Abstract 243: Chloroquine Treatment Increases the Threshold of Aortic Contractile Responses to Norepinephrine in a Nitric Oxide Synthase-dependent Manner in Spontaneously Hypertensive Rats

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Abstract

Toll-like receptors (TLRs) are pattern recognition receptors of the innate immune system that are located either on the plasma membrane or on membrane of endosomes. TLR activation in immune cells leads to a pro-inflammatory phenotype and TLRs have been associated with the development of hypertension. However, the role of TLRs in the development of vascular dysfunction, a hallmark of hypertension, has not been extensively investigated. Chloroquine (CQ), due to its ability to inhibit autophagy and block lysosomal degradation, has been used as a non-specific inhibitor of TLRs located on endosomes. We hypothesized that treatment with CQ (40mg/kg/day) for 21 days would attenuate aortic contractile responses in young spontaneously hypertensive rats (SHRs; 5-6 weeks old) compared to saline (Veh) control. Concentration response curves to norepinephrine (NE; 10-11-10-6 M), in the presence or absence of nitric oxide synthase (NOS) inhibitor L-NNA (10-4 M), were performed in isolated aortic rings ex vivo on a pin myograph. CQ increases the threshold of aortic contractile responses to NE compared to Veh (logEC20 CQ: -8.8±0.1 vs. Veh: -9.6±0.3, p<0.05). In the presence of L-NNA, there was a significant difference between CQ and CQ+L-NNA (logEC20 CQ: -8.8±0.1 vs. CQ+L-NNA: -9.4±0.2, *p<0.05) (A); however, this difference was absent between Veh and Veh+L-NNA (logEC20 Veh: -9.4±0.3 vs. Veh+L-NNA: -10.0±0.4, p>0.05) (B). These data illustrate that CQ improves the threshold for SHR aortic contraction to NE by preserving NO. Therefore, maintenance of NOS activity and NO bioavailability by inhibition of endosomal TLRs could be a therapeutic target against the development of hypertension.

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