Dexamethasone improves vascular hyporeactivity induced by LPS in vivo by modulating ATP-sensitive potassium channels activity

Abstract

(1) Septic shock represents an important risk factor for patients critically ill. This pathology has been largely demonstrated to be a result of a myriad of events. Glucocorticoids represent the main pharmacological therapy used in this pathology. (2) Previously we showed that ATP-sensitive potassium (KATP) channels are involved in delayed vascular hyporeactivity in rats (24 h after Escherichia coli lipopolysaccharide (LPS) injection). In LPS-treated rats, we observed a significant hyporeactivity to phenylephrine (PE) that was reverted by glybenclamide (GLB), and a significant increase in cromakalim (CRK)-induced hypotension. (3) We evaluated the effect of dexamethasone (DEX 8 mg kg-1 i.p.) whether on hyporeactivity to PE or on hyperreactivity to CRK administration, in vivo, in a model of LPS (8 x 106 U kg-1 i.p.)-induced endotoxemia in urethane-anaesthetised rats. (4) DEX treatment significantly reduced, in a time-dependent manner, the increased hypotensive effect induced by CRK in LPS-treated rats. This effect was significantly (P<0.05) reverted by the glucocorticoid receptor antagonist RU38486 (6.6 mg kg-1 i.p.). (5) GLB-induced hypertension (40 mg kg-1 i.p.), in LPS-treated rats, was significantly inhibited by DEX if administered at the same time of LPS. (6) Simultaneous administration of DEX and LPS to rats completely abolished the hyporeactivity to PE observed after 24 h from LPS injection. (7) In conclusion, our results suggest that the beneficial effect of DEX in endotoxemia could be ascribed, at least in part, to its ability to interfere with KATP channel activation induced by LPS. This interaction may explain the improvement of vascular reactivity to PE, mediated by DEX, in LPS-treated rats, highlighting a new pharmacological activity to the well-known anti-inflammatory properties of glucocorticoids.

Figure 1

DEX (8 mg kg⁻¹; i.p.) was administered together with LPS or saline (DEX-0), 18 h (DEX-18) or 23 h (DEX-23) after LPS or saline injection. In another set of experiments, RU38486 was administered 0.5 h before LPS or LPS+DEX or saline only. At 24 h after LPS or saline haemodynamic studies were performed, at this same time point, we analysed CRK- or GTN-induced hypotension and PE or GLB increase in MAP.

Figure 2

(a) Time-dependent effect of DEX (8 mg kg⁻¹; i.p.) on CRK (150 μg kg⁻¹; i.v.)-induced hypotension in saline- or LPS-treated rats. DEX was administered at 0, 18 or 23 h after LPS or saline injection, (b) Effect of DEX-0 on GTN (500 μg kg⁻¹; i.v.)-induced hypotension in saline- or LPS-treated rats. Data are expressed as mean±s.e.m. of five to eight separate experiments and calculated as percentage of hypotension of MAP versus each basal value. *P<0.05 versus saline-treated rats; ^#P<0.05 versus LPS-treated rats; ^##P<0.005 versus LPS-treated rats.

Figure 3

Effect of RU 38486 (6.6 mg kg⁻¹; i.p.) on CRK (150 μg kg⁻¹; i.v.)-induced hypotension in the presence of DEX-0 (8 mg kg⁻¹; i.p.), in saline- and LPS-treated rats. Data are expressed as mean±s.e.m. of five to eight separate experiments and calculated as percentage of hypotension of MAP versus each basal value. P<0.05 versus LPS-treated rats; ^##P<0.005 versus LPS-treated rats.

Figure 4

Effect of DEX-0 (8 mg kg⁻¹; i.p.), DEX-18 or DEX-23 on GLB (40 mg kg⁻¹; i.p.) increase in MAP in LPS-treated rats. Data are expressed as mean ±s.e.m. of 6–8 separate experiments and calculated as percentage of increase in MAP versus each basal value. ^#P<0.05 versus LPS alone; **P<0.01 versus saline.

Figure 5

DEX-0 (8 mg kg⁻¹; i.p; simultaneously with LPS) effect on the hyporeactivity to PE (30 μg kg⁻¹, i.v.) in LPS-treated rat. Data are expressed as mean±s.e.m. of five to six separate experiments and calculated as increase in MAP (%) versus basal value. ^#P<0.05 versus saline-treated rats; *P<0.05 versus LPS+DEX-0-treated rats.