• Top
• Introduction
• Methods
• Results
• Conclusion

Introduction

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.

Methods

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.

Results

In vitro

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 (T_max) while SOV increased the response to PE; T_max (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 vivo

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).

Conclusion

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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