Abstract
Vascular alterations in diabetes cause or contribute to the etiology of microvascular complications such as nephropathy, neuropathy, and retinopathy. The endothelium controls the vascular smooth muscle tone through the production of vasodilator mediators such as nitric oxide, prostacyclin, and a still-elusive endothelium-derived hyperpolarizing factor (EDHF). Although EDHF is a prominent vasodilator, particularly in smaller arteries, little attention has been paid to the potential role of EDHF responses in diabetes. EDHF function may involve the participation of mediators, including several diffusible factors and non-diffusible factors, (e.g., conduction of hyperpolarization via myoendothelial gap junctions). Indeed, in several vessels, cyclic adenosine 3,5-monophosphate (cAMP) facilitates EDHF responses by enhancing electrotonic conduction via gap junctions. It has been demonstrated that the alterations in EDHF relaxation seen in mesenteric arteries from diabetic rats may be attributable to an increase in phosphodiesterase3 (PDE3) activity, leading to a reduction in the action of cAMP, and moreover the activity of protein kinase A (PKA) is decreased in such arteries. Although an improvement in EDHF responses has not been, as yet, the subject of any direct pharmaceutical effort, increasing cAMP/PKA signaling (e.g., by inhibiting PDE3 activity) has potential as an interesting therapeutic target in diabetic microvascular disease.
Keywords: EDHF, cAMP, diabetes, phosphodiesterase3, cilostazol, gap junction
3