Abstract 11436: Brain Senses the Circulating Angiotensin II Subsequently Leading to Left Ventricular Diastolic Dysfunction through the Central Sympathoexcitation
Background: Sympathoexcitation contributes to the progression of heart failure (HF). Although activation of brain angiotensin II (Ang II) type 1 receptors (AT1R) causes central sympathoexcitation, it remains unknown whether the circulating Ang II level observed in HF induces central sympathoexcitation and leads to cardiac dysfunction. In the brain, subfornical organ (SFO) is one of the primary sensors for circulating Ang II, and rostral ventrolatreal medulla (RVLM) is the cardiovascular center determining sympathetic activity. Thus, we assessed the hypothesis that the increase in circulating Ang II comparable to that reported in HF model affects cardiac function through the central sympathoexcitation via activating AT1R in the SFO and RVLM.
Methods and Results: In Sprague-Dawley rats, the subcutaneous infusion of Ang II at 100 ng/kg/min for 14 days increased the circulating Ang II level comparable to that reported in HF model rats after myocardial infarction (100±9l vs. 42±6 pg/ml, n=8, p<0.01). In comparison with the control, Ang II infusion increased the AT1R expression level within the RVLM as well as SFO (n=4, p<0.05), urinary norepinephrine excretion (1.25±0.03 vs. 0.92±0.05 μ g/24 hrs, n=8, p<0.01), and systolic blood pressure (139±1 vs. 126±1 mmHg, n=8, p<0.01). Ang II infusion hypertrophied left ventricular (LV) (2D echo, IVS+PW thickness: 3.63±0.08 vs. 3.26±0.09 mm, n=8, p<0.01) without changing chamber dimensions while increased end-diastolic pressure (5.0±0.3 vs. 2.7±0.3 mmHg, n=8, p<0.01). The LV pressure-volume relationship (conductance volumetry) indicated that Ang II did not impact on the end-systolic elastance, whereas significantly increased end-diastolic elastance (the stiffness constant (EDPVR): 0.040±0.003 vs. 0.024±0.002, n=4, p<0.01). Chronic intracerebroventricular infusion of AT1R blocker, losartan (660 ng/kg/min), attenuated these Ang II-induced changes.
Conclusion: Circulating Ang II in HF is capable of inducing sympathoexcitation through the activation of AT1R in the SFO and RVLM, subsequently leading to LV diastolic dysfunction.
- © 2012 by American Heart Association, Inc.