Alterations in the Medullary Endocannabinoid System Contribute to Age-related Impairment of Baroreflex Sensitivity

Abstract

As they age, Sprague-Dawley (SD) rats develop elevated systolic blood pressure associated with impaired baroreflex sensitivity (BRS) for control of heart rate. We previously demonstrated in young hypertensive (mRen2)27 rats that impaired BRS is restored by CB1 cannabinoid receptor blockade in the solitary tract nucleus (NTS), consistent with elevated content of the endocannabinoid 2-arachidonoylglycerol (2-AG) in dorsal medulla relative to normotensive SD rats. There is no effect of CB1 receptor blockade in young SD rats. We now report in older SD rats that dorsal medullary 2-AG levels are two-fold higher at 70 versus 15 weeks of age (4.22 ± 0.61 vs. 1.93 ± 0.22 ng/mg tissue; P < 0.05). Furthermore, relative expression of CB1 receptor mRNA is significantly lower in aged rats, while CB2 receptor mRNA is significantly higher. In contrast to young adult SD rats, microinjection of the CB1 receptor antagonist SR141716A (36 pmol) into the NTS of older SD rats normalized BRS in animals exhibiting impaired baseline BRS (0.56 ± 0.06 baseline vs. 1.06 ± 0.05 ms/mmHg after 60 min; P < 0.05). Therefore, this study provides evidence for alterations in the endocannabinoid system within the NTS of older SD rats that contribute to age-related impairment of BRS.

Medullary Endocannabinoids Contribute to the Differential Resting Baroreflex Sensitivity in Rats with Altered Brain Renin-Angiotensin System Expression

“…The present data suggest an upregulated brain endocannabinoid system in Ang II-dependent hypertension associated with a deficiency in the counterbalancing actions of Ang-(1-7) may contribute to the impaired BRS typical of these conditions, and that blockade of CB 1 receptors improves BRS. We observed a similar pattern in older SD rats with age-related impairments in BRS known to be associated with Ang-(1-7) deficiency with the NTS (Schaich et al, 2015 ). CB 1 receptor blockade within the NTS restored BRS to levels similar to younger SD rats and this was associated with elevated 2-AG content in dorsomedial medulla of the older rats (Schaich et al, 2015 ).…”

“…We observed a similar pattern in older SD rats with age-related impairments in BRS known to be associated with Ang-(1-7) deficiency with the NTS (Schaich et al, 2015 ). CB 1 receptor blockade within the NTS restored BRS to levels similar to younger SD rats and this was associated with elevated 2-AG content in dorsomedial medulla of the older rats (Schaich et al, 2015 ). Therefore, CB 1 receptor-mediated impairments in BRS resulting from increased endocannabinoid production may contribute to factors permissive in the development of elevated AP in populations with elevated Ang II and/or deficiencies in Ang-(1-7).…”

“…BRS values obtained by the spontaneous as compared with evoked methods reflect changes over a much smaller range (beat-to-beat) in a closed-loop model. Despite differences in the two methods, a highly significant correlation exists between them (Shaltout and Abdel-Rahman, 2005 ), especially with vagal components, as illustrated in this study and a recent study in older SD rats, which also found comparable results between the evoked and spectral analysis methods (Schaich et al, 2015 ). Furthermore, the absence of alterations in chemosensitive vagal fiber responses supports the specificity of SR141716A actions on BRS because these responses are mediated by chemoreceptor fibers that converge with baroreceptor inputs within the NTS (Paton, 1998 ).…”

The renin–angiotensin system in cardiovascular autonomic control: recent developments and clinical implications

“…The effects of Ang II on baroreflex function involve the NTS, a brainstem region that is the first central locus receiving afferent baroreceptor input. Several neuropeptide or intracellular mediators are implicated in the ability of Ang II to suppress baroreflex function including substance P, nitric oxide pathways, GABA release, the Rho kinase pathway, and endocannabinoids [20,[27][28][29]. Ang-(1-12) also impairs baroreflex sensitivity for control of heart rate and sympathetic activity when given in the NTS and CVLM, respectively, with effects requiring conversion to Ang II by ACE or chymase and subsequent binding to AT 1 receptors [30,26].…”

The Endocannabinoid System May Modulate Sleep Disorders in Aging

“…Diurnal variation of endocannabinoids has been detected in cerebrospinal fluid, pons, hippocampus, or hypothalamus in rats [ 134 , 135 ]. For example, anandamide in CSF showed an enhancement during the lights-on period whereas decreased across the lights-off period in young rats whereas anandamide and 2-AG levels are decreased in aging [ 126 , 136 , 137 ].…”