Activation of CB1 receptors in the solitary tract nucleus (NTS) over a 100-fold dose range elicits biphasic effects, with high doses inhibiting baroreflex sensitivity (BRS) for control of heart rate and lower doses facilitating BRS. There is growing evidence for signaling interactions between the endocannabinoid system (ECS) and pathogenic actions of angiotensin (Ang) II at AT1 receptors in hypertension and the metabolic syndrome. Hypotensive ASrAOGEN (AS) rats, overexpressing an angiotensinogen antisense in glia, have significantly elevated medullary tissue glutamate levels and enhanced BRS compared to normotensive Sprague-Dawley (SD) rats (1.42 ± 0.11 vs. 1.04 ± 0.05 ms/mmHg; n = 5 - 6; P = 0.02). Transgenic (mRen2)27 rats, a monogenetic Ang II-dependent model of hypertension, have markedly impaired BRS compared to SD rats (0.43 ± 0.06 vs. 1.04 ± 0.05 mmHg; n = 5; P < 0.0001). There is no effect of the CB1 receptor antagonist SR141716 on BRS when microinjected into the NTS of SD rats; however, SR141716 injected into the NTS of hypertensive (mRen2)27 rats dose-dependently improved BRS. In contrast, SR141716 injected into the NTS of hypotensive AS rats dose-dependently reduced BRS. Microinjection of 0.36 pmol SR141716 (n = 3) reduced BRS from a baseline of 1.23 ± 0.05 ms/mmHg to 0.81 ± 0.14 (P = 0.01) and 36 pmol SR141716 (n = 3) decreased BRS from 1.60 ± 0.17 to 0.48 ± 0.06 ms/mmHg (P = 0.001), a level comparable with baseline BRS of hypertensive (mRen2)27 rats. The effects of CB1 receptor blockade on BRS parallel the endogenous levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) as measured by mass spectrometry with lower 2-AG in AS compared to (mRen2)27 rats (1.17 ± 0.09 vs. 2.70 ± 0.28 ng/mg tissue; n = 4 - 5; P = 0.002). Normotensive SD rats had intermediate 2-AG levels (1.85 ± 0.27 ng/mg tissue; n = 5; n.s. vs. other strains). These observations reveal that an upregulated ECS contributes to RAS-dependent suppression of BRS. That there is a reduction in BRS in response to NTS CB1 receptor blockade in hypotensive AS rats exhibiting elevated glutamate levels suggests differential regulatory functions of the brain ECS that may involve alterations in transmitters known to influence BRS and that parallel the Ang II:Ang-(1-7) ratio in these animals.