Modulation by Central MAPKs/PI3K/sGc of the TNF-α/iNOS-dependent Hypotension and Compromised Cardiac Autonomic Control in Endotoxic Rats.
Reduced blood pressure (BP) and cardiac autonomic activity are early manifestations of endotoxemia. We investigated whether these effects are modulated by central mitogen-activated protein kinases (MAPKs) and related phosphoinositide-3-kinase (PI3K)/soluble guanylate cyclase (sGC) signaling in conscious rats. The effect of pharmacologic inhibition of these molecular substrates on BP, heart rate (HR), and heart rate variability (HRV) responses evoked by intravascular lipopolysaccharide (LPS) (10 mg/kg) were assessed. LPS (1) lowered BP (2) increased HR, (3) reduced time [SD of beat-to-beat intervals (SDNN), and root mean square of successive differences in R-R intervals (rMSSD)], and frequency domain indices of HRV (total power and spectral bands of low and high-frequency), and (4) elevated serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels. The inhibition of TNF-α (pentoxifylline) or inducible nitric oxide synthase (iNOS, aminoguanidine) abolished hemodynamic, HRV, and inflammatory actions of LPS. Intracisternal (i.c.) injection of ODQ (sGC inhibitor), wortmannin (PI3K inhibitor), and SP600125 (MAPKJNK inhibitor) mitigated the hypotensive and tachycardic actions of LPS but failed to affect associated decreases in HRV. MAPKp38 inhibition by i.c. SB203580 produced exactly opposite effects. None of the LPS effects was altered after i.c. PD98059 (MAPKERK1/2 inhibitor). Overall, central MAPKs/PI3K/sGC pathways variably contribute to the TNF-α/iNOS-dependent reductions in BP and HRV seen during endotoxic shock.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Marwa Y
MY
Sallam
Sahar M
SM
El-Gowilly
Abdel-Galil A
AG
Abdel-Galil
Mahmoud M
MM
El-Mas
D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D001794:Blood Pressure; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000294:innervation*; D006339:Heart Rate; D007022:Hypotension / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D008070:Lipopolysaccharides; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017208:Rats, Wistar; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013610:Tachycardia / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D058539:Phosphatidylinositol 3-Kinase; D020928:Mitogen-Activated Protein Kinases; D000071756:Soluble Guanylyl Cyclase