title: Nitric oxide induces dilation of rat aorta via inhibition of rho-kinase signaling.
abstract: NO induces vasodilation through cGMP-dependent protein kinase--dependent and --independent mechanisms. A recent study demonstrated that recombinant cGMP-dependent protein kinase can phosphorylate the small G protein, RhoA, thus inhibiting its activity. Additionally, sodium nitroprusside was found to reverse the phenylephrine-induced translocation of RhoA, which is further indicative of the inhibition of RhoA activity. RhoA is known to be involved in the Ca(2+) sensitization of vascular smooth muscle through the actions of one of its downstream effectors, Rho-kinase. This study examined whether NO endogenously induces the relaxation of intact rat aorta via the inhibition of the Rho-kinase--mediated Ca(2+)-sensitizing pathway. Endogenous Rho-kinase inhibitor activity was inhibited by the selective compound Y-27632. Treatment of endothelium-intact rat aorta with Y-27632 (1 micromol/L) resulted in an attenuation of maximal force generated in response to phenylephrine. In endothelium-denuded rings, however, 1 micromol/L Y-27632 was ineffective at inhibiting the phenylephrine-induced contraction. Additionally, 1 micromol/L Y-27632 was significantly less effective at inhibiting the phenylephrine-induced contraction of endothelium-intact rings in the presence of inhibitors of NO synthase or guanylate cyclase (N(omega)-nitro-L-arginine and 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, respectively). Interestingly, sodium nitroprusside restored the ability of 1 micromol/L Y-27632 to attenuate phenylephrine-induced contraction. Rho-kinase inhibition was also found to increase the sensitivity of the endothelium-denuded aorta to sodium nitroprusside. These data demonstrate that NO inhibits Rho-kinase activity in the intact rat aorta, supporting the hypothesis that endogenous NO-mediated vasodilation occurs through the inhibition of Rho-kinase constrictor activity in the intact rat aorta.
authors.affiliation: Department of Physiology, Medical College of Georgia, Augusta 30912-3000, USA. kanchanc@umich.edu
authors.forename: Kanchan
authors.initials: K
authors.lastname: Chitaley
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
mesh_terms: D000577:Amides / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D000077191:Wortmannin; D054460:rho-Associated Kinases
chemical_list: D000577:Amides; D000730:Androstadienes; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009125:Muscle Relaxants, Central; D011725:Pyridines; C108830:Y 27632; D010656:Phenylephrine; D009569:Nitric Oxide; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D000077191:Wortmannin