Abstract 16493: Neuregulin-1/ErbB Pathway Modulation of Major Neurotransmitters in the Cardiovascular Center is Crucial for Neural Regulation of Blood Pressure -Possible Involvement of Neuregulin-1/ErbB Pathway in Neural Mechanisms of Hypertension-
Background: Neuregulin-1 (NRG-1) is a member of the epidermal growth factor (EGF) family. The biological effects of NRG-1 are mediated by a set of tyrosine kinase receptors (ErbB2, ErbB3, and ErbB4) that dimerize on ligand binding, thereby inducing phosphorylation and downstream signaling. In the brain, NRG-1 affects both glutamatergic and γ-aminobutyric acid (GABA)-ergic function, but its physiological role in the brainstem remains unknown.
Hypothesis: The NRG-1/ErbB pathway in the brainstem contributes to neural blood pressure regulation and thus plays a pivotal role in the pathogenesis of neural hypertension.
Methods and Results: NRG-1 (5.0–500 nM) microinjected into the rostral ventrolateral medulla (RVLM) in anesthetized Wistar rats dose-dependently decreased mean arterial pressure (MAP) and heart rate (HR; n=5 each). Injection of NRG-1 into the RVLM attenuated a glutamate-induced pressor response (ΔMAP 10.8±0.6 vs. 23.4±1.0mmHg, p<0.01), whereas injection of a GABA-A receptor antagonist into the RVLM attenuated a NRG-1 induced-depressor response (ΔMAP −4.6±2.0 vs. −22.9±2.9mmHg; n=5 for each, p<0.01). The depressor response of microinjected NRG-1 into the RVLM was significantly smaller in SHR than in WKY (ΔMAP −23.3±2.5 vs. −12.5±1.7 mmHg, n=5 for each, p<0.01). Although NRG-1, ErbB2, and ErbB4 are expressed (Western blotting) in the brainstem in spontaneously hypertensive rats (SHR) and Wistar Kyoto-rats (WKY; 4 and 12 weeks old), ErbB2 expression levels were significantly lower in SHR than in WKY (n=3 for each, p<0.05). ErbB2 antagonist (10μM) microinjected into the RVLM in anesthetized Wistar rats increased MAP and HR (ΔMAP 17.6±2.3mmHg, ΔHR 16.5±1.1bpm, n=5). Furthermore, chronic intracisternal infusion (14 days) of an ErbB2 antagonist increased telemetrically measured MAP and HR and increased sympathetic nerve activity in Wistar rats (n=5).
Conclusions: The NRG-1/ErbB pathway in the RVLM contributes to neural blood pressure regulation through its sympathoinhibitory effects. The NRG-1/ErbB pathway manifests its sympathoinhibitory effects by decreasing glutamatergic function and increasing GABA-ergic function. Dysfunction of the NRG-1/ErbB pathway in the RVLM is a possible neural mechanism of hypertension in SHR.
- © 2010 by American Heart Association, Inc.