S-isopetasin, a sesquiterpene of Petasites formosanus, allosterically antagonized carbachol in isolated guinea pig atria

We investigated the antimuscarinic effect of S-isopetasin in isolated guinea pig atria to clarify whether it preferentially acts on muscarinic M₂ or M₃ receptors. The tension changes of isolated atria were isometrically recorded on a polygraph. S-Isopetasin at 50 and 100 μM significantly inhibited baselines of contractile tension and heart rate, but atropine at 1 μM enhanced both. S-Isopetasin (10-100 μM) did not significantly alter the concentration-negative inotropic response curves of carbachol (CCh) in left atria. S-Isopetasin (10-100 μM) allosterically antagonized negative inotropic and chronotropic responses induced by CCh in spontaneously beating right atria, based on the slopes of Schild plots significantly differing from unity. On the contrary, atropine (0.01-1 μM) competitively antagonized all the above responses to CCh. The pA₂ values of S-isopetasin were significantly less than that of S-isopetasin in guinea pig trachealis, suggesting that S-isopetasin may preferentially act on tracheal muscarinic M₃, but not cardiac muscarinic M₂ receptors. However, atropine preferentially acts neither. This finding reveals that S-isopetasin may have benefit in the treatment of asthma.