Lack of cyclic nucleotide regulation of MBCQ-induced relaxation of rat ileal smooth muscle.
The effects of the type V phosphodiesterase (PDE V) inhibitors, MBCQ, zaprinast and dipyridamole, on the relationship between relaxation and cyclic nucleotide content were investigated in rat ileal smooth muscle. Each of MBCQ (0.01-10 microM), zaprinast (0.1-100 microM) and dipyridamole (0.1-100 microM) inhibited carbachol (CCh; 10 microM)-induced contractions in a concentration-dependent manner. When compared with the concentrations of these agents producing 50% relaxation (IC50) of CCh-induced contraction, MBCQ was 14-20 fold more potent than the other agents. The inhibitory potency of these agents against high K+ (65 mM KCl)-induced contractions were similar to that for CCh. MBCQ (1, 10 microM) did not significantly increase the cGMP content above control levels in the presence of CCh (10 microM). Both Zaprinast (1-100 microM) and dipyridamole (1-100 microM) increased the cGMP content of smooth muscle preparations in a concentration-dependent manner. There was a positive correlation between the inhibition of the CCh-induced contraction and the increase in cGMP content elicited by zaprinast and dipyridamole (zaprinast; r=0.72, P<0.05, dipyridamole; r=0.92, P<0.05). However, MBCQ at a concentration which induced a medium-sized relaxation did not significantly increase the cGMP content. Neither MBCQ, zaprinast nor dipyridamole significantly increased the cAMP content of the preparations above control. In summary, it is suggested that the inhibition of CCh-induced contractions by zaprinast and dipyridamole involves increases in cGMP content via inhibition of PDE V. However the inhibition of CCh-induced contraction by MBCQ may not involve cyclic nucleotides in rat ileal smooth muscle.
Kaneda
Takeharu
T
Division of Veterinary Pharmacology, Nippon Veterinary and Animal Science University, 7-1 Kyonan-cho 1-chome, Musashino, Tokyo 180-8602, Japan. t-kaneda@nvau.ac.jp
Yamamoto
Hideyuki
H
Azegami
Yoshihiro
Y
Shimizu
Kazumasa
K
Urakawa
Norimoto
N
Nakajyo
Shinjiro
S
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004176:Dipyridamole / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
C485966:((3,4-(methylenedioxy)benzyl)amino)-6-chloroquinazoline; D018679:Cholinergic Agonists; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011799:Quinazolines; D004176:Dipyridamole; D002217:Carbachol; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; C011145:zaprinast; D006152:Cyclic GMP; D011188:Potassium