Effects of Advanced EA on Hypertension: Role of nNOS-NO in the Dorsal Medulla

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DESCRIPTION (provided by applicant): The gracile nucleus and nucleus tractus solitarius (NTS) receive somatosensory afferent inputs from the hindlimb, and low-frequency electroacupuncture (EA) stimulation of hindlimb acupoint ST36 produces long-lasting sympathoinhibition and arterial blood depressor in humans and rats. We have found that hypertension is successfully reduced by advanced EA ST36 (two phases over 2 hrs separated by an 80 min interval) in Dahl salt- sensitive (DS) rats but not significantly decreased by EA with a short stimulation period. Expression of neuronal nitric oxide (NO) synthase (nNOS) is predominantly reduced in the gracile nucleus and NTS regions in DS rats, and decreased nNOS expression in the areas is restored by advanced EA ST36. Consistently, our preliminary results show that the depressor responses to EA ST36 are facilitated by microinjection of L-arginine in the gracile nucleus in DS rats. The facilitating effects of NO donors on the hypotensive responses to EA ST36 are inhibited by microinjection of either an antagonist of GABA receptors or an ihhibitor of guanylyl cyclase into gracile nucleus. We hypothesize that impaired nNOS-NO generation in the gracile nucleus and/or NTS causes hypertension in DS rat; advanced EA ST36 induces nNOS-NO-GABA in the brain nuclei, resulting in central inhibitory regulation of cardiovascular functions for hypertension control. In view of the critical importance of NO on arterial blood pressure regulation, our major aims are: 1) Examine whether hypertension in DS rats with salt load is improved and nNOS expressions in the gracile nucleus and/or NTS are restored by advanced EA ST36; 2) Determine whether endogenous NO-GABA releases in the gracile nucleus and mNTS are induced and paralleled to cardiovascular responses to advanced EA ST36; 3) Define whether L-arginine-derived NO synthesis and NO-cGMP-GABA cascade in the gracile nucleus and/or mNTS contribute to cardiovascular responses to advanced EA ST36 in hypertensive rats. The physiological recordings of arterial blood pressure and heart rate will be incorporated with neuropharmacological manipulations, molecular examinations and histochemical studies to test the hypotheses in a DS rat model. The results should develop an effective advanced therapy to restore impaired nNOS in the gracile nucleus/NTS for hypertension control and yield new insights into central mechanisms of NO-cGMP-GABA on EA signaling and cardiovascular regulation in the dorsal medulla. PUBLIC HEALTH RELEVANCE: These studies should advance our understanding of sites and mechanisms of nitric oxide (NO) in the dorsal medulla for cardiovascular regulation and reveal a novel mechanism of NO-GABA for signal transduction of electroacupuncture (EA) ST36 in the central pathways. The results should benefit public health by providing a theraputic mechanism of acupuncture, and establish a gold-standard EA therapy based on scientific evidence of inducing NO and its synthase in the dorsal medulla for clinical treatment of hypertension and other cardiovascular diseases.