Abstract
The anticholinergic effects of 7 benzodiazepines, bromazepam, camazepam, chlordiazepoxide, diazepam, lorazepam, medazepam and triazolam, were compared by examining their inhibitory effects on the acetylcholine receptor-operated potassium current (IK.ACh) in guinea-pig atrial myocytes. All of these benzodiazepines (0.3–300 μM) inhibited carbachol (1 μM)-induced IK.ACh in a concentration-dependent manner. The ascending order of IC50 values for carbachol-induced IK.ACh was as follows; medazepam, diazepam, camazepam, triazolam, bromazepam, lorazepam and chlordiazepoxide (>300 μM). The compounds, except for bromazepam, also inhibited IK.ACh activated by an intracellular loading of 100 μM guanosine 5’-[γ-thio]triphosphate (GTPγS) in a concentration-dependent manner. The ascending order of IC50 values for GTPγS-activated IK.ACh was as follows; medazepam, diazepam, camazepam, lorazepam, triazolam chlordiazepoxide (>300 μM) and bromazepam (>300 μM). To clarify the molecular mechanism of the inhibition, IC50 ratio, the ratio of IC50 for GTPγS-activated IK.ACh to carbachol-induced IK.ACh, was calculated. The IC50 ratio for camazepam, diazepam, lorazepam, medazepam and triazolam was close to unity, while it for chlordiazepoxide could not be calculated. These compounds would act on the GTP binding protein and/or potassium channel to achieve the anticholinergic effects in atrial myocytes. In contrast, since the IC50 ratio for bromazepam is presumably much higher than unity judging from the IC50 values (104.0 ± 30.0 μM for carbachol-induced IK.ACh and >300 μM for GTPγS-activated IK.ACh), it would act on the muscarinic receptor. In summary, benzodiazepines had the anticholinergic effects on atrial myocytes through inhibiting IK.ACh by different molecular mechanisms.
