Shinichi Asano1, Nandini D P K Manne2, Geeta Nandyala3, Bing Ma4, Vellaisamy Selvaraj4, Ravikumar Arvapalli3, Kevin M Rice3, Eric R Blough5. 1. Center for Diagnostic Nanosystems, Marshall University, Huntington, WV, USA; Department of Pharmaceutical Sciences and Research, School of Pharmacy, Marshall University, Huntington, WV, USA. Electronic address: sasano@hsc.wvu.edu. 2. Center for Diagnostic Nanosystems, Marshall University, Huntington, WV, USA; Department of Pharmaceutical Sciences and Research, School of Pharmacy, Marshall University, Huntington, WV, USA; Department of Public Health, Marshall University, Huntington, WV, USA. 3. Center for Diagnostic Nanosystems, Marshall University, Huntington, WV, USA. 4. Center for Diagnostic Nanosystems, Marshall University, Huntington, WV, USA; Department of Pharmaceutical Sciences and Research, School of Pharmacy, Marshall University, Huntington, WV, USA. 5. Center for Diagnostic Nanosystems, Marshall University, Huntington, WV, USA; Department of Pharmaceutical Sciences and Research, School of Pharmacy, Marshall University, Huntington, WV, USA; Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA.
Abstract
AIMS: Sepsis is a life threatening condition that is characterized by the loss of vascular reactivity. The factor(s) responsible for the diminished vascular function seen in sepsis are not well understood. The purpose of this study was to characterize the vascular dysfunction from the rat cecal inoculum (CI) sepsis model using cecal ligation and puncture (CLP), and lipopolysaccharide (LPS) sepsis as reference models. MATERIALS AND METHODS: Experiments were performed on isolated aorta from CI, CLP and LPS treated rats using a combination of pharmacological approaches. KEY FINDINGS: Phenylephrine (PE)-induced aortic contraction was significantly decreased in each model (p<0.05) and not normalized by L-NAME or indomethacin. The vascular response elicited in the CI model for acetylcholine (Ach) was more similar to that seen in the CLP than the LPS model. The removal of the endothelial layer increased sensitivity to L-NAME (p<0.05) in aortae from CI group. Inhibition of the large conductance Ca(2+)/voltage sensitive K(+) (BKCa) channel did not normalize PE hyporesponsiveness but did abolish sepsis-induced contractile oscillation. Inhibition of the voltage dependent Kv1.5 channel was not able to reverse the vascular hyporesponsiveness, however, inhibition of the ATP dependent (KATP) channel inhibition partially restored the contractile response (p<0.05). Elevation of VCAM expression and aortic structural alternation were observed in each model. SIGNIFICANCE: These results suggest that the CI model may be an additional tool that could be used to investigate the mechanisms of vascular hyporesponsiveness in sepsis.
AIMS: Sepsis is a life threatening condition that is characterized by the loss of vascular reactivity. The factor(s) responsible for the diminished vascular function seen in sepsis are not well understood. The purpose of this study was to characterize the vascular dysfunction from the rat cecal inoculum (CI) sepsis model using cecal ligation and puncture (CLP), and lipopolysaccharide (LPS) sepsis as reference models. MATERIALS AND METHODS: Experiments were performed on isolated aorta from CI, CLP and LPS treated rats using a combination of pharmacological approaches. KEY FINDINGS:Phenylephrine (PE)-induced aortic contraction was significantly decreased in each model (p<0.05) and not normalized by L-NAME or indomethacin. The vascular response elicited in the CI model for acetylcholine (Ach) was more similar to that seen in the CLP than the LPS model. The removal of the endothelial layer increased sensitivity to L-NAME (p<0.05) in aortae from CI group. Inhibition of the large conductance Ca(2+)/voltage sensitive K(+) (BKCa) channel did not normalize PEhyporesponsiveness but did abolish sepsis-induced contractile oscillation. Inhibition of the voltage dependent Kv1.5 channel was not able to reverse the vascular hyporesponsiveness, however, inhibition of the ATP dependent (KATP) channel inhibition partially restored the contractile response (p<0.05). Elevation of VCAM expression and aortic structural alternation were observed in each model. SIGNIFICANCE: These results suggest that the CI model may be an additional tool that could be used to investigate the mechanisms of vascular hyporesponsiveness in sepsis.
Authors: Shinichi Asano; Grant C O'Connell; Kent C Lemaster; Evan R DeVallance; Kayla W Branyan; James W Simpkins; Jefferson C Frisbee; Taura L Barr; Paul D Chantler Journal: Exp Physiol Date: 2017-09-02 Impact factor: 2.969