title: The role of voltage-operated and non-voltage-operated calcium channels in endothelin-induced vasoconstriction of rat cerebral arteries.
abstract: Endothelin-1 has been identified as a potential mediator in the pathogenesis of ischaemic stroke and cerebral vasospasm. The aim of this study was to analyse the role of voltage-operated calcium channels (VOCC) and non-VOCC in endothelin-1 induced vasoconstriction of rat cerebral arteries. Arterial segments were dissected from different regions of the cerebral circulation and responses assessed using wire myography. Endothelin-1 concentration-contraction curves were constructed in calcium-free medium or in the presence of nifedipine, NNC 55-0396 ((1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride) or SK&F 96365 (1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole) to inhibit the l-type VOCC, T-type VOCC and non-VOCC, respectively. Inhibition of the calcium channels or removal of calcium from the medium variably decreased the maximum effects (Emax) of endothelin-1, however its potency (pEC50) was unaltered. Endothelin-1 caused a small contraction (<22%) in calcium-free solution. Pre-treatment with nifedipine (1µM) did not affect responses to low concentrations of endothelin-1 but decreased Emax, while NNC 55-0396 (1µM) and SK&F 96365 (30-100µM) generally attenuated the endothelin-1-induced contraction. Combination of nifedipine with SK&F 96365 further decreased the Emax. The relaxant effect of the calcium channel antagonists was also assessed in pre-contracted arteries. Only nifedipine and SK&F 96365 relaxed the arteries pre-contracted with endothelin-1. In conclusion, VOCC and non-VOCC calcium channels are involved in different phases of the endothelin-1 contraction in rat cerebral vessels. T-type VOCC may be involved in contraction induced by low concentrations of endothelin-1, while l-type VOCC mediate the maintenance phase of contraction. VOCC and non-VOCC may work in concert in mediating contraction induced by endothelin-1.
authors.affiliation: Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria 3010, Australia. Electronic address: ymamo@student.unimelb.edu.au.
authors.forename: Yohannes A
authors.initials: YA
authors.lastname: Mamo
authors.affiliation: Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria 3010, Australia. Electronic address: jamesaa@unimelb.edu.au.
authors.forename: James A
authors.initials: JA
authors.lastname: Angus
authors.affiliation: Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria 3010, Australia. Electronic address: jamesz@unimelb.edu.au.
authors.forename: James
authors.initials: J
authors.lastname: Ziogas
authors.affiliation: Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria 3010, Australia. Electronic address: paulsoeding@bigpond.com.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Soeding
authors.affiliation: Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria 3010, Australia. Electronic address: cewright@unimelb.edu.au.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Wright
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D015220:Calcium Channels / Q000145:classification / Q000502:physiology*; D002536:Cerebral Arteries / Q000187:drug effects* / Q000502:physiology*; D003521:Cyclopropanes / Q000008:administration & dosage / Q000494:pharmacology; D004347:Drug Interactions; D019332:Endothelin-1 / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D009543:Nifedipine / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology*
chemical_list: D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D003521:Cyclopropanes; D019332:Endothelin-1; D007093:Imidazoles; D009281:Naphthalenes; C484287:NNC 55-0396; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D009543:Nifedipine
keywords: Calcium channels; Endothelin-1; Endothelin-1 (PubChem CID: 16132423); NNC 55-0396 (PubChem CID 11957578); Nifedipine (PubChem CID 4485); Rat cerebral arteries; SK&F 96365 (PubChem CID 104955); Sarafotoxin S6c (PubChem CID 16132429); Vasoconstriction