title: Hindlimb claudication reflects impaired nitric oxide-dependent revascularization after ischemia.
abstract: Although vascular remodeling is important in preventing tissue damage and restoring muscle function, there is no evidence of a relationship between vascular remodeling and muscle function after peripheral vascular occlusion. Nitric oxide (NO) has been implicated in the process of vascular remodeling in hindlimb ischemia. Thus, development of alterations in hindlimb gait after ischemia may be associated with impaired nitric oxide-dependent, vascular blood flow recovery. We evaluated hindlimb gait as an index of ischemia-induced revascularization and tested the effects of NO synthase inhibition on both hindlimb blood flow and hindlimb gait locomotion. After 14 days of ischemia, the ischemic hindlimb showed no significant differences in gait locomotion compared to the sham-operated hindlimb. However, hindlimb ischemia drastically reduced hindlimb blood flow from 46+/-3 mL/min/100 g to 12+/-2 mL/min/100 g which reverted to 33+/-5 mL/min/100 g after 14 days of ischemia. eNOS mRNA expression levels at 3, 7, 14, and 28 days after initiation of ischemia, were increased by 50+/-5%, 100+/-10%, 140+/-8% and 270+/-12% respectively and eNOS protein expression levels at 7, 14, and 28 days, were increased by 28+/-3%, 62+/-6% and 80+/-16% respectively. However, eNOS inhibition caused by l-NAME treatment prevented blood flow recovery and correction of abnormal gait locomotion in rats. Thus, the duration of the stride-swing phase increased and the stride length decreased. The knee joint angle decreased during flexion and extension with eNOS inhibition. In conclusion, ischemia-induced revascularization is associated with recovery of both hindlimb blood flow and normal gait locomotion. Moreover, prevention of NO synthesis, a key messenger in ischemia-induced revascularization, is associated with impairment in hindlimb locomotion. Thus, gait locomotion represents a functional model that could be used to evaluate the degree of ischemia-induced revascularization.
authors.affiliation: Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional 2508, Colonia San Pedro Zacatenco, México City, Mexico.
authors.forename: Diana
authors.initials: D
authors.lastname: Luque Contreras
authors.forename: Ismael
authors.initials: I
authors.lastname: Jiménez Estrada
authors.forename: Daniel
authors.initials: D
authors.lastname: Martínez Fong
authors.forename: Bertha
authors.initials: B
authors.lastname: Segura
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Guadarrama
authors.forename: Ramón
authors.initials: R
authors.lastname: Paniagua Sierra
authors.forename: Hilda
authors.initials: H
authors.lastname: Vargas Robles
authors.forename: Amelia
authors.initials: A
authors.lastname: Rios
authors.forename: Bruno
authors.initials: B
authors.lastname: Escalante
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications; D001696:Biomechanical Phenomena; D001783:Blood Flow Velocity / Q000187:drug effects; D004195:Disease Models, Animal; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005684:Gait / Q000187:drug effects; D006614:Hindlimb; D007383:Intermittent Claudication / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D007511:Ischemia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016491:Peripheral Vascular Diseases / Q000150:complications; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019331:NG-Nitroarginine Methyl Ester