Novel α1-adrenoceptor antagonism by the fluroquinolone antibiotic trovafloxacin

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 (1–30 µM) with a pKB of 5.54 and 5.32, respectively, in rat mesenteric small arteries isolated for myography. In comparison, prazosin (1–10 nM) antagonised methoxamine concentration-response curves with a pKB of 9.76. Trovafloxacin (1–30 µM) 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.