Reduction in focal cerebral ischemia by agents acting at imidazole receptors.
Treatment with the alpha 2-adrenergic antagonist idazoxan (IDA) can provide protection from global cerebral ischemia. However, IDA also recognizes another class of receptors, termed imidazole (IM) receptors, which differ from alpha 2-adrenergic receptors and are responsible for the hypotensive actions of some centrally acting agents such as the oxazole rilmenidine (RIL). We therefore sought to determine whether RIL, an agent highly selective for IM receptors, offered protection from focal cerebral ischemia elicited in rat by ligation of the middle cerebral artery (MCA). We compared the effects of RIL with the effects of IDA and the selective non-IM alpha 2-antagonist SKF 86466 (SKF). In addition, we examined whether the neuroprotective effects of RIL and IDA could be attributed to changes in local CBF (LCBF). The MCA was occluded and animals either received immediate administration of drug while arterial pressure was maintained for 1 h or had local CBF increased to 200% of control for 1 h by hypercapnia or hypertension. RIL elicited a significant dose-dependent preservation of tissue to 33% of control at optimal dose (0.75 mg/kg). IDA (3 mg/kg) significantly reduced the size of ischemic infarction by 22%. In contrast, SKF (15 mg/kg) as well as doubling of LCBF did not preserve ischemic tissue. We conclude that both RIL and IDA can reduce focal ischemic infarction but that the mechanism does not appear secondary to antagonism of alpha 2-adrenergic receptors or elevation of LCBF. Occupation of IM receptors, either in the ischemic zone or at remote brain sites, may be responsible for neuroprotection of RIL and IDA.
Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021.
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Maiese
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Pek
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Berger
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Reis
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004146:Dioxanes / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D019329:Idazoxan; D007093:Imidazoles / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010080:Oxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011955:Receptors, Drug / Q000378:metabolism; D000077769:Rilmenidine
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D001552:Benzazepines; D004146:Dioxanes; D007093:Imidazoles; D010080:Oxazoles; D011955:Receptors, Drug; C029899:imidazole; D000077769:Rilmenidine; D019329:Idazoxan; C039139:benalfocin