PMID- 28115173
OWN - NLM
STAT- MEDLINE
DCOM- 20170407
LR  - 20170407
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Linking)
VI  - 797
DP  - 2017 Feb 15
TI  - Cyclosporine counteracts endotoxemia-evoked reductions in blood pressure and 
      cardiac autonomic dysfunction via central sGC/MAPKs signaling in rats.
PG  - 143-152
LID - S0014-2999(17)30033-X [pii]
LID - 10.1016/j.ejphar.2017.01.023 [doi]
AB  - The immunosuppressant drug cyclosporine A (CSA) improves survivability in 
      endotoxemia and offsets associated loss in vascular reactivity and hypotension. 
      We tested the hypothesis that central phosphoinositide-3-kinase (PI3K)/soluble 
      guanylate cyclase (sGC)/mitogen activated protein kinases (MAPKs) cascade 
      modulates the CSA counteraction of endotoxic hypotension and cardiac autonomic 
      dysfunction. The effects of pharmacologic inhibition of these molecular 
      substrates in central pools on CSA interaction with cardiovascular responses 
      evoked by lipopolysaccharide (LPS) were evaluated in conscious rats. CSA 
      (10mg/kg) reversed the LPS-evoked (i) hypotension and tachycardia, (ii) decreases 
      in time and spectral measures of heart rate variability (HRV), and (iii) 
      increases in serum TNFalpha and IL-6. These CSA effects disappeared after 
      intracisternal (i.c.) administration of ODQ (sGC inhibitor) but not wortmannin 
      (PI3K inhibitor). When used alone, ODQ or wortmannin abolished the LPS-evoked 
      hypotension and tachycardia, but had no effect on the concomitant reductions in 
      HRV. We also report that the reversal by CSA of LPS hypotension disappeared after 
      treatment with i.c SB203580 (MAPK(p38) inhibitor) or PD98059 (MAPK(ERK) 
      inhibitor), in contrast to little effect for SP600125 (MAPK(JNK) inhibitor). 
      Alternatively, the CSA amelioration of LPS-evoked reductions in HRV was abolished 
      in presence of SP600125 or PD98059, but not SB203580. The single exposure to 
      SP600125 reduced the decreases in blood pressure, but not HRV, caused by LPS 
      whereas SB203580 produced the exact opposite effects. Together, while central 
      sGC/MAPKs circuits modulate the CSA counteraction of endotoxic manifestations, 
      the recruitment of individual MAPKs into this interaction depends on the nature 
      of the cardiovascular response.
CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
FAU - Sallam, Marwa Y
AU  - Sallam MY
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria 
      University, Alexandria, Egypt.
FAU - El-Gowilly, Sahar M
AU  - El-Gowilly SM
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria 
      University, Alexandria, Egypt.
FAU - Abdel-Galil, Abdel-Galil A
AU  - Abdel-Galil AA
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria 
      University, Alexandria, Egypt.
FAU - El-Mas, Mahmoud M
AU  - El-Mas MM
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria 
      University, Alexandria, Egypt. Electronic address: mahelm@hotmail.com.
LA  - eng
PT  - Journal Article
DEP - 20170120
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Lipopolysaccharides)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 4.6.1.2 (Soluble Guanylyl Cyclase)
SB  - IM
MH  - Animals
MH  - Autonomic Nervous System/drug effects/*physiopathology
MH  - Blood Pressure/*drug effects
MH  - Cyclosporine/*pharmacology
MH  - Drug Interactions
MH  - Endotoxemia/pathology/*physiopathology
MH  - Heart/drug effects/*innervation
MH  - Hemodynamics/drug effects
MH  - Lipopolysaccharides/pharmacology
MH  - MAP Kinase Signaling System/*drug effects
MH  - Male
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Soluble Guanylyl Cyclase/*metabolism
OTO - NOTNLM
OT  - Cyclosporine
OT  - Endotoxemia
OT  - Heart rate variability
OT  - Hypotension
OT  - Inflammatory mediators
OT  - Mitogen activated protein kinases
EDAT- 2017/01/25 06:00
MHDA- 2017/04/08 06:00
CRDT- 2017/01/25 06:00
PHST- 2016/12/20 00:00 [received]
PHST- 2017/01/13 00:00 [revised]
PHST- 2017/01/19 00:00 [accepted]
PHST- 2017/01/25 06:00 [pubmed]
PHST- 2017/04/08 06:00 [medline]
PHST- 2017/01/25 06:00 [entrez]
AID - S0014-2999(17)30033-X [pii]
AID - 10.1016/j.ejphar.2017.01.023 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2017 Feb 15;797:143-152. doi: 10.1016/j.ejphar.2017.01.023. Epub 
      2017 Jan 20.