Matsumoto, Takayuki, Kentaro Wakabayashi, Tsuneo Kobayashi, and Katsuo Kamata. Diabetes-related changes in cAMPdependent protein kinase activity and decrease in relaxation response in rat mesenteric artery. Am J Physiol Heart Circ Physiol 287: H1064 -H1071, 2004. First published May 6, 2004; 10.1152/ ajpheart.00069.2004.-Using superior mesenteric artery rings isolated from age-matched controls and streptozotocin (STZ)-induced diabetic rats, we recently demonstrated that EDHF-type relaxation is impaired in STZ-induced diabetic rats, possibly due to a reduced action of cAMP via increased phosphodiesterase (PDE) activity (Matsumoto T, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 285: H283-H291, 2003). Here, we investigated the activity and expression of cAMP-dependent protein kinase (PKA), an enzyme that is produced by a pleiotropic and plays key roles in the transduction of many external signals through the cAMP second messenger pathway and in cAMP-mediated vasorelaxation. The relaxation induced by cilostamide, a selective PDE3 inhibitor, was significantly weaker in superior mesenteric artery rings from STZ-induced diabetic rats than in those from age-matched controls. The relaxation responses to 8-bromo-cAMP (8Br-cAMP) and N 6 ,O 2 -dibutyryl-adenosinecAMP (db-cAMP), a cell-permeant cAMP analog, were also impaired in the STZ diabetic group. PKA activity in the db-cAMP-treated mesenteric artery was significantly lower in the STZ diabetic group. The expression levels of the mRNA and protein for PKA catalytic subunit Cat-␣ were significantly decreased in the STZ diabetic group, but those for PKA regulatory subunit isoform RII- were increased. We conclude that the abnormal vascular relaxation responsiveness seen in STZ-induced diabetic rats may be attributable not only to increased PDE activity but also to decreased PKA activity. Possibly, the decreased PKA activity may result from an inbalance between PKA catalytic and regulatory subunit expressions.protein kinase A; streptozotocin ADENOSINE 3Ј,5Ј-CYCLIC MONOPHOSPHATE (cAMP) acts as a second messenger in the intracellular signal transduction of a wide variety of extracellular stimuli in several tissues (3, 39). In the vascular system, cAMP plays important roles in the regulation of vascular tone and in the maintenance of the mature contractile phenotype in smooth muscle cells (31, 41). The intracellular levels of cAMP are tightly regulated, both by control of its rate of synthesis (by adenylyl cyclases) in response to extracellular signals and by rate of control of its hydrolysis [by cyclic nucleotide phosphodiesterases (PDEs)] (3, 38, 39). The newly minted cAMP then binds to its receptor, cAMP-dependent protein kinase (PKA), and causes reversible phosphorylation of protein substrates that regulate a vast number of cellular processes, such as metabolism, cell growth and differentiation, apoptosis, gene expression, ion channel conductivity, and vascular tone (41, 53, 55).There are two types of PKA, type I (PKA-I) and type II (PKA-II), and these share ...