The arterial baroreceptors provide a powerful beat-to-beat regulation of blood pressure (BP) via a well- defined CNS reflex. The physiological importance of the baroreflex is underscored by the consequences of impaired baroreflex function - volatile BP, orthostatic hypotension, and occasionally malignant vagotonia. The primary baroreceptor afferent fibers make their first excitatory synapse onto second-order neurons in the nucleus tractus solitarius (NTS). This is a pivotal regulatory moment because the signal conditioning at these gateway synapses determines the magnitude, pattern and duration of the baroreceptor signals transmitted to the central network to coordinate baroreflex output. In prior studies, evidence was obtained that suggested that endocannabinoids (ECBs), endogenous agonists of neural cannabinoid receptors (CB1Rs), provide a presynaptic mechanism that modulates central integration of baroreceptor inputs in the NTS and thus provide a regulatory mechanism for baroreflex function. ECB agonists and ECBs produced in the NTS were found to activate CB1Rs and modulated inhibitory (GABA) transmission, resulting in enhanced baroreflex sympathoin- hibition in normotensive rats. However, the effects of ECBs in the NTS of spontaneously hypertensive rats (SHRs), which have enhanced GABAergic function in the NTS, were greatly attenuated. In addition, density of CB1Rs in the NTS of SHRs was significantly reduced as compared to normotensive rats. It was not clear if the changes in the ECB system in the SHR were a cause or an effect to development of hypertension. Thus, the goal of the proposed studies is to determine the extent of alteration of the ECB system during devel- opment of hypertension and determine if the changes in function of the ECB system are the consequences of, or contributors to, the development or maintenance of hypertension. As a more global goal, data from this study will also help to determine if the ECB system provides a mechanism for modulation of synaptic processing in the brainstem that has not been described previously. It is possible that modulation of the endogenous ECB system could provide therapeutic benefits in the treatment of conditions in which alteration of autonomic control is compromised.
Specific Aim 1 - Determine the correlation of timing between the development of hypertension versus the effects of ECBs in the NTS by examining the effects of ECBs on baroreflex-evoked sympathoinhibition and either 1) changes in CB1R binding density in the dorsal medulla, including the NTS, or 2) CB1R message using quantitative reverse transcription-polymerase chain reaction (RT-PCR) specifically in the NTS in spontaneously hypertensive animals.
Specific Aim 2 - Determine the effects of ECBs on baroreflex-evoked sympathoinhibition and either 1) CB1R density in the dorsal medulla, including the NTS or 2) CB1R message using RT-PCR specifically in the NTS during the development of hypertension in models other than SHR which are also distinguished by decreases in baroreflex control and increases in sympathetic nerve activity and NTS GABAergic function.
Specific Aim 3 - Examine the consequences of the prolonged loss of CB1R activity in normotensive rats, using pharmacologic or recombinant techniques to recapitulate the changes seen in CB1R density in the SHR model. If attenuated function of the ECB system is found to correlate with the development or maintenance of hypertension, it is possible that increasing levels of ECBs or CB1Rs within the NTS could help to correct hypertension through enhancing activity of an endogenous regulatory system. Characterizing this mechanism and precisely how and when it acts will help to understand central baroreflex control in general and may also lead to new insights into baroreflex dysfunction - a feature not only of cardiovascular diseases but also of diabetes and CNS disorders, including Parkinson's, depression, and anxiety.
Hypertension afflicts more than 50 million Americans and is a primary contributor to the development of stroke and cardiac dysfunction, yet the cause(s) of 90-95% of hypertension cases are not known. Recent studies support an increasing role for an elevation in sympathetic activity as a contributor to the development of hypertension. Our prior studies have shown that dysfunction of an endogenous regulatory mechanism, endocannabinoid signaling, in the brainstem is present in hypertensive animals and can lead to increases in sympathetic activity. It is possible that methods to upregulate the function of this regulatory system could have a potential anti-hypertensive therapeutic role. This study will examine if targeting modulation of the endocannabinoid system in the brain could be to a novel way to treat hypertension in humans using endogenous pathways, particularly hypertension refractory to current treatments.
