Imbalance of Angiotensin Receptor Expression and Function in the Spinal Cord: Potential Mechanism of Sympathetic Overactivity in CHF Rats

Abstract

In a recent study we showed that angiotensin II (AII) in the intermediolateral cell column (IML) of the spinal cord plays a critical role in the regulation of mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) in normal rats. In this study, the role of IML AII in sympatho‐excitation of chronic heart failure (CHF) rat induced by coronary‐ligation was studied. AT1R and AT2R expression in the IML was measured by Western blot and immunostaining. Compared with sham rats, CHF rats exhibited a higher AT1R and lower AT2R expression. Then effects of microinjecting AII, losartan (AT1R blocker), or PD123319 (AT2R blocker) into the IML were evaluated. AII evoked significantly stronger pressor and sympatho‐excitatory responses in CHF rats than that in sham rats (ΔMAP: 26 ± 1 vs 15 ± 2 mmHg, RSNA: 210 ± 9 vs 142 ± 6 % of baseline). Losartan significantly decreased basal RSNA and attenuated AII evoked responses in CHF rats, while PD123319 failed to affect MAP and RSNA. Finally, the effect of AII on electrophysiological properties of cultured IML neurons was assessed using whole‐cell patch clamp. AII significantly inhibited the K+ current (from 167 ± 9 to 39 ± 5 pA/pF at +80 mV) and elevated the resting membrane potential (from −55 ± 1 to −31 ± 1 mV). In conclusion, the change of AT1R and AT2R expression in the IML contributes to the sympatho‐excitation in CHF, possibly by elevating neuronal excitability via K+ current inhibition.