Evolving mechanisms of action of alverine citrate on phasic smooth muscles

Background and purpose: We have investigated the mechanisms underlying the paradoxical ability of the antispasmodic, alverine, to enhance spontaneous activity in smooth muscles while suppressing evoked activity. Experimental approach: The effects of alverine on spontaneous and induced contractile activity were examined in preliminary experiments with various smooth muscles. More detailed effects were also investigated by recording membrane potential, intracellular Ca2+ concentration ([Ca2+](i)) and tension from single-bundle detrusor smooth muscle (DSM) of the guinea-pig urinary bladder. Key results: Alverine (10 mu M) increased the frequency and amplitude of spontaneous action potentials, transient increases in [Ca2+](i) and associated contractions. Alverine also decreased action potential rate of decay, suggesting inhibition of L-type Ca channel inactivation. Charybdotoxin (50 nM) but neither cyclopiazonic acid (10 mu M) nor Bay K 8644 (10 mu M) attenuated alverine-induced enhancement of spontaneous contractions. Alverine suppressed contractions produced by high K (40mM) or ACh (10 mu M), without affecting electrical responses and with little suppression of increases in [Ca2+](i). This feature was very similar to that of the effects of the Rho kinase inhibitor Y-27632 (10 mu M). Conclusions and implications: Alverine may increase Ca influx during action potentials due to inhibition of the inactivation of L-type Ca channels, but may also suppress evoked activity by inhibiting the sensitivity of contractile proteins to Ca2+. The proportional contribution of Ca-dependent and Ca-independent contractions in DSM may differ between spontaneous and evoked activity, necessitating further investigations into the interactions between these pathways for assessing the therapeutic potential of alverine to treat DSM dysfunction.