title: Novel α1-adrenoceptor antagonism by the fluroquinolone antibiotic trovafloxacin.
abstract: Trovafloxacin, a fluroquinolone antibiotic, was recently found to be an inhibitor of pannexin-1 channels through which ATP is released as "find-me" signals in apoptotic Jurkat cells. Our interest in the role of pannexin-1 channels in α1-adrenoceptor-mediated vasoconstriction led us to the novel finding reported here. Concentration-response curves to methoxamine and phenylephrine were competitively antagonised by trovafloxacin (1-30µM) with a pKBof 5.54 and 5.32, respectively, in rat mesenteric small arteries isolated for myography. In comparison, prazosin (1-10nM) antagonised methoxamine concentration-response curves with a pKBof 9.76. Trovafloxacin (1-30µM) had no effect on either the thromboxane mimetic (U46619) or endothelin-1 concentration-contraction curves. Interestingly, the concentration range is similar for trovafloxacin antagonising the 3 distinct pharmacological targets: (i) fourth generation fluroquinolone antibiotic, (ii) pannexin-1 channel inhibitor in apoptotic cells, and now (iii) as an α1-adrenoceptor antagonist. When trovafloxacin was in use clinically, CNS side effects of dizziness, flushing and headache consistent with α1-adrenoceptor antagonism were common. We conclude that trovafloxacin with its quinolone moiety is a weak α1-adrenoceptor competitive antagonist in comparison with prazosin.
authors: Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria 3010, Australia. Electronic address: jamesaa@unimelb.edu.au.
authors: James A
authors: JA
authors: Angus
authors: Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria 3010, Australia. Electronic address: cewright@unimelb.edu.au.
authors: Christine E
authors: CE
authors: Wright
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024841:Fluoroquinolones / Q000494:pharmacology*; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D009287:Naphthyridines; D018340:Receptors, Adrenergic, alpha-1; C080163:trovafloxacin
keywords: Endothelin-1 (PubChem CID: 16132423); Methoxamine hydrochloride (PubChem CID: 6081); Pannexin-1 channels; Phenylephrine hydrochloride (PubChem CID: 5284443); Prazosin; Prazosin hydrochloride (PubChem CID: 68546); PubChem CID: 16219283); Trovafloxacin; Trovafloxacin mesylate (PubChem CID: 62960); U46619 (9,11-dideoxy-9α,11α-methanoepoxyprostaglandin F2α; Vascular contraction; α(1)-adrenoceptors