Novel α-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 α-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 pK 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 pK 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 α-adrenoceptor antagonist. When trovafloxacin was in use clinically， CNS side effects of dizziness， flushing and headache consistent with α-adrenoceptor antagonism were common. We conclude that trovafloxacin with its quinolone moiety is a weak α-adrenoceptor competitive antagonist in comparison with prazosin.