Nitric oxide regulates cardiac-sympathetic responses in the rostral ventrolateral medulla:role of its synthase isoforms

【Author】

TJEN-A-LOOI Stephanie C;LONGHURST John C;

【Abstract】

<正>Metabolites(e.g.,bradykinin)produced during myocardial ischemia stimulate cardiac sympathetic afferents and evoke excitatory cardiovascular reflexes,including acute hypertension and tachyarrhythmias,which lead to significant patient morbidity and mortality.The precise mechanisms underlying the control of these reflexes in the central nervous system are unknown.Our previous studies have shown that nitric oxide synthase(NOS)-containing neurons in the rostral ventrolateral medulla(rVLM)are activated during cardiac sympathoexcitatory reflexes.However,the precise function of nitric oxide(NO)in the rVLM in regulation of these reflexes has not been defined.Three isoforms of NOS,i.e.,neuronal NOS(nNOS),inducible NOS(iNOS)and endothelial NOS (eNOS),are located in the rVLM.Therefore,we have explored the relationship of cells containing these NOS isoforms to C1 premotor neurons in the rVLM,and the role of NO,derived from different NOS isoforms in the rVLM,in processing cardiac-sympathetic reflexes using anatomical,reflex and electrophysiological approaches. First,we found that the majority(60%)of cells containing nNOS,iNOS or eNOS are in close apposition to rVLM C1 neurons of the cat.Then,we observed that in anesthetized cats,increased mean arterial blood pressure(MAP) and renal sympathetic nerve activity(RSNA)elicited by epicardial application of bradykinin(BK,10μg/mL,50μL) were significantly attenuated following unilateral rVLM microinjection of the non-selective NOS inhibitor,N~w-nitro-L -arginine methyl ester(L-NAME,50 nmol/50 nL;n=7,both P<0.05),or a specific nNOS inhibitor,7-nitroindazole (7-NI,5-10 pmol/50 nL;both P<0.05,n=6).In contrast,the responses of MAP and RSNA to cardiac BK stimulation were not changed after unilateral rVLM was treated with D-NAME(an inactive isomer of L-NAME,50 nmol/ 50 nL,n=5),3%-6%methanol(the vehicle for 7-NI;n=4),an iNOS inhibitor,N~6-(l-iminoethyl)-L-lysine(250 pmol/50 nL;n=4)or a specific inhibitor of eNOS,N5-(l-iminoethyl)-L-ornithine(250 pmol/50 nL;n=3).Furthermore, in three separate cats,we noted that iontophoresis of 7-NI(0.1 mmol/L)reduced the increased discharge of cardiovascular-sympathoexcitatroy rVLM neurons in response to cardiac stimulation with BK.These neurons were characterized by their responses to inputs from baroreceptors and their cardiac rhythmicity determined with frequency and time domain analysis,correlating to arterial blood pressure and cardiac sympathetic efferent nerve activity.These data suggest that NO,specifically nNOS,in the rVLM mediates sympathetic cardiac-cardiovascular responses.

【Keywords】

nitric oxide;;heart;;rostral ventrolateral medulla;;cardiovascular reflex

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