Reversal of lipopolysaccharide-induced hyporeactivity in rat aorta and human mesenteric artery in vitro by orthovanadate

Background

Endotoxemia is characterised by vascular hyporeactivity (VHR) that is partially caused by the excess of nitric oxide (NO) production. The agent that affects Ca²⁺ transport or the Ca²⁺ sensitivity of contraction may theoretically reverse VHR.

Methods

The VHR was induced in vitro by incubating (for 6 hours) rat aortal rings, with or without endothelium (± ENDO), or human mesenteric arterial rings (HMA) endothelium intact (+ENDO), with lipopolysaccharide Escherichia coli (LPS) (10^-3 g/l). In addition, the preparations (12 groups, n = 7 each) were preincubation (10 min) with various concentrations of sodium-orthovanadate (OV) (10^-7, 10^-6, or 10^-5 M) and then the contractile response to phenylephrine (PE) was examined in vitro.

Results

We found that the presence of endothelium diminished sensitivity to PE in rat aorta (+ENDO, EC50: 5.88 ± 0.11 vs -ENDO, EC50: 6.84 ± 0.15, respectively), a result probably of an overproduction of nitric oxide and potassium channel activation. The preincubation with OV had no effect on sensitivity to PE in rat aorta (± ENDO) and HMA (+ENDO) as compared with corresponding controls (without OV [-OV]). However, preincubation with OV increased maximal tension (Tmax) to PE, as compared with the control (-OV). Tmax (kg/g, dry muscle), control versus OV (concentration): rat aorta (-ENDO): 0.87 ± 0.19 vs 1.42 ± 0.23 (10^-7 M), 1.56 ± 0.28 (10^-6 M) and 2.33 ± 0.69 (10^-5 M); rat aorta (+ENDO): 0.88 ± 0.21 vs 1.53 ± 0.35 (10^-7 M), 1.35 ± 0.30 (10^-6 M) and 2.55 ± 0.68 (10^-5 M); and human mesenteric artery (+ENDO): 1.12 ± 0.23 vs 0.37 ± 0.14 (10^-7 M), 2.06 ± 0.21 (10^-6 M) and 3.00 ± 0.07 (10^-5 M), respectively.

Conclusion

These findings demonstrated that the VHR in rat aorta and human mesenteric artery could be reversed by an inhibition of calcium removal and/or inhibition of tyrosine phosphatase activity. It should be verified whether in human preparations taken from septic patients orthovanadate could have some beneficial effects on vascular hyporeactivity.

Figure 1

(abstract P47)