Central Pathways of MAPKp38 and MAPKJNK Mediate TNFα/iNOS‐Dependent Endotoxic Manifestations of Hypotension and Compromised Heart Rate Variability in Rats

Abstract

We investigated whether TNFα‐coupled mitogen‐activated protein kinases (MAPKs) in central neurons modulate the early hemodynamic responses evoked by endotoxemia in rats. Changes in blood pressure (BP), heart rate (HR), and HR variability (HRV) caused by i.v. lipopolysaccharide (LPS, 10 mg/kg) were assessed in absence and presence of pharmacologic inhibitors of TNFα, inducible nitric oxide synthase (iNOS), MAPKERK1/2, MAPKp38, or MAPKJNK. Compared with saline, LPS caused significant falls in BP and increases in HR that appeared 30 min post treatment and continued for the following 60 min. The time (standard deviation of beat‐to‐beat intervals, SDNN, and the root mean square of successive beat‐to‐beat differences in R‐R intervals, rMSSD) and frequency domain indices (total power and spectral bands of low and high‐frequency) of HRV were all reduced by LPS. The inhibition of TNFα (pentoxifylline) or iNOS (aminoguanidine) abolished the hemodynamic and HRV effects of LPS. Intracisternal (i.c.) injection of ODQ (guanylate cyclase inhibitor), wortmannin (PI3K inhibitor), SP600125 (MAPKJNK inhibitor) mitigated the LPS‐evoked reductions in BP and HR, but failed to affect the associated decreases in HRV. MAPKp38 inhibition by i.c. SB203580 produced exactly the opposite effects. The reduction in BP or HRV caused by LPS remained unaltered after i.c. PD98059, suggesting no role for MAPKERK1/2 in the LPS responses. Together, the data suggest that central TNFα/iNOS/GC/PI3K pathways linked to MAPKp38 and MAPKJNK are pivotal for provoking the reductions in BP and HRV, respectively, seen during endotoxic shock.