Pyrrolidine Dithiocarbamate Reduces Vascular Prostanoid-Induced Responses in Aged Type 2 Diabetic Rat Model

Abstract

It has been shown that enhancement of vasoconstrictor prostanoids plays an important role in the development of cardiovascular diseases. The aim of the present study was to examine the effects of pyrrolidine dithiocarbamate (PDTC), a low-molecular-weight thiol antioxidant and a potent inhibitor of nuclear factor-kappaB (NF-kappaB), on both the response to and production of prostanoids in arterial vessels isolated from rats at the chronic stage of type 2 diabetes. Using aortas from type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, control Long-Evans Tokushima Otsuka (LETO) rats, and LETO and OLETF rats treated with PDTC (30 mg/kg, s.c., daily, for 1 week), we measured the production of prostanoids and NF-kappaB activity. The arachidonic acid-induced contraction and the acetylcholine-induced endothelium-derived contracting factor (EDCF)-mediated contraction in mesenteric arteries were also compared among these groups. OLETF rats exhibited (vs. age-matched LETO rats) the following: increased responses to both arachidonic acid and EDCF and greater productions of PGE(2) and TXA(2). Treatment with PDTC resulted in the following: 1) reduced arachidonic acid- and EDCF-mediated contractions, 2) suppressed the production of prostanoids, and 3) normalized NF-kappaB activity. These results suggest that PDTC has beneficial effects against the abnormal vasoconstrictor prostanoid signaling present in rats at the chronic stage of type 2 diabetes.