Caffeine- and noradrenaline-induced contractions of human vas deferens: Contrasting effects of procaine, ryanodine and W-7

1. The effects of ryanodine, procaine, and N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7) on noradrenaline (NA)- and caffeine-induced contractions of human vas deferens were investigated. 2. In the presence of nifedipine (1 mu M), NA (100 mu M) evoked biphasic contractions. Caffeine (20 mM) evoked repeatable tonic contractions. 3. Ryanodine (30 mu M) inhibited the initial but not the secondary component of NA contractions. Procaine (1 and 10 mM) inhibited both components. Contractions induced by caffeine were unaffected by ryanodine or procaine. 4. The calmodulin antagonist W-7 (100 mu M) reduced, in a reversible manner, both components of NA induced response. Caffeine-induced contractions were also reduced in most preparations (8 of 11). In all preparations, contractions induced by caffeine were markedly inhibited after the washout of W-7. Higher doses of W-7 (300 mu M) induced an increase in basal tension. 5. These results indicate that NA contracts the longitudinal muscle of human vas deferens by a ryanodine-sensitive calcium-induced calcium release (CICR) mechanism and, in addition, a ryanodine-insensitive pathway: both are sensitive to procaine. Tn contrast, contraction induced by caffeine is mediated by a pathway that is atypically insensitive to either ryanodine or procaine. The sensitivity of NA and caffeine induced contraction to W-7 suggests a role for calcium and its interaction with calmodulin in the response to both agents. The paradoxical action of W-7 is discussed. GEN PHARMAC 31;3:419-424, 1998. (C) 1998 Elsevier Science Inc.