Bilateral Renal Denervation Ameliorates Isoproterenol-Induced Heart Failure through Downregulation of the Brain Renin-Angiotensin System and Inflammation in Rat.

Heart failure (HF) is characterized by cardiac dysfunction along with autonomic unbalance that is associated with increased renin-angiotensin system (RAS) activity and elevated levels of proinflammatory cytokines (PICs). Renal denervation (RD) has been shown to improve cardiac function in HF, but the protective mechanisms remain unclear. The present study tested the hypothesis that RD ameliorates isoproterenol- (ISO-) induced HF through regulation of brain RAS and PICs. Chronic ISO infusion resulted in remarked decrease in blood pressure (BP) and increase in heart rate and cardiac dysfunction, which was accompanied by increased BP variability and decreased baroreflex sensitivity and HR variability. Most of these adverse effects of ISO on cardiac and autonomic function were reversed by RD. Furthermore, ISO upregulated mRNA and protein expressions of several components of the RAS and PICs in the lamina terminalis and hypothalamic paraventricular nucleus, two forebrain nuclei involved in cardiovascular regulations. RD significantly inhibited the upregulation of these genes. Either intracerebroventricular AT1-R antagonist, irbesartan, or TNF-α inhibitor, etanercept, mimicked the beneficial actions of RD in the ISO-induced HF. The results suggest that the RD restores autonomic balance and ameliorates ISO-induced HF and that the downregulated RAS and PICs in the brain contribute to these beneficial effects of RD.

Activation of central PPAR-γ attenuates angiotensin II-induced hypertension.

Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that the activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg per minute) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA-binding activity was reduced. mRNA for interleukin-1ß, tumor necrosis factor-α, cyclooxygenase-2, and angiotensin II type 1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA-binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension.

Early interference with p44/42 mitogen-activated protein kinase signaling in hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension.

Blood-borne angiotensin II (ANG II) can upregulate p44/42 mitogen-activated protein kinase (MAPK) signaling and ANG II type-1 receptors in the hypothalamic paraventricular nucleus (PVN), a critical cardiovascular and autonomic center. We tested the hypothesis that brain p44/42 MAPK signaling contributes to the development of ANG II-induced hypertension. The ANG II infusion (120 ng/kg per min, subcutaneously) induced increases in phosphorylated p44/42 MAPK and ANG II type-1 receptors in the PVN after 1 week, before the onset of hypertension, that were sustained as hypertension developed during a 2- or 3-week infusion protocol. Bilateral PVN microinjections of small interfering RNAs for p44/42 MAPK, at the onset of the ANG II infusion or 1 week later, prevented the early increase in p44/42 MAPK activity. The early treatment normalized ANG II type-1 receptor expression in the PVN and attenuated the hypertensive response to the 2-week infusion of ANG II. The later small interfering RNA microinjections had a transient effect on ANG II type-1 receptor expression in PVN and no effect on the hypertensive response to the 3-week infusion of ANG II. The early treatment also normalized the pressure response to ganglionic blockade. The ANG II infusion induced increases in mRNA for proinflammatory cytokines that were not affected by either small interfering RNA treatment. These results suggest that the full expression of ANG II-induced hypertension depends on p44/42 MAPK-mediated effects. A potential role for p44/42 MAPK in modulating the ANG II-induced central inflammatory response might also be considered. MAPK signaling in PVN may be a novel target for early intervention in the progression of ANG II-dependent hypertension.