Cyclic AMP-mediated inhibition of noradrenaline-induced contraction and Ca2+ 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 ([Ca2+]i) in the epididymal side of guinea-pig vas deferens. NA (100 microM) 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 Ca2+-free solution. Pretreatment with 10 microM nifedipine, an L-type Ca2+ 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 Ca2+ influx, especially in the tonic phase. Cyclic AMP-increasing agents such as forskolin (0.5-10 microM), IBMX (5-500 microM) 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 microM) and IBMX (100 microM) reduced the [Ca2+]i response to NA, but had no effect on the [Ca2+]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 Ca2+ influx and by a mechanism independent of a reduction in [Ca2+]i.
Kato
K
K
Department of Cell Physiology and Laboratory of Experimental Animals, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8585, Japan. kenkato@college.fdcnet.ac.jp
Furuya
K
K
Tsutsui
I
I
Ozaki
T
T
Yamagishi
S
S
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D006168:Guinea Pigs; D007425:Intracellular Membranes / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology*; D009994:Osmolar Concentration; D011188:Potassium / Q000494:pharmacology; D014649:Vas Deferens / Q000378:metabolism*
D002121:Calcium Channel Blockers; D005576:Colforsin; D002110:Caffeine; D000242:Cyclic AMP; D009543:Nifedipine; D011188:Potassium; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine; D009638:Norepinephrine