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Cyclosporine Ameliorates Reductions in Blood Pressure and Heart Rate Variability Caused by Endotoxemia in Rats: Modulation by Central PI3K/sGC/MAPKs Signaling
Author(s) -
ElMas Mahmoud M,
Sallam Marwa Y,
AbdelGalil AbdelGalil A,
ElGowilly Sahar M
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1200.3
Subject(s) - wortmannin , mapk/erk pathway , blood pressure , pharmacology , medicine , heart rate , kinase , endocrinology , p38 mitogen activated protein kinases , lipopolysaccharide , pi3k/akt/mtor pathway , chemistry , signal transduction , biochemistry
Cyclosporine A (CSA) improves survivability in endotoxemia and offsets the associated loss in vascular reactivity and hypotension. We tested the hypothesis that CSA abrogates the reduced blood pressure (BP) and cardiac autonomic dysfunction in endotoxic rats via the modulation of phosphoinositide‐3‐kinase (PI3K)/soluble guanylate cyclase (sGC)/mitogen activated protein kinases (MAPKs) cascade in central neurons. The effects of individual pharmacologic inhibition of these molecular substrates on the interaction of CSA with hemodynamic and cardiac autonomic responses, as reflected by heart rate variability (HRV) measurement, evoked by lipopolysaccharide (LPS) were evaluated. CSA (10 mg/kg i.v.) reversed the decreases in BP and increases in HR elicited by LPS (10 mg/kg i.v.) in conscious rats. Likewise, the decreases caused by LPS in time‐domain (standard deviation of beat‐to‐beat intervals, SDRR, and the root mean square of successive beat‐to‐beat differences in R‐R intervals, rMSSD) and frequency domain (total power and low and high‐frequency spectral powers) measures of HRV were abolished by CSA. These advantageous effects of CSA disappeared in endotoxic rats treated intracisternally (i.c.) with ODQ (sGC inhibitor) in contrast to no effect for wortmannin (PI3K inhibitor). We also report divergent roles for central MAPKs in the CSA‐LPS interaction. The reversal by CSA of the hypotensive effect of LPS disappeared in rats treated concurrently with i.c SB203580 (MAPK p38 inhibitor) or PD98059 (MAPK ERK inhibitor), in contrast to little effect for SP600125 (MAPK JNK inhibitor). Alternatively, the amelioration by CSA of the LPS‐evoked reductions in HRV was abolished in presence of SP600125 or PD98059, but not SB203580. Collectively, the facilitation of central circuits of sGC/MAPKs contributes to CSA counteraction of the cardiovascular actions of endotoxemia. However, the identity of the MAPK isoform involved in the CSA‐LPS interaction largely depends on the specificity of the cardiovascular response. Support or Funding Information Supported by the Science and Technology Development Fund, Egypt (STDF Grant No. 14895).