NITRIC-OXIDE STIMULATES SKELETAL-MUSCLE GLUCOSE-TRANSPORT THROUGH A CALCIUM CONTRACTION-INDEPENDENT AND PHOSPHATIDYLINOSITOL-3-KINASE-INDEPENDENT PATHWAY/

Recently published data have provided evidence that nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) are signaling intermediates in the pathway through which muscle contraction stimulates glucose tra nsport. As exercise promotes both NO production and calcium flux, we e xamined the relationships between NO-stimulated glucose uptake and cal cium-, contraction-, and phosphatidylinositol-3-kinase (PI-3-K)-mediat ed glucose transport in the isolated incubated rat epitrochlearis musc le preparation. The NO donor sodium nitroprusside (SNP; 10 mmol/l) and dibutyryl cGMP (100 mu mol/l) accelerated epitrochlearis glucose tran sport four-to fivefold above basal levels (P < 0.001) in a manner simi lar to in vitro contractile activity and the calcium releasing agent N -(6-aminohexyl)5-chloro-1-naphthalenesulfonamide (W7; 100 mu mol/l). I n the case of SNP, this effect could be completely attributed to an in crease in cell surface GLUT4. The effect of SNP on glucose transport w as not inhibitable by either wortmannin (1.5 mu mol/l) or dantrolene ( 12.5 mu mol/l). Similarly, neither calcium nor contraction stimulation of glucose transport was affected by the NO synthase inhibitors NG-mo nomethyl-L-arginine (L-NMMA; 100 mu mol/l) or 7-nitroindazole (1 mmol/ l). Furthermore, whereas SNP raised epitrochlearis cGMP levels tenfold (P < 0.001), neither in vitro contractile activity nor W7 significant ly elevated cGMP. These results indicate that NO/cGMP can markedly sti mulate skeletal muscle glucose transport by increasing GLUT4 levels at the cell surface by a mechanism that does not depend on activation of PI-3-K. In addition, since calcium/contraction-stimulated glucose tra nsport is not blocked by NO synthase inhibition and did not elevate cG MP, NO/cGMP may be part of a novel pathway that is distinct from both the insulin-and contraction-activated mechanisms.