Abstract
CB1 cannabinoid receptors are expressed on vagal afferent fibers and neurons within the solitary tract nucleus (NTS), providing anatomical evidence for their role in arterial baroreflex modulation. To better understand the relationship between the brain renin-angiotensin system (RAS) and endocannabinoid expression within the NTS, we measured dorsal medullary endocannabinoid tissue content and the effects of CB1 receptor blockade at this brain site on cardiac baroreflex sensitivity (BRS) in ASrAOGEN rats with low glial angiotensinogen, normal Sprague-Dawley rats and (mRen2)27 rats with upregulated brain RAS expression. Mass spectrometry revealed higher levels of the endocannabinoid 2-arachidonoylglycerol in (mRen2)27 compared to ASrAOGEN rats (2.70 ± 0.28 vs. 1.17 ± 0.09 ng/mg tissue; P < 0.01), while Sprague-Dawley rats had intermediate content (1.85 ± 0.27 ng/mg tissue). Microinjection of the CB1receptor antagonist SR141716A (36 pmol) into the NTS did not change cardiac BRS in anesthetized Sprague-Dawley rats (1.04 ± 0.05 ms/mmHg baseline vs. 1.17 ± 0.11 ms/mmHg after 10 min). However, SR141716A in (mRen2)27 rats dose-dependently improved BRS in this strain: 0.36 pmol of SR141716A increased BRS from 0.43 ± 0.03 to 0.71 ± 0.04 ms/mmHg (P < 0.001), and 36 pmol of SR141716A increased BRS from 0.47 ± 0.02 to 0.94 ± 0.10 ms/mmHg (P < 0.01). In contrast, 0.36 pmol (1.50 ± 0.12 vs. 0.86 ± 0.08 ms/mmHg; P < 0.05) and 36 pmol (1.38 ± 0.16 vs. 0.46 ± 0.003 ms/mmHg; P < 0.01) of SR141716A significantly reduced BRS in ASrAOGEN rats. These observations reveal differential dose-related effects of the brain endocannabinoid system that influence cardiovagal BRS in animals with genetic alterations in the brain RAS.
Highlights
Tonic overactivation of the endocannabinoid system is implicated in the maintenance of cardiovascular diseases and its risk factors, including hypertension, atherosclerosis and metabolic syndrome (Pacher et al, 2006; Després, 2007)
We report for the first time the endocannabinoid content and relative receptor mRNA levels associated with the FIGURE 4 | 2-AG and anandamide content in dorsal medulla of SD,27 and ASrAOGEN rats. (A) Mass spectrometry revealed levels of 2-AG were significantly higher in the dorsal medullary tissue of 15-week-old27 rats (n = 5) relative to ASrAOGEN rats (n = 4). (B) Anandamide was detected at levels 1000-fold lower than 2-AG in the same tissue samples, and there were no significant differences among strains. **P < 0.01 vs. ASrAOGEN
Endocannabinoid system are differentially expressed in the dorsal medulla of27 and ASrAOGEN rats compared to SD rats
Summary
Tonic overactivation of the endocannabinoid system is implicated in the maintenance of cardiovascular diseases and its risk factors, including hypertension, atherosclerosis and metabolic syndrome (Pacher et al, 2006; Després, 2007). To test our hypothesis that endocannabinoid content influences cardiac BRS at the level of the NTS in animals with altered brain RAS expression, we studied dorsal medullary endocannabinoid content and function in hemizygous transgenic (mRen2) rats, a monogenetic model of Ang II-dependent hypertension in which the mouse Ren renin gene was transfected into the genome of the normotensive Hannover SD rat. These rats have a phenotype of chronic hypertension while conscious with markedly impaired BRS for control of HR compared to SD controls (Bader et al, 1992; Borgonio et al, 2001). These strains provide insights into the contribution of the brain RAS and its influence on factors involved in regulation of BRS (Sakima et al, 2007; Diz et al, 2008) and were used to provide functional and biochemical evidence for altered endocannabinoid tone at the level of the NTS
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