Schisandrin A Suppresses Guinea Pig Ileal Longitudinal Smooth Muscle Contraction through Functional Inhibition of L-Type Ca²⁺ Channels

Schisandrin A (SA), a major lignan isolated from the fruits of Schisandra chinensis, has been reported to modulate smooth muscle (SM) function in several tissues; however, its direct effects on intestinal SM have not been fully characterized. In the present study, we investigated the effects of SA on contractile responses in guinea pig (GP) ileal longitudinal smooth muscle (ILSM) and examined the involvement of L-type voltage-dependent Ca²⁺ channels (VDCCs). SA (1-100 µM) concentration-dependently inhibited contractions induced by acetylcholine (1 µM), histamine (1 µM), and prostaglandin F2α (10 µM). These agonist-induced contractions were completely suppressed by the L-type VDCC inhibitor diltiazem (10 µM). SA also attenuated depolarization-induced contractions evoked by high-KCl (80 mM), which were similarly sensitive to diltiazem. In A7r5 vascular SM cells, high-KCl (100 mM) elicited marked increases in intracellular Ca²⁺ concentration ([Ca²⁺]i), and these responses were substantially inhibited by SA (30 µM) as well as by diltiazem (30 µM). Furthermore, molecular docking simulations using the CaV1.2 channel structure (PDB ID: 8HMA) suggested that SA may interact with the tetrandrine-binding pocket, potentially forming a hydrogen bond with Tyr1508. Taken together, these findings indicate that SA suppresses intestinal SM contraction primarily by inhibiting Ca²⁺ influx through L-type VDCCs, likely via direct interaction with CaV1.2. This mechanism may partly underlie the traditional use of S. chinensis fruits in the treatment of gastrointestinal disorders such as diarrhea.