NITRATE TOLERANCE--ROLE OF NO IN POSTERIOR HYPOTHALAMUS

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Noradrenergic transmission in the posterior hypothalamus (PH) plays an important role in the central control of circulation, and norepinephrine (NE) in the PH increases sympathetic nerve activity and arterial pressure. Our previous studies have shown that nitroglycerin (NTG), a nitric oxide (NO) donor, increases the central release and synthesis of NE. NTG affects the excitability of central neurons in the nucleus tractus solitarius and the PH. Consistent with its postulated role, microinjection of NTG into PH causes pressor responses which attenuate the decrease in arterial pressure induced by intravenous injection of the drug. Locally injected guanethidine produces noradrenergic blockade in the PH and reverses the acute tolerance responses to NTO accompanied by a marked attenuation of the sympathetic nerve activity. Our recent results show that systemica1ly administered NTG increases the concentration of nitrite and NE turnover in the PH. We hypothesize that generation of NO from peripheral NTG administration increases noradrenergic activation in the PH which facilitates sympathetic nerve activity and contributes to nitrate tolerance. In view of the critical importance of NTG /NO on cardiovascular functions in the PH, our major aims are to elucidate: l) If NO in the PH mediates sympatho-excitatory effects of NTG and nitrate tolerance; 2) If tolerance to NTG is prevented by blockade of neuronal function or noradrenergic function in the PH; 3) Whether dialysate NE, NTG and NO metabolites in the PH are increased and correlated to NTG tolerance development and recovery intervals; 4) If extracellular activities and intrinsic membrane properties of PH neurons are affected by NO- and NTO-induced release/synthesis of NE; and 5) If neuronal and electrophysiological responses to NTG-NO in the PH are mediated by ADP-ribosylation and/or inhibiting cellular respiration. Direct quantification of arterial pressure, sympathetic nerve activity associated with dialysate NE, NTO and NO metabolites in the PH will be combined with neuropharmacological manipulations and electrophysiological recordings to test the hypotheses in anesthetized and conscious rats. The results should enhance our understanding of the noradrenergic and cellular mechanisms by which NTG-NO influence NE release and neurocardiovascular regulation in the PH. This work will provide new information about the role of central NO systems on homeostatic neurocirculatory control and will develop new insights into nitrate tolerance and pharmacodynamics for clinical medicine.