.1228 10.1007/BF01908053 10.1007/BF01249091 10.1097/00005344-198405000-00006 10.1002/mrm.1910040102 10.1007/BF00647840 |
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in the dog heart publication-title: J Cardiovasc Pharmacol doi: 10.1097/00005344-198501000-00030 contributor: fullname: Wada – volume: 44 start-page: A38 year: 1988 ident: 10.1016/0002-9343(89)90209-X_BIB29 article-title: 31P NMR magnetization transfer in the rat brain: effects of barbiturates and calcium antagonists publication-title: Experientia contributor: fullname: Rudin – volume: 48 start-page: 650 year: 1981 ident: 10.1016/0002-9343(89)90209-X_BIB3 article-title: The selective inhibition of serotonin-induced contractions of rabbit cerebral vascular smooth muscle by calcium antagonistic dihydropyridines publication-title: Circ Res doi: 10.1161/01.RES.48.5.650 contributor: fullname: Towart – volume: 78 start-page: 375 year: 1983 ident: 10.1016/0002-9343(89)90209-X_BIB4 article-title: Calcium antagonists and the peripheral circulation: differences and similarities between PY 108-068, nicardipine, verapamil and diltiazem publication-title: Br J Pharmacol doi: 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ident: 10.1016/0002-9343(89)90209-X_BIB21 article-title: Validation studies for the use of the microsphere method in cats and young minipigs publication-title: Basic Res Cardiol doi: 10.1007/BF01910452 contributor: fullname: Hof – volume: 42 start-page: 477 year: 1987 ident: 10.1016/0002-9343(89)90209-X_BIB15 article-title: Application of NMR imaging and spectroscopy to the pharmacology of cerebrovascular disorders publication-title: Therapie contributor: fullname: Rudin – volume: 59 start-page: 30B year: 1987 ident: 10.1016/0002-9343(89)90209-X_BIB5 article-title: Selective effects of PN 200-110 (isradipine) on the peripheral circulation and the heart publication-title: Am J Cardiol doi: 10.1016/0002-9149(87)90079-8 contributor: fullname: Hof – volume: 80 start-page: 860 year: 1983 ident: 10.1016/0002-9343(89)90209-X_BIB27 article-title: A unitary mechanism of calcium antagonist drug action contributor: fullname: Murphy – volume: 17 start-page: 1228 year: 1986 ident: 10.1016/0002-9343(89)90209-X_BIB14 article-title: Calcium antagonists reduce the extent of infarction in rat middle cerebral artery occlusion model as determined by quantitative magnetic resonance imaging publication-title: Stroke doi: 10.1161/01.STR.17.6.1228 contributor: fullname: Sauter – volume: 76 start-page: 630 year: 1981 ident: 10.1016/0002-9343(89)90209-X_BIB20 article-title: Trapping and intramyocardial distribution of microspheres with different diameters in cat and rabbit hearts in vitro publication-title: Basic Res Cardiol doi: 10.1007/BF01908053 contributor: fullname: Hof – volume: 60 start-page: 149 year: 1984 ident: 10.1016/0002-9343(89)90209-X_BIB12 article-title: The interaction of [H3]PY 108-068 and of [H3]PN 200-110 with calcium channel binding sites in rat brain publication-title: J Neural Transm doi: 10.1007/BF01249091 contributor: fullname: Supavilai – year: 1989 ident: 10.1016/0002-9343(89)90209-X_BIB17 article-title: Cytoprotective characteristics of dihydropyridine calcium antagonists in a rat model of stroke: implications for clinical trials contributor: fullname: Sauter – start-page: 378 year: 1988 ident: 10.1016/0002-9343(89)90209-X_BIB30 article-title: Dihydropyridine calcium antagonists reduce the flux through the creatinine kinase reaction. A 31P saturation transfer study in rat brain contributor: fullname: Rudin – volume: 6 start-page: 407 year: 1984 ident: 10.1016/0002-9343(89)90209-X_BIB6 article-title: Effects of the new calcium antagonist PN 200-110 on the myocardium and the regional peripheral circulation in anaesthetized cats and dogs publication-title: J Cardiovasc Pharmacol doi: 10.1097/00005344-198405000-00006 contributor: fullname: Hof – year: 1986 ident: 10.1016/0002-9343(89)90209-X_BIB10 – volume: 4 start-page: 1 year: 1987 ident: 10.1016/0002-9343(89)90209-X_BIB28 article-title: Effects of calcium antagonists on high energy phosphates measured by 31P NMR spectroscopy publication-title: Magn Reson Med doi: 10.1002/mrm.1910040102 contributor: fullname: Sauter – volume: 324 start-page: 64 year: 1983 ident: 10.1016/0002-9343(89)90209-X_BIB2 article-title: Tissue specific susceptibility of alpha-adrenoceptor mediated vasoconstriction to nifedipine publication-title: Naunyn Schmiedebergs Arch Pharmacol doi: 10.1007/BF00647840 contributor: fullname: Müller-Schweinitzer |
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SubjectTerms | Animals Antihypertensive Agents - pharmacology Brain - drug effects Brain Chemistry Brain Ischemia - physiopathology Calcium Channel Blockers - pharmacology Cats Cerebral Infarction - pathology Cerebral Infarction - physiopathology Cerebrovascular Circulation - drug effects Cerebrovascular Disorders - physiopathology Dose-Response Relationship, Drug Isradipine Male Microspheres Pyridines - pharmacology Rabbits Rats Rats, Inbred SHR |
Title | Cerebrovascular, biochemical, and cytoprotective effects of isradipine in laboratory animals |
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