Abstract 117: Contribution of Endocannabinoids via CB1 Receptors to the Impaired Baroreflex Sensitivity in (mRen2)27 Transgenic Hypertensive Rats

Abstract

There is growing evidence for a role of the endocannabinoid system in the pathogenesis of hypertension and associated metabolic syndrome. Presynaptic CB1 cannabinoid receptors, the neuronal target of endocannabinoids, are densely expressed in the solitary tract nucleus (NTS), the primary site for termination of baroreceptor afferent nerve fibers, and in vagal afferent neurons of the nodose ganglion. Our studies in anesthetized, normotensive Sprague-Dawley rats suggest that activation of cannabinoid receptors within the NTS via bilateral microinjection of the CB1 agonist CP55,940 modulates baroreflex sensitivity (BRS) for control of heart rate (HR) in a dose-related biphasic manner. Administration of the CB1-selective antagonist SR141716A (36 pmol) fully prevented or reversed these changes in BRS, and there was no significant effect of the antagonist alone in these normotensive animals (1.04 ± 0.05 ms/mmHg baseline vs. 1.12 ± 0.11 ms/mmHg after antagonist treatment, n = 5). We have now determined the effects of blockade of CB1 receptors in a model of angiotensin (Ang) II-dependent hypertension and insulin resistance with impaired BRS. In contrast to observations in normotensive rats, SR141716A dose-dependently improved BRS for control of HR when microinjected into the NTS of hypertensive, transgenic (mRen2)27 rats with impaired baseline BRS, without changing resting MAP or HR. Microinjection of 0.36 pmol SR141716A (n = 5) increased BRS from a baseline of 0.43 ± 0.03 ms/mmHg to 0.68 ± 0.02 (p < 0.001), and 36 pmol SR141716A (n = 5) increased BRS from 0.47 ± 0.02 to 1.05 ± 0.07 ms/mmHg (p < 0.001), a level that was comparable with baseline BRS of normotensive Sprague-Dawley rats. The demonstration of dose-dependent actions of the CB1 agonist on BRS in normotensive animals coupled with new findings that blockade of CB1 receptors improves BRS, an index of vagal function, in (mRen2)27 hypertensive animals is consistent with the interpretation that elevated endocannabinoids within the NTS contribute to impaired BRS. Thus, our findings suggest that blockade of CB1 receptors will influence cardiovagal reflexes in a positive manner in the context of hypertension and metabolic syndrome.