The effects of enalapril and losartan on mechanical ventilationeinduced sympathoadrenal activation and oxidative stress in rats Hale Zerrin Toklu, PhD, a,b,c, * Oh-Sung Kwon, PhD, d Yasemin Sakarya, a,b Scott K. Powers, PhD, d Katherine Llinas, a Nataliya Kirichenko, MSc, a,b Kurt J. Sollanek, MSc, d Michael P. Wiggs, PhD, d Ashley J. Smuder, PhD, d Erin E. Talbert, PhD, d Philip J. Scarpace, PhD, b and Nihal Tu ¨ mer, PhD a,b, ** a Malcom Randall Veterans Affairs Medical Center, Geriatric Research Education and Clinical Center, Gainesville, Florida b Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, Florida c Department of Pharmacology, Marmara University School of Pharmacy, Istanbul, Turkey d Department of Applied Physiology and Kinesiology, College of Health & Human Performance, University of Florida, Gainesville, Florida article info Article history: Received 1 November 2013 Received in revised form 7 January 2014 Accepted 30 January 2014 Available online xxx Keywords: Mechanical ventilation Angiotensin Losartan Enalapril NPY Thyrosine hydroxylase Dopamine beta hydroxylase Sympathetic Noradrenergic Norepinephrine abstract Background: Mechanical ventilation (MV) is a method of maintaining appropriate gas ex- change in patients who are unable to sustain adequate alveolar ventilation. While life- saving in the short-term, prolonged MV leads to altered cardiovascular responses and enhanced lung injury, but the exact mechanism is unknown. Therefore, we investigated the involvement of the sympathoadrenergic and renineangiotensin system in MV-induced altered cardiovascular responses. Methods: SpragueeDawley rats were divided into six groups: (1) spontaneous breathing (SB); (2) SB þ enalapril (100 mg/kg intravenous infusion); (3) SB þ losartan (100 mg/kg infusion); (4) 12 h of MV; (5) MV þ enalapril; and (6) MV þ losartan. After the animals were sacrificed, blood and tissue samples were collected. Tyrosine hydroxylase, dopamine beta hydroxy- lase, and neuropeptide Y were measured in adrenal medulla and hypothalamus, whereas AT1 was measured in lung tissues by Western blot. Norepinephrine enzyme-linked immunosorbent assay and total antioxidant capacity were assayed in plasma. Results: Our findings indicated that MV increases the sympathetic activation markers in ad- renal medulla and hypothalamus. Moreover, oxidative stress was increased in lung and brain tissues. Treatment with enalapril or losartan reduced the lipid peroxidation in lung and brain tissues, while preserving the tissue glutathione content and plasma antioxidant capacity. Conclusions: These data demonstrate that the inhibition of the renineangiotensin system by enalapril or losartan may reduce the MV-induced increase in sympathetic activity markers and oxidative stress, and thus, may have a beneficial effect as adjuvant therapy. ª 2014 Elsevier Inc. All rights reserved. * Corresponding author. Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, P.O. Box 100267, Gainesville, FL 32610. ** Corresponding author. Pharmacology & Therapeutics, College of Medicine, University of Florida, P.O. Box 100267, Gainesville, FL 32610. E-mail addresses: [email protected](H.Z. Toklu), ntumer@ufl.edu (N. Tu ¨ mer). Available online at www.sciencedirect.com ScienceDirect journal homepage: www.JournalofSurgicalResearch.com journal of surgical research xxx (2014) 1 e7 0022-4804/$ e see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2014.01.054
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j o u rn a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1e7
The effects of enalapril and losartan on mechanicalventilationeinduced sympathoadrenal activationand oxidative stress in rats
Hale Zerrin Toklu, PhD,a,b,c,* Oh-Sung Kwon, PhD,d Yasemin Sakarya,a,b
Scott K. Powers, PhD,d Katherine Llinas,a Nataliya Kirichenko, MSc,a,b
Kurt J. Sollanek, MSc,d Michael P. Wiggs, PhD,d Ashley J. Smuder, PhD,d
Erin E. Talbert, PhD,d Philip J. Scarpace, PhD,b and Nihal Tumer, PhDa,b,**aMalcom Randall Veterans Affairs Medical Center, Geriatric Research Education and Clinical Center, Gainesville,
