Abstract 261: Chloroquine, an Inhibitor of Endosomal Toll-like Receptors, Improves Blood Pressure and Endothelial Function in Spontaneously Hypertensive Rats

Abstract

HBPR 2014 Circulating mitochondrial DNA (mtDNA) is elevated in spontaneously hypertensive rats (SHR) and the enzyme responsible for its degradation, DNase II, has decreased activity in SHR tissues. Moreover, a synthetic mtDNA mimetic, specific for TLR 9, causes endothelial dysfunction and elevated blood pressure. Therefore, we sought to inhibit the contribution of mtDNA on innate immune system activation, via inhibition of Toll-like receptor (TLR)9, in SHR. We treated 12-15 week old SHR and Wistar-Kyoto rats (WKY) with chloroquine (CQ; 40mg/kg/day) or vehicle (veh; saline) for 21 days via intraperitoneal injection ( i.p. ). We hypothesized that CQ treatment would improve endothelial function and decrease blood pressure in SHR. Blood pressure was measured pre- and post-treatment via tail cuff and endothelial function was measured via mesenteric resistance artery (MRA) relaxation to acetylcholine (ACh; 10 -9 -10 -5 M) using a wire myograph. Treatment with CQ lowered post-systolic blood pressure in SHR (mmHg, Veh: 201±2 vs. CQ: 185±5 mmHg; p<0.05). No effects of treatment were observed on blood pressure in WKY (p>0.05). CQ abolished the contractile effect to high concentrations of ACh [AUC (%NE pre-contraction), Veh: 160±25 vs. CQ: 277±20; p<0.05] in MRA from SHR. However, no differences were observed in endothelium-independent relaxation to NO-donor sodium nitroprusside [E max (%NE pre-contraction), Veh: 97±12 vs. CQ: 102±26; p<0.05] in MRAs from SHR. Again, no effects of treatment were observed for endothelium-dependent or -independent relaxation in WKY (p>0.05). These data demonstrate the inhibition of endosomal TLRs, including TLR9, improves blood pressure and endothelial function in SHR. Inhibition of TLR9 abrogates the potentially deleterious contribution of increased mtDNA and impaired DNase II activity on innate immune system activation in hypertension.