Transmission of Arterial Baroreflex Signals Depends on Neuronal Nitric Oxide Synthase

Abstract

Abstract-Because inhibition of neuronal nitric oxide synthase in the nucleus tractus solitarii blocks cardiovascular responses to activation of local glutamate receptors, and because glutamate is a neurotransmitter of baroreceptor afferent nerves, we sought to test the hypothesis that neuronal nitric oxide synthase inhibition would block baroreflex transmission and cause hypertension. We determined reflex heart rate responses to intravenous phenylephrine and sodium nitroprusside in 5 anesthetized rats before and after bilateral microinjection (100 nL) of the neuronal nitric oxide synthase inhibitor AR-R 17477 (7.5 nmol) into the nucleus tractus solitarii. The inhibitor significantly increased mean arterial pressure without affecting heart rate, and it significantly reduced the gain of the baroreflex. After administration of the inhibitor, reflex responses of heart rate to changes in mean arterial pressure were always less than those responses to the same, or less, change in mean arterial pressure in the same animal without administration of the inhibitor. Microinjection of saline (100 nL) bilaterally into the nucleus tractus solitarii did not lead to hypertension or change baroreflex responses. These data support the hypothesis and suggest that neuronal nitric oxide synthase is critical to transmission of baroreflex signals through the nucleus tractus solitarii. Key Words: baroreceptor reflex Ⅲ nitric oxide Ⅲ nitric oxide synthase Ⅲ rat A s the primary site of termination of baroreceptor and other cardiovascular and visceral afferent nerve fibers, 1-3 the nucleus tractus solitarii (NTS) plays a critical role in regulation of arterial pressure (AP) and peripheral blood flow. Stimulation of NTS leads to marked changes in AP and regional blood flow, 4 and lesions lead to acute hypertension in humans 5 and experimental animals. 6 Changes in AP regulation may be persistent with chronic perturbations of transmission in NTS. 7 There is broad support for the hypothesis that glutamate (Glu) is a transmitter released from baroreceptor afferent nerve terminals in NTS, 8,9 but Glu likely also participates in processing other cardiovascular signals such as those from chemoreceptor afferents. 10 Changes in responsiveness to Glu injected into NTS in hypertensive rats 11 suggest that alterations in Glu transmission may play a role in the genesis of some forms of hypertension. Thus, improved understanding of glutamatergic neurotransmission in the NTS in normotensive rats could shed new light not only on basic mechanisms of AP control but also on mechanisms that could contribute to hypertension.Recent studies indicate that nitric oxide (NO⅐) may participate in generating responses elicited by Glu. For example, NO⅐ may exert presynaptic and postsynaptic effects and may play a role in cardiovascular regulation at the level of NTS. 12 Furthermore, responses to injection of NO⅐ donors into NTS of anesthetized and awake animals mimic those elicited by injection of Glu agonists in anesthetized rats. [13][14][15] However, it is not clea...

Endothelial NO Synthase Activity in Nucleus Tractus Solitarii Contributes to Hypertension in Spontaneously Hypertensive Rats

“…40,41 Data are also inconsistent when either NO donors or L-arginine are microinjected into the NTS (no change 40,42 or decreased [43][44][45][46][47][48] ). Previous studies describing the effects of NOS inhibitors in the NTS on baroreceptor reflex gain are also inconsistent (no change, 40,49 increased, 39 or decreased 38,50,51 ). It should be noted that both nNOS and eNOS isoforms are found in the NTS, and both neurones and fibers, some of which are vagal afferents, contain nNOS.…”

“…59 Moreover, exogenous NO in the NTS enhances both glutamate release in vivo 60 and evoked excitatory postsynaptic potentials in vitro, 61 and both of the latter may explain the bradycardia/depressor responses (for references see above) and depressed baroreceptor reflex gain after nNOS blockade. 38,51 In addition, Dias et al 38 have described that N G -nitro-L-arginine methyl ester blockade of NOS in the NTS reduces the depressor response evoked by N-methyl-D-aspartate. Considering a positive interaction between NO and glutamatergic transmission in the NTS in the regulation of arterial pressure, the question arises as to why selective eNOS antagonism seems to produce cardiovascular effects (bradycardia, depressor, and increased sBRG in SHR) that are opposite to those produced using eNOS overexpression or pharmacological antagonism of eNOS/nNOS or nNOS.…”

Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension

“…NO is an important mediator of intracellular signaling in various tissues, including the CNS (32,118,119). NO acts via the second messenger cyclic GMP (32).…”

“…L-NAME enhances the rapid adaptation of the arterial baroreflex control of renal sympathetic nerve activity in rabbits (41). Transmission of arterial baroreflex signals depends on NO (27,118). It was reported that the baroreceptor reflex gain in awake animals was increased by NO in the bradycardic component, although in these studies NOS inhibitors were administered systemically to examine the role of NO on baroreflex function (78,87).…”

NO and Central Cardiovascular Control

“…14 That, when considered with the observation that inhibition of neuronal NO synthesis leads to hypertension, 15 raised the possibility that NO derived from eNOS served an excitatory role both in baroreflex transmission, as well as in cardiopulmonary afferent transmission in the NTS. As is clear from the studies out of the Bristol laboratories, even that conclusion is overly simplistic.…”