Phosphodiesterases in the Vascular System.

Abstract

Cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) are second messengers involved in the intracellular signal transduction of a variety of extracellular stimuli in several tissues. In the vascular system, these nucleotides play important roles in the regulation of vascular tone and in the maintenance of the mature contractile phenotype in smooth muscle cells. Given that cyclic nucleotide signaling regulates a wide variety of cellular functions, it is not surprising that cyclic nucleotide phosphodiesterases (PDEs). In paticular, the accumulating data showing that there are a large number of different PDE isozymes have triggered an equally large increase in interest about these enzymes. At least 11 different gene families of PDEs are currently known to exist in mammalian tissues. Most families contain several distinct genes, and many of these genes are expressed in different tissues as functionally unique alternative splice variants. This article reviews many of the important aspects about the structure, cellular localization, and regulation of each family of PDEs. Particular emphasis is placed on new information obtained in the last few years about vascular disease. The development of novel methods to deliver more potent and selective PDE inhibitors to individual cell types and subcellular locations will lead to new therapeutic uses for this class of drugs in diseases of the vascular system.

Maternal Vascular Physiology in Preeclampsia

“…72 The enzymes phosphodiesterases regulate cGMP, which is downstream of the interaction of NO with sGC in vascular smooth muscle cells. 73 Serum phosphodiesterases is increased, and cGMP concentrations are attenuated in pregnancies with preeclampsia. Sildenafil, a phosphodiesterases-5 inhibitor, has been used in various experimental and clinical settings to overcome the increased phosphodiesterases activity and improve pregnancy outcomes in preeclampsia.…”

Acetylcholine-induced vasodilation in the perfused kidney of the streptozotocin-induced diabetic rat: role of prostacyclin

“…Thus, evidence has accrued to suggest Correspondence to: Katsuo Kamata, Ph.D., Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan Phone: that EDRFs other than NO may contribute to the vascular actions of ACh (Triggle et al, 2003;Matsumoto et al, 2004a;Tanaka et al, 2004). It is well appreciated that ACh stimulates the endothelial production of vasodilatory prostaglandins (Salom et al, 1991;Majid and Navar, 1992;Vizioli et al, 2005), and current evidence suggests that an endothelium-derived hyperpolarizing factor (EDHF) may also contribute to the vasodilator actions of ACh (Busse et al, 2002;Chen et al, 1988;Matsumoto et al, 2003aMatsumoto et al, , 2003bMatsumoto et al, , 2005Matsumoto et al, , 2006aMatsumoto et al, , 2006bTakano et al, 2005;Yamamoto and Suzuki, 2005). Thus, EDRFs distinct from NO may mediate part of the ACh-induced vasodilation.…”

Cilostazol improves endothelium-derived hyperpolarizing factor-type relaxation in mesenteric arteries from diabetic rats

“…Furthermore, elevations in smooth muscle cAMP levels have been shown to facilitate electrotonic signaling within the vascular media and thereby to amplify and prolong the transmission of ACh-induced hyperpolarizations to smooth muscle cells remote from the endothelium (15). The intracellular level of cAMP is tightly regulated by both control of its rate of synthesis [by adenylyl cyclases (ACs)] (9) in response to extracellular signals and control of its rate of hydrolysis [by phosphodiesterases (PDEs)] (4,32,35). After an intracellular elevation of cAMP, reversible phosphorylation of several protein substrates, including the gap-junction component connexin, by cAMP-dependent PKA exerts influences over many physiological processes (26,36,49).…”