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1 Institute of Medicinal Chemistry, Department of Physiology and Morphology, Hoshi University, Shinagawa-ku, Tokyo/142-8501, Japan
* To whom correspondence should be addressed. E-mail: kamata{at}hoshi.ac.jp.
We previously reported that in mesenteric arteries from streptozotocin (STZ)-induced diabetic rats: (a), endothelium-derived hyperpolarizing factor (EDHF)-type relaxation is impaired, possibly due to a reduced action of cAMP via increased phosphodiesterase 3 (PDE3) activity (Am J Physiol Heart Circ Physiol 285: H283-H291, 2003), and (b) protein kinase A (PKA) activity is decreased (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: (a) cilostazol treatment (2 weeks) improved ACh-, A23187-, and cyclopiazonic acid- induced EDHF-type relaxations, (b) the ACh-induced cAMP accumulation was transient, it was sustained in arteries from cilostazol-treated STZ rats, (c) the EDHF-type relaxation was significantly decreased by a PKA inhibitor in the cilostazol-treated group, but not in the cilostazol-untreated group, (d) cilostazol treatment improved both the relaxations induced by cAMP analogs and the PKA activity level, and (e) PKA catalytic subunit (Cat 
) protein was significantly decreased, but the regulatory subunit RII 
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/PKA signaling.
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