Pharmacological evidence for an interaction between constituents (blend effect) of the Japanese‐Sino medicine “Keishi‐ka‐zyutubu‐tō” in neuromuscular blockade in diabetic mice

The pharmacological interaction between constituents of Keishi‐ka‐zyutubu‐tō (composed of 7 crude drugs, namely peony, liquorice, jujube, cassia, ginger, Atractylodes lancea , and aconite), a medicine of Japanese‐Sino origin, was investigated in in situ sciatic nerve‐gastrocnemius muscle preparations using genetically dlabetic KK‐CA y mice. When administered intra‐arterially, the drug caused a degree of inhibition of the diabetic neuromuscular junction 280 times greater than normal. The two constituents, peony‐liquorice, were only 2.6 times more potent in diabetic muscles. When further combined with peony‐liquorice, the potency ratio was increased 4.9 times for cassia, 5.9 times for ginger and 8.7 times for Atractylodes lancea . In combination with the representative compounds contained in the above crude drugs except for jujube, the potency ratio of paeoniflorin (PF) and glycyrrhizin (GLR) was increased 6.6 times for cinnamaldehyde, 6.1 times for [8]‐gingerol and 14 times for β‐eudesmol in diabetic muscles. Aconite potentiated the blocking effects of peony‐liquorice to the same extent in diabetic muscles as in normal muscles. This tendency was also confirmed when mesaconitine was combined with PF‐GLR. The single effect of β‐eudesmol or [8]‐gingerol was 5.2 times or 3.7 times more potent, respectively, on diabetic muscles than on normal muscles. Cinnamaldehyde or mesaconitine demonstrated the same degree of sensitivity in both diabetic and normal muscles. These results indicated that the preferentially more potent neuromuscular blocking effects of Keishi‐ka‐zyutubu‐tō in diabetic muscles were mainly attributable to β‐eudesmol, a major component of Atractylodes lancea .