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Tyrosine phosphorylation modulates rat vascular response to experimental endotoxemia in vivo and in vitro
Critical Care volume 11, Article number: P6 (2007)
Endotoxemia is characterized by vascular hyporeactivity, hypotension and microcirculatory changes that are partially linked to the excess of nitric oxide production. The agents that can influence Ca2+ transport (affect Ca-ATPase) or modulate Ca2+ sensitivity of the smooth muscle contraction (modulate phosphorylation) may theoretically influence some of the above-mentioned effects.
We evaluated the effects of tyrosine phosphatase or kinase inhibitors, sodium orthovanadate (SOV) or genistein (GEN). The effects of these agents were examined in vitro, in a model of vascular hyporeactivity of sepsis, in rings of rat aorta (RA), with or without endothelium (± ENDO), or in human mesenteric artery (HMA). In vivo, the intestinal microcirculation (terminal ileum) of endotoxemic rats (LEW.1A) that received i.v. lipopolysaccharide (LPS), 15 mg/kg BW, was examined using intravital microscopy.
The nitric oxide production inhibitor L-NAME (5 × 10-4) and cGMP inhibitor ODQ (5 × 10-5) abolished LPS-induced hyporeactivity. GEN attenuated maximal tension (Tmax) while SOV increased the response to PE; Tmax (kg/g, dry muscle): controls vs SOV, RA (-ENDO): 0.87 ± 0.19 vs 1.42 ± 0.23 (10-7); 1.56 ± 0.28 (10-6) and 2.33 ± 0.69 (10-5); RA (+ENDO): 0.88 ± 0.21 vs 1.53 ± 0.35 (10-7); 1.35 ± 0.30 (10-6) and 2.55 ± 0.68 (10-5); and HMA (+ENDO): 1.12 ± 0.23 vs 0.37 ± 0.14 (10-7); 2.06 ± 0.21 (10-6) and 3.00 ± 0.07 (10-5).
In the LPS group GEN increased mucosal functional capillary density (FCD, cm/cm2; mean ± SD; LPS vs GEN, 105.5 ± 44.6 vs 174.7 ± 39.1; P = 0.018). SOV (7.5 mg/kg) increased FCD not only in mucosa (163.7 ± 40.0; P = 0.024) but also in the longitudinal muscular layer (LPS vs SOV, 111.9 ± 24.0 vs 172.2 ± 19.5; P < 0.001). Surprisingly, the SOV (15 mg/kg) alone (without LPS) increased leukocyte sticking in the venules V1 (LPS vs SOV, number of stickers/mm2, 403.3 ± 113.9 vs 669.8 ± 150.8; P = 0.027).
The tyrosine phosphorylation pathway may play an important role in modulation of the LPS-induced vascular hyporeactivity and could enhance terminal ileum microcirculation. This might be a result of both modulation of tyrosine phosphorylation by genistein and sodium orthovanadate, and/or plasma membrane Ca-ATPase inhibition by SOV.
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Lehmann, C., Hammann, T., Adamek, O. et al. Tyrosine phosphorylation modulates rat vascular response to experimental endotoxemia in vivo and in vitro. Crit Care 11, P6 (2007). https://doi.org/10.1186/cc5166
- Tyrosine Phosphorylation
- Nitric Oxide Production
- Sodium Orthovanadate
- Functional Capillary Density