Roles of Nitric Oxide Synthase Isoforms in the Rostral Ventrolateral Medulla in Regulation of Cardiac‐Sympathetic Excitatory Reflexes

Abstract

Our previous studies have shown that nitric oxide synthase (NOS)-containing neurons in the rostral ventrolateral medulla (rVLM) are activated during cardiac sympathoexcitatory reflexes. Furthermore, non-selective inhibition of NOS in rVLM attenuates these reflexes. Three isoforms of NOS, i.e. neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS), are found in rVLM. However, the precise function of each of the NOS isoforms in regulation of cardiac sympathoexcitatory reflexes has not been elucidated. The present study examined the relationship of cells containing different NOS isoforms to C1 premotor neuron in rVLM, and roles of three NOS isoforms in this area in regulation of excitatory cardiovascular reflexes during cardiac stimulation with bradykinin (BK). Using double-immunohistochemical labeling, we observed that a few cells labeled with nNOS or iNOS (~5%) co-localize with C1 neurons and the majority (60%) of these cells are in close apposition to C1 neurons of the cat. Cells containing eNOS are in close proximity to C1 neurons. In anesthetized cats, cardiac pressor responses and increased renal sympathetic nerve activity induced by epicardial application of BK (10 μg/ml, 50 μl) were reduced by unilateral microinjection of a specific inhibitor of nNOS, 7-Nitroindazole (7-NI, 5-10 pmol/50 nl; 31±5 to 18±4 mmHg, and 18±2 to 5±1% of basal discharge, respectively; both P<0.05, n=6), but not by specific inhibitors of iNOS, N6-(1-iminoethyl)-L-lysine (250 pmol/50 nl; n=4) or eNOS, N5-(1-iminoethyl)-L-ornithine (250 pmol/50 nl; n=3). These data suggest that nitric oxide, particularly produced by nNOS, in rVLM mediates sympathoexcitatory cardiac-cardiovascular reflexes. (supported by the AHA, WSA 0160077Y and 0365064Y, NIH HL-66217).