The difference in the inhibitory mechanisms of papaverine on vascular and intestinal smooth muscles.
Papaverine (0.3-100 microM) more potently inhibited phenylephrine (1 microM)-induced contraction than 65 mM K+-induced contraction of the aorta, while it equally inhibited contractions induced by 65 mM K+ and carbachol (1 microM) in ileal smooth muscle. In phenylephrine-treated aorta, papaverine (1-10 microM) increased the cAMP and cGMP content. However, in carbachol-treated ileum, 30 microM papaverine partially increased the cAMP content while it maximally relaxed the preparation. In fura2-loaded aorta, papaverine (0.3-10 microM) inhibited both the contraction and the increase in intracellular Ca2+ level ([Ca2+]i) induced by phenylephrine in parallel. However, papaverine inhibited carbachol-induced contraction with only a small decrease in [Ca2+]i. Papaverine (1-30 microM) inhibited the carbachol-induced increase in oxidized flavoproteins, an indicator of increased mitochondrial oxidative phosphorylation, in ileal smooth muscle whereas it did not change the phenylephrine-induced increase in the aorta. These results suggest that papaverine inhibits smooth muscle contraction mainly by the accumulation of cAMP and/or cGMP due to the inhibition of phosphodiesterase in the aorta whereas, in ileal smooth muscle, papaverine inhibits smooth muscle contraction mainly by the inhibition of mitochondrial respiration.
Division of Veterinary Pharmacology, Nippon Veterinary and Animal Science University, Musashino, Tokyo, Japan.
T
T
Kaneda
K
K
Shimizu
S
S
Nakajyo
N
N
Urakawa
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005420:Flavoproteins / Q000378:metabolism; D007082:Ileum / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D010208:Papaverine / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology*
D005420:Flavoproteins; D010726:Phosphodiesterase Inhibitors; D014665:Vasodilator Agents; D010208:Papaverine; D000242:Cyclic AMP; D006152:Cyclic GMP; D002118:Calcium