Potentiation of aminoglycoside-induced neuromuscular blockade by protons in vitro and in vivo.

pH-dependent effects of 100 microM streptomycin and various aminoglycosides were examined at frog (Rana pipiens pipiens) sciatic sartorii in vitro by using the intracellular microelectrode recording technique. pH-dependent effects of streptomycin were also examined on indirectly elicited (nerve-stimulated) and directly elicited sartorius muscle twitches in vitro. Furthermore, in vivo effects of systemic pH alterations on neomycin-induced mortality were examined in Sprague-Dawley rats. There was a direct correlation between aminoglycoside potency and the number of basic groups per drug molecule (r = 0.95). At pH 7.2 and 9.0, the effect of pH on aminoglycoside potency correlated inversely with the pKa of the aminoglycoside (r = -0.98). At 0.7 and 2.2 pH units below 7.2, however, aminoglycoside-induced inhibitions of quantal content, end-plate potential amplitude and the indirectly elicited muscle twitch were potentiated by a pH-dependent mechanism that was independent of the pKa of the aminoglycoside. At these pH values, qualitatively similar drug effects were not observed on miniature end-plate potential amplitude and frequency or the directly elicited muscle twitch. Potentiation of aminoglycoside action was observed on mortality of rats, however, when the pH was 0.1 pH unit below 7.4. Thus, potentiation of aminoglycoside-induced neuromuscular blockade by protons in vitro and in vivo was demonstrated and appears to involve the pH-dependent activity of a prejunctional membrane component that regulates voltage-dependent, Ca++-mediated transmitter release.