Abstract 5835: Brain Calcium/Calmodulin Dependent Protein Kinase II Contributes to Angiotensin II-induced Sympatho-excitatory Responses in Heart Failure Rats
Introduction: Recent studies show that calcium/calmodulin dependent protein kinase II (CaMKII) plays an important role in angiotensin II (ANG II)-mediated remodeling in heart failure (HF). ANG II is a major neurohumoral factor contributing to augmented sympathetic drive in heart failure. The link between brain ANG II and CaMKII in regulating sympathetic nerve activity has not been studied.
Hypothesis: Brain CaMKII mediates ANG II-induced sympatho-excitatory responses in HF.
Methods: Normal rats, rats with HF induced by coronary artery ligation, and sham-operated controls (SHAM) were studied. Immunohistochemical (c-fos) and immunofluorescent (phosphorylated [p]-p44/42 MAPK) studies of hypothalamic paraventricular nucleus (PVN) were performed in normal rats infused for 2 hr with intracerebroventricular (ICV) ANG II and in HF and SHAM rats that were treated for 4 wks with ICV vehicle, CaMKII inhibitor KN-93 (0.25 μg/hr), O2− scavenger tempol (25 μg/hr), or AT1 receptor antagonist losartan (1.15 μg/hr). Renal sympathetic nerve activity (RSNA), mean blood pressure (MBP) and heart rate (HR) were recorded in untreated anesthetized HF or SHAM rats at 4 wks, and in baroreceptor denervated normal rats treated acutely with ICV ANG II before and after ICV KN-93 (5 μg).
Results: Compared with vehicle, chronic ICV treatment with KN-93, losartan or tempol reduced c-fos and p-p44/42 MAPK activity in PVN in HF rats. Continuous 2 hr ICV infusion of ANG II (500 ng/hr) increased c-fos and p-p44/42 MAPK expression in PVN of normal rats; these responses were reduced by concomitant ICV infusion of KN-93 (50 μg/hr). In acute experiments, ICV administration of KN-93 significantly (*p<0.05) reduced RSNA (−9.9±0.7 %*), MBP (−8.7±1.0 mmHg*) and HR (−15.8±2.5 bpm*) in HF rats, but not in SHAM rats. In baroreceptor denervated rats, ICV ANG II (100 ng/kg) increased RSNA (12.2±1.3 %*), MBP (21.7±2.8 mmHg*) and HR (12.2±0.8 bpm*); these responses were significantly (p<0.05) reduced by pretreatment with ICV KN-93.
Conclusion: Inhibition of central CaMKII reduces p44/42 MAPK expression and neuronal excitation in the PVN of rats with HF. The data suggest that CaMKII contributes to ANG II-induced activation of the sympathetic nervous system in HF by stimulating MAPK activity.