title: The calcilytics Calhex-231 and NPS 2143 and the calcimimetic Calindol reduce vascular reactivity via inhibition of voltage-gated Ca2+channels.
abstract: The present study investigates the effect of commonly used negative and positive allosteric modulators of the calcium-sensing receptor (CaSR) on vascular reactivity. In wire myography studies, increasing [Ca2+]ofrom 1mM to 6mM induced concentration-dependent relaxations of methoxamine-induced pre-contracted rabbit mesenteric arteries, with 6mM [Ca2+]oproducing almost complete relaxation. [Ca2+]o-induced relaxations were attenuated in the presence of the calcilytics Calhex-231 and NPS 2143, and abolished by the removal of the endothelium. In addition to their calcilytic effects, Calhex-231 and NPS 2143 also produced concentration-dependent inhibitions of methoxamine- or KCl-induced precontracted tone, which were unaffected by removal of the endothelium and unopposed in the presence of the calcimimetic Calindol. In vessels with depleted Ca2+stores, contractions mediated by Ca2+influx via voltage-gated Ca2+channels (VGCCs) were inhibited by Calhex231. In freshly isolated single rabbit mesenteric artery smooth muscle cells, Calhex-231 and NPS 2143 inhibited whole-cell VGCC currents. Application of Calindol also inhibited methoxamine- and KCl-induced pre-contracted tone, and inhibited whole-cell VGCC currents. In conclusion, in addition to their CaSR-mediated actions in the vasculature, Calhex-231, NPS 2143 and Calindol reduce vascular contractility via direct inhibition of VGCCs.
authors.affiliation: Vascular Biology Research Centre, Institute of Cardiovascu lar & Cell Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK. Electronic address: m0600877@sgul.ac.uk.
authors.forename: Harry Z E
authors.initials: HZE
authors.lastname: Greenberg
authors.affiliation: Vascular Biology Research Centre, Institute of Cardiovascu lar & Cell Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Kazi S
authors.initials: KS
authors.lastname: Jahan
authors.affiliation: Vascular Biology Research Centre, Institute of Cardiovascu lar & Cell Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Jian
authors.initials: J
authors.lastname: Shi
authors.affiliation: Vascular Biology Research Centre, Institute of Cardiovascu lar & Cell Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: W-S
authors.initials: WS
authors.lastname: Vanessa Ho
authors.affiliation: Vascular Biology Research Centre, Institute of Cardiovascu lar & Cell Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Albert
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D057966:Calcimimetic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism*; D003514:Cyclohexylamines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008729:Methoxamine / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D011817:Rabbits; D044169:Receptors, Calcium-Sensing / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: C506457:(R)-2-(1-(1-naphthyl)ethyl-aminom-ethyl)indole; D001549:Benzamides; D057966:Calcimimetic Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D003514:Cyclohexylamines; D007211:Indoles; C482333:N(1)-(4-chlorobenzoyl)-N(2)-(1-(1-naphthyl)ethyl)-1,2-diaminocyclohexane; C436740:N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine; D009281:Naphthalenes; D044169:Receptors, Calcium-Sensing; D011189:Potassium Chloride; D008729:Methoxamine; D002118:Calcium
keywords: Calcilytic; Calcimimetic; Calcium-sensing receptor; Calhex-231; Calindol; NPS 2143