nNOS and eNOS modulate cGMP formation and vascular response in contracting fast-twitch skeletal muscle

1 Department of Physiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9040 2 Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, New York 14642-8711 3 Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129 Lau, Kim S., Robert W. Grange, Eiji Isotani, Ingrid H. Sarelius, Kristine E. Kamm, Paul L. Huang, and James T. Stull. nNOS and eNOS modulate cGMP formation and vascular response in contracting fast-twitch skeletal muscle. Physiol. Genomics 2: 21–27, 2000.—Nitric oxide (NO) from Ca 2+ -dependent neuronal nitric oxide synthase (nNOS) in skeletal muscle fibers may modulate vascular tone by a cGMP-dependent pathway similar to NO derived from NOS in endothelial cells (eNOS). In isolated fast-twitch extensor digitorum longus (EDL) muscles from control mice, cGMP formation increased ~166% with electrical stimulation (30 Hz, 15 s). cGMP levels were not altered in slow-twitch soleus muscles. The NOS inhibitor N -nitro- L -arginine abolished the contraction-induced increase in cGMP content in EDL muscles, and the NO donor sodium nitroprusside (SNP) increased cGMP content ~167% in noncontracting EDL muscles. SNP treatment but not electrical stimulation increased cGMP formation in muscles from nNOS -/- mice. cGMP formation in control and stimulated EDL muscles from eNOS -/- mice was less than that obtained with similarly treated muscles from control mice. Arteriolar relaxation in contracting fast-twitch mouse cremaster muscle was attenuated in muscles from mice lacking either nNOS or eNOS. These findings suggest that increases in cGMP and NO-dependent vascular relaxation in contracting fast-twitch skeletal muscle may require both nNOS and eNOS. endothelial nitric oxide synthase; neuronal nitric oxide synthase; arteriolar relaxation