Cyclic Amp‐Mediated Inhibition of Noradrenaline‐Induced Contraction and Ca 2+ Influx in Guinea‐Pig vas Deferens

The relaxation effects of forskolin and methylxanthines on noradrenaline (NA)‐induced contractions were investigated by measuring isotonic contraction and intracellular calcium concentration ([Ca 2+ ] i ) in the epididymal side of guinea‐pig vas deferens. NA (100 μM) and high K+ (55 mM) induced a biphasic contraction; fast, transient (phasic) and slow, sustained (tonic) phases. Both phases in either NA or high K+ stimulation were abolished in Ca 2+ ‐free solution. Pretreatment with 10 μM nifedipine, an L‐type Ca 2+ channel blocker, reduced both phasic and tonic contractions induced by high K+. In the case of NA‐induced contraction, however, nifedipine reduced the phasic contraction but not the tonic contraction. The nifedipine‐insensitive tonic contraction was relaxed by the application of polyvalent cations (Mn2+, Co2+, Cd2+ and La3+). These findings indicate that NA‐induced biphasic contraction is mainly due to nifedipine‐insensitive Ca 2+ influx, especially in the tonic phase. Cyclic AMP‐increasing agents such as forskolin (0.5‐10 μM), IBMX (5‐500 μM) and caffeine (1‐20 mM) relaxed the NA‐induced contraction extensively in a concentration‐dependent manner. However, these agents only partially relaxed the high K+‐induced contraction. Forskolin (10 μM) and IBMX (100 μM) reduced the [Ca 2+ ] i response to NA, but had no effect on the [Ca 2+ ] i response to high K+. These results suggest that an increase in intracellular cAMP may relax the NA‐induced contraction by attenuating a nifedipine‐insensitive Ca 2+ influx and by a mechanism independent of a reduction in [Ca 2+ ] i .