Abstract 415: Brain Epidermal Growth Factor Receptor and c-Src Tyrosine Kinase Contribute to Sympathetic Excitation Induced by Systemically Administered Aldosterone in Rats

Abstract

Introduction: Epidermal growth factor receptor (EGFR) and c-Src tyrosine kinase mediate multiple functions of aldosterone and angiotensin II in peripheral cardiovascular tissues by regulating mitogen-activated protein kinase (MAPK) signaling. Hypothesis: EGFR and c-Src activity in cardiovascular regions of the brain contribute to sympatho-excitatory responses induced by circulating aldosterone. METHODS: In anesthetized rats, we recorded renal sympathetic nerve activity (RSNA), mean blood pressure (MBP) and heart rate (HR) at baseline and for 4 hours during intravenous infusion of aldosterone (30 μg/hr), with or without concomitant intracerebroventricular (ICV) infusion of the EGFR inhibitor AG1478 (1 nmol/hr), the mineralocorticoid receptor (MR) antagonist RU28318 (10 μg/hr) or the p44/42 MAPK inhibitor PD98059 (5 μg/hr), or pretreatment with a bolus ICV injection of the c-Src inhibitor SU6656 (1 nmol). In some rats, hypothalamic paraventricular nucleus (PVN) tissues were collected to examine the expression of phosphorylated p44/42 MAPK. Results: Aldosterone infusion significantly (*p<0.05 vs baseline) increased RSNA (25.3 ± 4.6 %*), MBP (9.8 ± 2.2 mmHg*) and HR (28.2 ± 6.2 bpm*), as well as the PVN expression of phosphorylated p44/42 MAPK (86%, p<0.05), as compared with vehicle. Concomitant ICV infusion of the EGFR inhibitor AG1478 significantly (†p<0.05 vs aldosterone alone) diminished the phosphorylation of p44/42 MAPK (28 %†) in PVN and the increases in RSNA (3.6 ± 1.5 %†), MBP (3.2 ± 1.3 mmHg†) and HR (5.3 ± 5.1 bpm†) induced by aldosterone. ICV pretreatment with the c-Src inhibitor SU6656 had similar significant (p<0.05) inhibitory effects on the RSNA, MBP and HR responses to aldosterone. Concomitant ICV infusion of either the MR antagonist RU28318 or the p44/42 MAPK inhibitor PD98059 prevented the aldosterone-induced sympathetic excitation. Conclusion: Central inhibition of EGFR and c-Src significantly reduced the brain MR- and MAPK-dependent sympathetic excitation elicited by systemically administered aldosterone. Brain EGFR and c-Src are potential therapeutic targets for cardiovascular disease states characterized by high circulating levels of aldosterone.