The American journal of physiology
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Mechanisms of circulatory effects induced by nitric oxide synthase inhibition in endotoxemia were investigated in 36 pigs randomized to 1) endotoxin infusion (1.7 micrograms.kg-1.h-1 iv) for 7 h and bolus NG-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg iv) after 3 h; 2) endotoxin infusion for 7 h; 3) saline infusion for 7 h and L-NAME after 3 h; and 4) saline infusion for 7 h. Fifteen minutes after L-NAME injection during endotoxemia, reductions in cardiac output (41%, P < 0.05), portal venous flow (51%, P < 0.05), and hepatic artery flow (50%, P < 0.05) were observed. Systemic vascular resistance increased by 82% (P < 0.05), and the portocaval vascular resistance increased by 101% (P < 0.05). ⋯ In conclusion, L-NAME decreased intravascular blood volume and increased splanchnic venous resistance. These effects will tend to reduce venous return. Combined with a marked increase in left ventricular after-load, L-NAME may thus compromise cardiovascular function in endotoxemia.
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Sepsis is believed to induce disturbances in microcirculatory flow and nutrient exchange, which may result in impaired tissue oxygenation. With the use of an established rat model of endotoxemia, voltametric measurements were made of skeletal muscle (tissue) oxygen tension (PtO2) and its response to inspired oxygen concentration (FIO2). Steady-state nutritive flow and the response of endotoxemic muscle to ischemia-reperfusion were also measured. ⋯ Endotoxemic muscle PtO2 values showed less heterogeneity than control groups and significant attenuation of the response to increasing FIO2 to 0.95 (mean rise in PtO2 +/- SE; 27 +/- 7 vs. 80 +/- 11 Torr for endotoxemic and control groups, respectively; P < 0.01). No steady-state differences in tissue perfusion or response to ligation-induced ischemia-reperfusion could be demonstrated between endotoxemic and control rats. These data suggest that there is significant tissue hypoxia and abnormal microvascular control of oxygenation in endotoxemia, even in the presence of normal microcirculatory perfusion.
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We used mice with deletions in either the endothelial nitric oxide synthase (eNOS) or neuronal NOS (nNOS) gene to investigate the role of eNOS and nNOS in acetylcholine (ACh)-induced relaxation of pial arterioles (20-30 microns). Pial arteriolar diameter was measured by intravital microscopy through a closed cranial window, and NOS activity was determined by the conversion of [3H]arginine to [3H]citrulline in subjacent cortex. ACh superfusion (1, 10 microM) caused atropine-sensitive dose-dependent arteriolar dilation in all three mouse strains. ⋯ The residual dilation after L-NNA in eNOS mutant mice could be blocked completely by TTX-plus L-NNA. Our findings indicate that 1) ACh dilates pial arterioles of wild-type mice by NOS-dependent mechanisms as reported in other species, 2) the response in nNOS mutant mice resembles the wild-type response except for enhanced dilation to ACh and reduced L-NNA sensitivity, and 3) surprisingly, the response in eNOS mutant mice is partially NOS dependent and attenuated by both TTX and L-NNA. Because nNOS is constitutively expressed in eNOS mutants, these findings coupled with the TTX results suggest that an nNOS-dependent mechanism may compensate for the chronic loss of eNOS activity after targeted gene disruption.
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Characterizing the resistances to O2 transport from the erythrocyte to the mitochondrion is important in understanding potential transport limitations. A steady-state model of this process was developed to predict the minimum (critical) end-capillary PO2 required to prevent hypoxia at maximal O2 consumption (VO2max) in a circular region of tissue surrounding the venular end of a capillary. Capillary density was used as a measure of O2 delivery, and mitochondrial density was used as a measure of O2 consumption. ⋯ No significant difference in end-capillary PO2 was found between similar muscles of athletic versus nonathletic animals. Predicted intracapillary O2 transport resistance ranged from 18 to 54% of the total transport resistance in the O2 pathway. Further investigation is required to explore the extent to which spatial and temporal heterogeneities in O2 delivery and consumption play a role in O2 transport.
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Beat-to-beat heart rate (HR) dynamics were studied by plotting each R-R interval as a function of the previous R-R interval (Poincaré plot) during incremental doses of atropine followed by exercise for 10 subjects and during exercise without autonomic blockade for 31 subjects. A quantitative two-dimensional vector analysis of a Poincaré plot was used by measuring separately the standard deviation of instantaneous beat-to-beat R-R interval variability (SD1) and the standard deviation of continuous long-term R-R interval variability (SD2) as well as the SD1/SD2 ratio. Quantitative Poincaré measures were compared with linear measures of HR variability (HRV) and with approximate entropy (ApEn) at rest and during exercise. ⋯ However, the SD1/SD2 ratio had a modest correlation with ApEn at rest (r = -0.69, P < 0.001), but not during exercise (r = 0.27, P = NS). All measures of vagal modulation of HR decreased progressively until the ventilatory threshold level was reached, when sympathetic activation was reflected as changes in the SD1/SD2 ratio. These results show that quantitative two-dimensional vector analysis of a Poincaré plot can provide useful information on vagal modulation of R-R interval dynamics during exercise that are not easily detected by linear summary measures of HRV or by ApEn.