[Influence of pH changes of the medium on relaxant actions of papaverine]

Influences of pH change in the medium on actions of papaverine were investigated in the intestinal smooth muscle of guinea pigs and compared with those of verapamil, a Ca2+ entry blocker. Papaverine contracted the ileal longitudinal muscle and inhibited the CaCl2-induced contraction of depolarized taenia coli. When the external pH was varied stepwise within the range of 6.8 to 7.6, both actions were equally facilitated with a lowering of the pH. A good correlation between these facilitated responses and the amount of ionized papaverine molecules was observed. Meanwhile, verapamil also induced the smooth muscle contraction and the inhibition of CaCl2-induced contraction. Although the dual action of verapamil were facilitated with a drop in the pH, the magnitudes of these facilitation were less than those of papaverine. Moreover, verapamil was less effective in inducing the smooth muscle contraction, but more potent in inhibiting the CaCl2-induced contraction, as compared to papaverine. These results indicate the possibility that ionized papaverine may displace bound calcium on the cell membrane of smooth muscle and this displacement may result in transient inward movement of Ca2+, leading to contraction and that subsequent blockade of Ca2+ entry by papaverine may block the contraction. These results also suggest that papaverine and verapamil may cause the dual action through a different mechanism.