Clonidine and Dexmedetomidine Increase the Pressor Response to Norepinephrine in Experimental Sepsis

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Abstract
Objective: During septic shock, vasopressors are a cornerstone of therapy. In septic shock, very high doses of vasopressors sometimes have to be used due to vascular desensitization, the mechanisms of which are poorly understood. This study assesses whether α-2 agonists increase pressor responsiveness following lipopolysaccharide administration. Design: Parallel groups of animals (n = 7 per group) subjected to pharmacologic interventions. Setting: Physiology laboratory. Subjects: Rats. Interventions: In anesthetized rats, the pressor responses to increasing doses of norepinephrine (norepinephrine-systolic pressure curve) were assessed during a baseline period, after injection of saline or lipopolysaccharide, and after subsequent injection of saline, dexmedetomidine (100 μg/kg IV), or clonidine (200 μg/kg IV). Measurements and Main Results: Differences in the slopes of the norepinephrine-pressure curves were assessed across drug treatments and intervals. The pressor dose of norepinephrine necessary to increase systolic pressure by 33 and 100 mm Hg (pressor dose 33 and pressor dose 100) was determined. Pressor responsiveness to norepinephrine decreased slightly over time in the saline-saline group (saline 1 or 2 vs baseline: mean decrease of the slope, 2 mm Hg/μg/kg norepinephrine; p < 0.05), whereas there was a large decrease after lipopolysaccharide (lipopolysaccharide vs baseline: mean decrease of the slope, 7.2; p < 0.001). Clonidine alone had no effect, but when administered following lipopolysaccharide, it caused a striking increase in pressor responsiveness (mean slope after lipopolysaccharide, 10.7 [95% CI, 9.9–11.6]; after clonidine, 17.5 [95% CI, 16.7–18.4]). Similarly, dexmedetomidine administered after lipopolysaccharide caused a large increase in pressor responsiveness above lipopolysaccharide values. Accordingly the pressor dose 33 and pressor dose 100 values were lowered following lipopolysaccharide and restored by α-2 agonists. Conclusions: The pressor response to norepinephrine was reduced following lipopolysaccharide and increased to baseline levels following α-2 agonists.

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