Estrogen dampens central cannabinoid receptor 1-mediated neuroexcitation and pressor response in conscious female...

Activation of the rostral ventrolateral medulla (RVLM) cannabinoid receptor-1 (CB₁R) causes neuronal nitric oxide synthase (nNOS)-dependent increases in sympathetic activity, blood pressure (BP) and heart rate (HR) in male rats. However, it remains unknown if the CB₁R-mediated neurochemical and cardiovascular responses are influenced by the ovarian sex hormones, particularly estrogen (E₂). Therefore, we studied the effects of intra-RVLM CB₁R activation (WIN 55,212-2) on BP and HR in conscious female rats under the following hormonal states: (1) highest E₂ level (proestrus sham-operated, SO); (2) E₂-deprivation (ovariectomized, OVX); (3) OVX with E₂ replacement (OVXE2). Intra-RVLM WIN55,212-2 elicited dose (100-400 pmol) dependent pressor and tachycardic responses, in OVX rats, which replicated the reported responses in male rats. However, in SO and OVXE2 rats, the CB₁R-mediated pressor response was attenuated and the tachycardic response reverted to bradycardic response. The neurochemical findings suggested a key role for the upregulated RVLM sympathoexcitatory molecules phosphorated protein kinase B, phosphorated nNOS and reactive oxygen species in the exaggerated CB₁R-mediated BP and HR responses in OVX rats, and an E₂-dependent dampening of these responses. The intra-RVLM WIN55212-2-evoked cardiovascular and neurochemical responses were CB₁R-mediated because they were attenuated by prior CB₁R blockade (AM251). Our findings suggest that attenuation of RVLM neuroexcitation and oxidative stress underlies the protection conferred by E₂, in female rats, against the CB₁R-mediated adverse cardiovascular effects.