FloridabDepartment of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FloridacDepartment of Pharmacology, Marmara University School of Pharmacy, Istanbul, TurkeydDepartment of Applied Physiology and Kinesiology, College of Health & Human Performance, University of Florida,
Gainesville, Florida
a r t i c l e i n f o
Article history:
Received 1 November 2013
Received in revised form
7 January 2014
Accepted 30 January 2014
Available online xxx
Keywords:
Mechanical ventilation
Angiotensin
Losartan
Enalapril
NPY
Thyrosine hydroxylase
Dopamine beta hydroxylase
Sympathetic
Noradrenergic
Norepinephrine
* Corresponding author. Department of PhaGainesville, FL 32610.** Corresponding author. Pharmacology & The
E-mail addresses: [email protected]/$ e see front matter ª 2014 Elsevhttp://dx.doi.org/10.1016/j.jss.2014.01.054
a b s t r a c t
Background: Mechanical ventilation (MV) is a method of maintaining appropriate gas ex-
change in patients who are unable to sustain adequate alveolar ventilation. While life-
saving in the short-term, prolonged MV leads to altered cardiovascular responses and
enhanced lung injury, but the exact mechanism is unknown. Therefore, we investigated
the involvement of the sympathoadrenergic and renineangiotensin system in MV-induced
altered cardiovascular responses.
Methods: SpragueeDawley rats were divided into six groups: (1) spontaneous breathing (SB);
12 h of MV; (5) MV þ enalapril; and (6) MV þ losartan. After the animals were sacrificed,
blood and tissue samples were collected. Tyrosine hydroxylase, dopamine beta hydroxy-
lase, and neuropeptide Y were measured in adrenal medulla and hypothalamus, whereas
AT1 was measured in lung tissues by Western blot. Norepinephrine enzyme-linked
immunosorbent assay and total antioxidant capacity were assayed in plasma.
Results: Our findings indicated that MV increases the sympathetic activation markers in ad-
renal medulla and hypothalamus. Moreover, oxidative stress was increased in lung and brain
tissues. Treatment with enalapril or losartan reduced the lipid peroxidation in lung and brain
tissues, while preserving the tissue glutathione content and plasma antioxidant capacity.
Conclusions: These data demonstrate that the inhibition of the renineangiotensin system by
enalapril or losartan may reduce the MV-induced increase in sympathetic activity markers
and oxidative stress, and thus, may have a beneficial effect as adjuvant therapy.
ª 2014 Elsevier Inc. All rights reserved.
rmacology and Therapeutics, College of Medicine, University of Florida, P.O. Box 100267,
rapeutics, College of Medicine, University of Florida, P.O. Box 100267, Gainesville, FL 32610.(H.Z. Toklu), [email protected] (N. Tumer).ier Inc. All rights reserved.
Table e Plasma total antioxidant capacity (tAOC) expressed as copper reducing equivalent (CRE) and NE concentrations inSB, enalapril, losartan, and MV groups at 12 h. Each group consists of six to eight rats.*P < 0.05 versus SB and D P < 0.05versus MV. Values are presented as mean ± standard error of mean.
j o u rn a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1e7 7
renineangiotensin system with the MV-induced sympathetic
activation (Fig. 4), further studies are needed to elucidate the
detailed mechanisms and implement it into the clinical
setting.
Acknowledgment
This work was supported by the Medical Research Service of
the Department of Veterans Affairs. The authors declare that
they have no conflict of interest.
Author contributions: H.Z.T. collected the data, performed
statistical analysis, and prepared the manuscript. O-S.K.
adapted the animal model, performed the surgery, and
collected the data. Y.S., K.L., and N.K. collected the data and
performed analysis. K.J.S., M.P.W., A.J.S., and E.E.T performed
the surgery, followup the animals, and collected the data. S.P.,
P.J.S., and N.T. were responsible for experimental design and
prepared the manuscript.
Disclosure
The authors reported no proprietary or commercial interest in
any product mentioned or concept discussed in this article.
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