Is nitric oxide involved in the tonic inhibition of central sympathetic outflow in humans?

Abstract

Recent studies in experimental animals have advanced the concept that neuronal nitric oxide is an important component of the signal transduction pathways that tonically restrain sympathetic vasoconstrictor outflow from the brain stem. To determine whether or not this concept can be extended to the control of sympathetic outflow in humans, we recorded muscle sympathetic nerve activity (microelectrodes, peroneal nerve) in healthy human subjects during intravenous infusion of the nitric oxide synthase inhibitor N G -monomethyl-L-arginine (L-NMMA) (3.6 to 6.7 tng/kg). The major new finding is that during intravenous L-NMMA mean arterial pressure increased (10±2 mm Hg, P<.05), whereas heart rate and sympathetic nerve activity decreased (P<.05) by 10±2 beats per minute and 61 ±5%, respectively. These reflex decreases were indistinguishable from those produced when S tudies in experimental animals have provided unequivocal evidence that endogenous synthesis of nitric oxide (NO) from L-arginine is of major importance in the tonic regulation of vasomotor tone and blood pressure.13 However, much less is known about the importance of NO in the regulation of the human cardiovascular system.In numerous species, pharmacological inhibitors of NO synthase such as /V°-monomethyl-L-arginine (L-NMMA) cause a robust increase in blood pressure that at first was attributed solely to inhibition of endothelial NO synthase. 49 However, the presence of NO synthase in specific brain regions such as the nucleus tractus solitarius and rostral ventrolateral medulla suggested that NO also might be involved in the central neural control of blood pressure.1012 Based on these neuroanatomic findings, several recent studies have implicated a major neurogenic component in the blood pressure increase produced by inhibition of NO synthesis: it is accompanied by increases in heart rate and sympathetic nerve activity (SNA) and is greatly attenuated by ganglionic blockade. 1317In intact rats, for example, intravenous L-NMMA produces a sustained elevation in blood pressure with a biphasic response in renal SNA: there is an initial transient decrease in SNA caused by baroreflex activation followed by a sustained increase in SNA caused by central neural activation.13 Thus, the increase in SNA was (1) augmented after denervation of sinoaortic baroreceptors and cardiopulmonary vagal afferents, (2) eliminated by cervical spinal cord transection, and (3) duplicated by microinjection of L-NMMA into the nucleus tractus solitarius in rabbits or the rostral ventrolateral medulla in cats and rats.13 " 16 Taken together, these extensive studies in experimental animals advanced the concept that the neuronal isoform of NO synthase is an important component of the signal transduction pathways that tonically restrain sympathetic vasoconstrictor outflow from the brain stem.A key unanswered question is whether or not this concept can be extended to the control of sympathetic outflow in conscious humans. To address this question, we recorded postganglionic SNA ta...

Systemic Inhibition of Nitric Oxide Synthase Unmasks Neural Constraint of Maximal Myocardial Blood Flow in Humans

“…35 We infused L-NMMA intravenously at a dose that has been shown to increase blood pressure and activate the baroreflex and to effectively block eNOS and nNOS in experimental animals 36 and humans. 14,37 Given that the coronary circulation extracts Ϸ5% of cardiac output, with our systemic doses of L-NMMA we would expect to achieve coronary concentrations of Ϸ50 mol (group 2) and 164 mol (groups 3 and 5), respectively, which compare well with the figures of 32, 30 125, 2 and 320 mol 3 shown to block coronary eNOS when administered via an intracoronary route. Thus, it is reasonable to assume that with our high-dose L-NMMA infusion, we have successfully blocked a substantial amount of both eNOS and nNOS.…”

“…4,40 -42 It remains controversial whether inhibition of nNOS elicits sympathoexcitatory effects 14 or not, 37 because it may exert opposing effects at different sites. 43 The present study is the first to report a net increase in adenosineinduced hyperemic MBF in response to L-NMMA.…”

Sympathetic activation and nitric oxide function in early hypertension

“…It is not clear, however, how important this mechanism is in restraining BP in humans; studies in favor and against this possibility can be found in the literature. In some studies, the increase in BP produced by systemic administration of L-NMMA is accompanied by a similar reflex decrease in muscle sympathetic nerve activity to that produced by an equipressor dose of phenylephrine (3,8), suggesting that NO does not tonically restrain central sympathetic outflow in humans. Other studies have reached the opposite conclusion; in one study, NOS inhibition increased BP but did not produce the expected baroreflex-mediated decrease in sympathetic nerve activity (15); in another, the increase in BP induced by NOS inhibition was partially reversed by the ␣-adrenergic antagonist phentolamine (21).…”

Contribution of Endothelial Nitric Oxide to Blood Pressure in Humans

“…In some studies, the increase in blood pressure produced by systemic administration of the NOS inhibitor N G -monomethyl-L-arginine (L-NMMA) results in a reflex decrease in muscle sympathetic nerve activity 5 that is similar to that produced by an equipressor dose of phenylephrine, suggesting that NO does not tonically restrain central sympathetic outflow in humans. 6 On the other hand, in other studies, NOS inhibition with N G -nitro-L-arginine methylester resulted in a larger increase in blood pressure that was partially reversed with the ␣-adrenergic antagonist phentolamine, most likely reflecting a tonic inhibition of sympathetic tone by nNOS. 7 The relative contribution of endothelial-derived NO to blood pressure, therefore, remains difficult to assess.…”