Abstract 1594: p44/42 Mitogen-Activated Protein Kinase Differentially Mediates Sympathetic Excitation in Heart Failure Rats
Introduction: Chronic heart failure (HF) is characterized by increased renin-angiotensin system activity and sympathetic drive. Angiotensin II (ANG II) acting at angiotensin type 1 receptor, triggers multiple intracellular signaling cascades involved in cardiovascular regulation and sympathetic nervous activity. ANG II robustly activates mitogen-activated protein kinase (MAPK) dependent signaling pathways that have been implicated in myocardial hypertrophy and inflammation in the periphery and neurotransmitter release in the brain.
Hypothesis: MAPK-dependent signaling pathways contribute to sympathetic excitation in HF rats.
Methods: HF and sham rats were produced by coronary ligation or sham ligation, respectively, 6 wks prior to study. All drugs were infused intracerebroventricularly (ICV, 40μl/hr) for a period of 1 hour. Mean arterial pressure (MAP, mmHg), heart rate (HR, bpm), renal and lumbar sympathetic nerve activity (RSNA and LSNA respectively, % change) were recorded in urethane-chloralose anesthetized rats.
Results: In HF rats (n=7), ICV infusion of PD98059 (0.025μg/μl), a selective p44/42 MAPK inhibitor, induced significant (p<0.05) decreases in MAP (−11.6 ± 2.0), HR (−17.8 ± 5.4) and RSNA (−63.1 ± 12.2), but had no effect on these variables in sham rats (n=4). ICV infusion of U0126 (0.05μg/μl), another selective p44/42 MAPK inhibitor, also significantly (p<0.05) reduced MAP (−14.4 ± 3.5), HR (−10.6 ± 3.3) and RSNA (−40.2 ± 5.6) in HF (n=4) but not in sham rats (n=4). In contrast, ICV infusion of PD98059 did not elicit obvious change on LSNA (−4.5 ± 3.0, n=4), even though MAP (−10.1 ± 3.5) and HR (−15.8 ± 4.9) were decreased. ICV infusion of the p38 MAPK inhibitor SB203580 (0.25μg/μl) and the c-Jun N-terminal kinase inhibitor SP600125 (0.1μg/μl) had no effect on MAP, HR or RSNA in HF (n=4) or sham (n=4) rats.
Conclusion: These data indicate that p44/42 is a critical intracellular signaling molecule in the MAPK pathway regulating renal but not lumbar sympathetic nerve activity in heart failure. Other MAPK are not involved. Further studies will assess whether ANG II drives the p44/42 MAPK-mediated renal sympathetic activation in HF.