Cilostazol improves endothelium-derived hyperpolarizing factor-type relaxation in mesenteric arteries from diabetic rats.
We previously reported that in mesenteric arteries from streptozotocin (STZ)-induced diabetic rats that 1) endothelium-derived hyperpolarizing factor (EDHF)-type relaxation is impaired, possibly due to a reduced action of cAMP via increased phosphodiesterase 3 (PDE3) activity (Matsumoto T, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 285: H283-H291, 2003) and that 2) PKA activity is decreased (Matsumoto T, Wakabayashi K, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 287: H1064-H1071, 2004). Here we investigated whether chronic treatment with cilostazol, a PDE3 inhibitor, improves EDHF-type relaxation in mesenteric arteries isolated from STZ rats. We found that in such arteries 1) cilostazol treatment (2 wk) improved ACh-, A-23187-, and cyclopiazonic acid-induced EDHF-type relaxations; 2) the ACh-induced cAMP accumulation was transient and sustained in arteries from cilostazol-treated STZ rats; 3) the EDHF-type relaxation was significantly decreased by a PKA inhibitor in the cilostazol-treated group, but not in the cilostazol-untreated group; 4) cilostazol treatment improved both the relaxations induced by cAMP analogs and the PKA activity level; and 5) PKA catalytic subunit (Cat-alpha) protein was significantly decreased, but the regulatory subunit RII-beta was increased (and the latter effect was significantly decreased by cilostazol treatment). These results strongly suggest that cilostazol improves EDHF-type relaxations in STZ rats via an increase in cAMP and PKA signaling.
Matsumoto
Takayuki
T
Dept. of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi Univ., Shinagawa-ku, Tokyo, Japan.
Kobayashi
Tsuneo
T
Wakabayashi
Kentaro
K
Kamata
Katsuo
K
D000818:Animals; D001685:Biological Factors / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D000001:Calcimycin / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D000077407:Cilostazol; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D007118:Immunoassay; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood; D007476:Ionophores / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood; D014665:Vasodilator Agents / Q000494:pharmacology*
D001685:Biological Factors; D001786:Blood Glucose; D007328:Insulin; D007476:Ionophores; D013777:Tetrazoles; D014280:Triglycerides; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D000001:Calcimycin; D002784:Cholesterol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000077407:Cilostazol