title: Clofibrate relaxes the longitudinal smooth muscle of the mouse distal colon through calcium-mediated desensitisation of contractile machinery.
abstract: Peroxisome proliferator-activated receptor α (PPAR-α) is a ligand-activated transcription factor that exerts strong effects on metabolic pathways. Our aim was to elucidate the effect of clofibrate, a PPAR-α agonist, on the longitudinal muscle of the mouse distal colon. We initially found that clofibrate induced a relaxation response in this muscle. Notably, the PPAR-α antagonists GW9662 and T0070907 did not attenuate this clofibrate-induced relaxation. The structurally related PPAR-α agonists fenofibrate and bezafibrate induced relaxation in the distal colon as effectively as clofibrate. In contrast, wy-14643, which activates PPAR-α more selectively than clofibrate, had no effect. Furthermore, clofibrate-induced relaxation was not affected by N-nitro-L-arginine, an NO synthase inhibitor, 1H-[1,2,4]-oxadiazolo-[4,3- a]quinoxaline-1-one, a soluble guanylate cyclase inhibitor, or H89, a protein kinase A inhibitor. Tetrodotoxin, an Na⁺ channel blocker, and glibenclamide, apamin, charybdotoxin and XE991, various K⁺ channel blockers, had no effect on clofibrate-induced relaxation. Importantly, clofibrate induced a relaxation response that was not accompanied by any alteration in the cytoplasmic Ca²⁺ concentration in the longitudinal muscle of the mouse distal colon. Moreover, calyculin A, a myosin light-chain phosphatase (MLCP) inhibitor, attenuated clofibrate-induced relaxation. Our findings indicate that clofibrate relaxes the longitudinal smooth muscle of the mouse distal colon by regulating MLCP activity.
authors.affiliation: Laboratory of Veterinary Pharmacology, Division of Veterinary Science, Osaka Prefecture University Graduate School of Life and Environmental Science, Izumisano, Japan. azuma@vet.osakafu-u.ac.jp
authors.forename: Yasu-Taka
authors.initials: YT
authors.lastname: Azuma
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Ai
authors.initials: A
authors.lastname: Morioka
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Nakajima
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Takeuchi
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D002994:Clofibrate / Q000378:metabolism / Q000494:pharmacology*; D003106:Colon / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D008297:Male; D008387:Marine Toxins; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000502:physiology; D009126:Muscle Relaxation / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D043263:Myosin-Light-Chain Phosphatase / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D026941:Sodium Channel Blockers / Q000494:pharmacology; D000071756:Soluble Guanylyl Cyclase
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000924:Anticholesteremic Agents; D001549:Benzamides; D008387:Marine Toxins; D010080:Oxazoles; D047493:PPAR alpha; D026902:Potassium Channel Blockers; D011725:Pyridines; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D026941:Sodium Channel Blockers; C458508:T 0070907; C059041:calyculin A; C006253:pirinixic acid; D019001:Nitric Oxide Synthase; D017868:Cyclic AMP-Dependent Protein Kinases; D043263:Myosin-Light-Chain Phosphatase; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D002994:Clofibrate; D002118:Calcium