The benzodiazepine receptor antagonist PK 11195 alters diazepam-induced changes of tetanic contractions in the rat phrenic nerve-diaphragm preparation

Abstract

Diazepam, 1×10−4 M, at frequencies of 10–50 Hz, significantly enhanced the tetanic contraction force (maximum effect 226%±30.1 in the 2nd cycle at 40 Hz) in the phrenic nerve-diaphragm preparation, except at 50 Hz. [One experimental cycle is defined as 5 subsequent stimulations at frequencies of 10, 20, 30, 40 and 50 Hz respectively, during 3 sec with intervals of 20 sec.] The enhancement in each cycle proceeded in two steps, i.e. an initial abrupt increase, followed by gradual abatement at higher frequencies. The maximum enforcement gradually decreased to 126%±17.5 in the 6th cycle at 30 Hz. PK 11195 (10−5 M) antagonized the enhancement, which eventually became biphasic in shape, i.e. initial enhancement of tetanic contractions followed by reduction of enhancement and subsequent suppression in the 1st and 2nd cycles. In the 3rd to 6th cycle only suppression of muscle contractions was observed. Diazepam, 2×10−4 M, induced an abrupt initial enhancement of contraction force (maximum 313%±24.0 in the 2nd cycle at 30 Hz), followed by suppression. A two-step response curve was only present in the 1st cycle. In the 5th and 6th cycles, at all frequencies employed, exclusive suppression of tetanic contractions was observed. PK 11195 (10−5 M) significantly antagonized the potentiation of the tetanic contraction force induced by 2×10−4 M diazepam. Only in the 1st cycle a biphasic response was observed. From the 2nd cycle onward the suppression induced by this concentration was intensified by PK 11195. In conclusion, responses to diazepam are dependent on its concentration, the stimulation frequency and the time of exposure. It is feasible that peripheral benzodiazepine receptors are involved in the effects of diazepam at the neuromuscular junction. © 1997 John Wiley & Sons, Ltd.