3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol and Hypertension

Previously, we found that endocannabinoids acting at cannabinoid 1 receptors in the nucleus tractus solitarius prolonged baroreflex inhibition of renal sympathetic nerve activity in normotensive Sprague Dawley rats. The current study investigated whether endocannabinoid signaling was altered in spontaneously hypertensive rats, a model marked by elevated sympathetic activity and depressed baroreflex responses. The effects of endocannabinoids in the nucleus tractus solitarius on baroreflex control of renal sympathetic nerve activity evoked by systemic pressor changes or by direct stimulation of nucleus tractus solitarius neurons, which produced depressor and sympathoinhibitory responses, were studied in Sprague Dawley rats, Wistar Kyoto rats, and spontaneously hypertensive rats. Evoked responses were compared before and after microinjection of AM404, which prolonged actions of endogenous endocannabinoids, or microinjection of an endocannabinoid, anandamide, into the baroreceptive region of the nucleus tractus solitarius. AM404 microinjections significantly prolonged evoked sympathoinhibition in Sprague Dawley and Wistar Kyoto rats, but had little effect in spontaneously hypertensive rats. Microinjections of anandamide prolonged sympathoinhibition in Sprague Dawley rats, with lesser effects in Wistar Kyoto rats and no effects in spontaneously hypertensive rats. Parallel studies found that density of binding sites of endocannabinoids in the nucleus tractus solitarius was significantly reduced in spontaneously hypertensive rats versus the normotensive rats. Results indicate that attenuated function of the endocannabinoid system in the nucleus tractus solitarius of spontaneously hypertensive rats resulted in less modulation of baroreflex-evoked sympathoinhibition and that reduced cannabinoid 1 receptor density could contribute to blunted baroreflex-induced sympathoinhibition and elevated sympathetic tone characteristic of spontaneously hypertensive rats.

Topics: Analgesics; Animals; Arachidonic Acids; Baroreflex; Blood Pressure; Cannabinoid Receptor Modulators; Cyclohexanols; Endocannabinoids; GABA Antagonists; Hypertension; Male; Protein Binding; Pyridazines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Cannabinoid, CB1; Solitary Nucleus; Sympathetic Nervous System; Time Factors; Tritium