cGMP Upregulates Nitric Oxide Synthase Expression in Vascular Smooth Muscle Cells

Abstract

Abstract 8-Bromo-guanosine 3′:5′-cyclic monophosphate (8-Br-cGMP), an analogue of cyclic guanosine monophosphate (cGMP), induced a time- and dose-dependent enhancement of interleukin-1–induced nitric oxide production in vascular smooth muscle cells. Human atrial natriuretic polypeptide, which stimulates cGMP accumulation in vascular smooth muscle cells, also enhanced interleukin-1–induced nitric oxide release at a concentration of 100 nmol/L. In contrast, coincubation with 10 μmol/L methylene blue, an inhibitor of soluble guanylate cyclase, inhibited interleukin-1–induced nitric oxide release from vascular smooth muscle cells. Furthermore, coincubation with 8-Br-cGMP also enhanced the interleukin-1–induced increase in inducible nitric oxide synthase messenger RNA in vascular smooth muscle cells. However, the enhancement of nitric oxide production induced by 8-Br-cGMP was significantly prevented by coincubation with neutralizing antibody against tumor necrosis factor–α. Furthermore, 8-Br-cGMP enhanced the interleukin-1–induced increase in tumor necrosis factor–α messenger RNA level in vascular smooth muscle cells. These findings indicate that cGMP may upregulate inducible nitric oxide synthase gene expression through the stimulation of tumor necrosis factor–α production in vascular smooth muscle cells. Thus, there may be a positive feedback mechanism between nitric oxide and the cGMP system in vascular smooth muscle cells.