An investigation of arterial insufficiency in rat hindlimb. An enzymic, mitochondrial and histological study.
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ABSTRACT:
SUBMITTER: Hayes DJ
PROVIDER: S-EPMC1146863 | biostudies-other | 1986 Jun
REPOSITORIES: biostudies-other
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Project description:A small animal model of arterial insufficiency is presented which involves unilateral femoral artery ligation and section. Invoked alterations in metabolism and perfusion of the affected muscle mass have been investigated 12 h, 4, 7 and 14 days post-ligation by 31P-n.m.r. and microsphere infusion, both at rest and during isometric muscle contraction at 1 Hz. At rest, the concentration of phosphocreatine was similar to the mean control value (36.0 +/- 1.0 mM) from 4 days post-ligation, but was significantly lower at 12 h (28.5 +/- 3.6 mM). Inorganic phosphate concentrations were significantly elevated for 7 days post-ligation. No significant differences were noted in intramuscular pH. Upon stimulation of the affected muscle mass, a time-dependent improvement in phosphocreatine utilization was observed such that 14 days post-ligation phosphocreatine utilization was not significantly different from mean control values. A similar amelioration was noted for the contraction-induced fall in intramuscular pH. At rest, no significant differences in bloodflow to the muscles of the ligated limb compared with the unaffected contralateral limb were observed. However, isometric contraction of the affected muscle mass resulted in a markedly reduced hyperaemic response 12 h post-ligation. Thereafter, a time-dependent improvement in tissue perfusion during stimulation was observed which paralleled the improvements in phosphocreatine utilization and intramuscular pH changes. The results presented are discussed with respect to the interrelationship between oxygen delivery, high energy phosphate utilization and force maintenance.
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Project description:Muscle bloodflow and the rate of glucose uptake and phosphorylation were measured in vivo in rats 7 days after unilateral femoral artery ligation and section. Bloodflow was determined by using radiolabelled microspheres. At rest, bloodflow to the gastrocnemius, plantaris and soleus muscles of the ligated limb was similar to their respective mean contralateral control values; however, bilateral sciatic nerve stimulation at 1 Hz caused a less pronounced hyperaemic response in the muscles of the ligated limb, being 59, 63 and 49% of their mean control values in the gastrocnemius, plantaris and soleus muscles respectively. The rate of glucose utilization was determined by using the 2-deoxy[3H]glucose method [Ferré, Leturque, Burnol, Penicaud & Girard (1985) Biochem. J. 228, 103-110]. At rest, the rate of glucose uptake and phosphorylation was statistically significantly increased in the gastrocnemius and soleus muscles of the ligated limb, being 126 and 140% of the mean control values respectively. Bilateral sciatic nerve stimulation at 1 Hz caused a 3-5-fold increase in the rate of glucose utilization by the ligated and contralateral control limbs; furthermore, the rate of glucose utilization was significantly increased in the muscles of the ligated limb, being 140, 129 and 207% of their mean control values respectively. For the range of bloodflow to normally perfused skeletal muscle at rest or during isometric contraction determined in the present study, a linear correlation between the rate of glucose utilization and bloodflow can be demonstrated. Applying similar methods of regression analysis to glucose utilization and bloodflow to muscles of the ligated limb reveals a similar linear correlation. However, the rate of glucose utilization at a given bloodflow is increased in muscles of the ligated limb, indicating an adaptation of skeletal muscle to hypoperfusion.
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Project description:Exposure to microgravity results in post-flight cardiovascular deconditioning and orthostatic intolerance in astronauts. Vascular oxidative stress injury and mitochondrial dysfunction have been indicated in this process. To elucidate the mechanism for this condition, we investigated whether mitochondria regulated NADPH oxidase in hindlimb unweighting (HU) rat cerebral and mesenteric arteries. Four-week HU was used to simulate microgravity in rats. Vascular superoxide generation, protein and mRNA levels of Nox2/Nox4, and the activity of NADPH oxidase were examined in the present study. Compared with control rats, the levels of superoxide increased in cerebral (P<0.001) but not in mesenteric vascular smooth muscle cells. The protein and mRNA levels of Nox2 and Nox4 were upregulated significantly (P<0.001 and P<0.001 for Nox2, respectively; P<0.001 and P<0.001 for Nox4, respectively) in HU rat cerebral arteries but not in mesenteric arteries. NADPH oxidases were activated significantly by HU (P<0.001) in cerebral arteries but not in mesenteric arteries. Chronic treatment with mitochondria-targeted antioxidant mitoTEMPO attenuated superoxide levels (P<0.001), decreased the protein and mRNA expression levels of Nox2/Nox4 (P<0.01 and P<0.05 for Nox2, respectively; P<0.001 and P<0.001 for Nox4, respectively) and the activity of NADPH oxidase (P<0.001) in HU rat cerebral arteries, but exerted no effects on HU rat mesenteric arteries. Therefore, mitochondria regulated the expression and activity of NADPH oxidases during simulated microgravity. Both mitochondria and NADPH oxidase participated in vascular redox status regulation.
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Project description:Repeated stress is one of the major risk factors for cerebrovascular disease, including stroke, and vascular dementia. However, the functional alterations in the cerebral hemodynamic response induced by chronic stress have not been clarified. Here, we investigated the in vivo cerebral hemodynamic changes and accompanying cellular and molecular changes in chronically stressed rats. After 3 weeks of restraint stress, the elicitation of stress was verified by behavioral despair in the forced swimming test and by physical indicators of stress. The evoked changes in the cerebral blood volume and pial artery responses following hindpaw electrical stimulation were measured using optical intrinsic signal imaging. We observed that, compared to the control group, animals under chronic restraint stress exhibited a decreased hemodynamic response, with a smaller pial arterial dilation in the somatosensory cortex during hindpaw electrical stimulation. The effect of chronic restraint stress on vasomodulator enzymes, including neuronal nitric oxide synthase (nNOS) and heme oxygenase-2 (HO-2), was assessed in the somatosensory cortex. Chronic restraint stress downregulated nNOS and HO-2 compared to the control group. In addition, we examined the subtypes of cells that can explain the environmental changes due to the decreased vasomodulators. The expression of parvalbumin in GABAergic interneurons and glutamate receptor-1 in neurons were decreased, whereas the microglial activation was increased. Our results suggest that the chronic stress-induced alterations in cerebral vascular function and the modulations of the cellular expression in the neuro-vasomodulatory system may be crucial contributing factors in the development of various vascular-induced conditions in the brain.
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