Novel α1-adrenoceptor antagonism by the fluroquinolone antibiotic trovafloxacin

• Published in: European journal of pharmacology Vol. 791; pp. 179 - 184
• Main Authors: Angus, James A., Wright, Christine E.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 15-11-2016
• Subjects: Pannexin-1 channels; Prazosin; Trovafloxacin; Vascular contraction; α1-adrenoceptors; Trovafloxacin; U46619; KPSS; U46619 (9,11-dideoxy-9α,11α-methanoepoxyprostaglandin F2α; Prazosin hydrochloride (PubChem CID: 68546); Trovafloxacin mesylate (PubChem CID: 62960); PubChem CID: 16219283; Methoxamine hydrochloride (PubChem CID: 6081); PSS; Phenylephrine hydrochloride (PubChem CID: 5284443); Prazosin; D100; Endothelin-1 (PubChem CID: 16132423); LOPAC1280; ATP; Pannexin-1 channels; Emax; α1-adrenoceptors; Vascular contraction
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2016.08.035

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 pKB of 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 pKB of 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.