62 Journal of Pharmacological Sciences ©2003 The Japanese Pharmacological Society Full Paper J Pharmacol Sci 93, 62 – 68 (2003) Relationship Between Phosphodiesterase Inhibition Induced by Several Kampo Medicines and Smooth Muscle Relaxation of Gastrointestinal Tract Tissues of Rats Yoshiki Saegusa, Atsushi Sugiyama*, Akira Takahara, Yoshinobu Nagasawa, and Keitaro Hashimoto Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Tamaho-cho, Nakakoma-gun, Yamanashi 409-3898, Japan Received May 6, 2003; Accepted June 30, 2003 Abstract. Given a lack of information, we assessed the effects of Kampo medicines: Dai-saiko- to, Tsu-do-san, San’o-shashin-to, and Sairei-to, which have been used for various gastrointestinal diseases, on the phosphodiesterase activity and smooth muscle tone of the gastrointestinal tract. Clinically relevant concentrations of each Kampo extract (0.1 – 1 mg / ml) decreased the phosphodiesterase activity as well as smooth muscle tone. The extent of phosphodiesterase inhibition as well as smooth muscle relaxation by these Kampo extracts was prominent for the lower gastrointestinal tract. Also, there was a good correlation between the extents of drug- induced phosphodiesterase inhibition and smooth muscle relaxation, indicating the presence of their causal link. These results may partially provide the basis for understanding the mechanism of the clinical utility of Kampo extracts in gastrointestinal tract diseases. Keywords: phosphodiesterase, Kampo medicine, gastrointestinal tract, relaxation, cyclic AMP Introduction In the gastrointestinal tract, cyclic AMP-dependent pathways have been reported to play an important role in physiological as well as pathophysiological regulation (1 – 3). For example, phosphodiesterase (PDE) inhibi- tors like 3-isobutyl-1-methylxanthine (IBMX), which increase the cellular cyclic AMP level, have been shown to relax gastrointestinal smooth muscles (4 – 9) in addition to inhibiting their pacemaker activity of slow waves (10, 11). Kampo medicines are now widely used as alternative or supplemental therapies to modern medicines (12 – 14). Indeed, some Kampo extracts have been used for the treatment of various gastrointestinal diseases includ- ing non-ulcer dyspepsia, functional bowel disease in- cluding spasmodic constipation for a “Jissho” (sthenic) person, acute gastroenteritis, and inflammatory bowel disease (12 – 14). Recently, we found that some Kampo medicines inhibit PDE activity at clinically relevant concentration (15). However, no information is available up to now regarding the relationship between the Kampo medicines-induced subcellular responses and functional consequences in the gastrointestinal tract. In this study, we first assessed regional differences of cyclic AMP hydrolyzing PDE activity using the membrane preparations obtained from the stomach, small intestine, and colon of rats. Next, we examined the effects of Kampo extracts, which are clinically used for gastrointestinal diseases (12 – 14) as shown in Table 1, on the PDE activities in these three different regions. Finally, we assessed the relaxant effects of Kampo extracts on carbachol (CCh)-induced contraction in isolated stomach, ileum, and colon of rats to clarify the relationship between the drug-induced PDE inhibition and the smooth muscle relaxation. We used a typical PDE inhibitor IBMX as a reference compound for both biochemical assay and functional study (16). Materials and Methods All experimentation was performed in accordance with the rules and regulations of the Committee for Research at the University of Yamanashi. Animals were obtained through the Animal Laboratory for Research of *Correspondence author. FAX: +81-55-273-6739 E-mail: atsushis@res.yamanashi-med.ac.jp