Abstract-Cardiac autonomic control is of prognostic significance in cardiac disease, yet the control mechanisms of this system remain poorly defined. Animal data suggest that nitric oxide (NO) modulates cardiac autonomic control. We investigated the influence of NO on the baroreflex control of heart rate in healthy human subjects. In 26 healthy male volunteers (mean age, 23Ϯ5 years), we measured heart rate variability and baroreflex sensitivity during inhibition of endogenous NO production with N G -monomethyl-L-arginine (L-NMMA) (3 mg/kg per hour) and during exogenous NO donation with sodium nitroprusside (1 to 3 mg/h). Increases from baseline (⌬) in high-frequency (HF) indexes of heart rate variability were smaller with L-NMMA in comparison to an equipressor dose of the control vasoconstrictor phenylephrine (12 to 42 g/kg per hour): ⌬root mean square of successive RR interval differences (⌬RMSSD)ϭ23Ϯ32 versus 51Ϯ48 ms (PϽ0.002); ⌬percentage of successive RR interval differences Ͼ50 ms (⌬pNN50)ϭ5Ϯ15% versus 14Ϯ12% (PϽ0.05); and ⌬HF normalized powerϭϪ2Ϯ7 versus 9Ϯ8 normalized units (PϽ0.01), respectively. Relative preservation of these indexes was observed during unloading of the baroreflex with sodium nitroprusside compared with a matched fall in blood pressure produced by a control vasodilator, hydralazine (9 to 18 mg/h): ⌬RMSSDϭϪ8Ϯ8 versus Ϫ24Ϯ15 ms (PϽ0.001); ⌬pNN50ϭϪ6Ϯ11% versus Ϫ15Ϯ19% (PϽ0.01); ⌬HF normalized powerϭϪ7Ϯ13 versus Ϫ13Ϯ11 normalized units (PϽ0.05), respectively. The change in cross-spectral ␣-index calculated as the square root of the ratio of RR interval power to systolic spectral power in the HF band (although not ␣-index calculated in the same way for the low-frequency bands or baroreflex sensitivity assessed by the phenylephrine bolus method) was attenuated with L-NMMA compared with phenylephrine (⌬ϭ4Ϯ8 versus 14Ϯ15 ms/mm Hg, respectively; PϽ0.02) and with sodium nitroprusside compared with hydralazine (⌬ϭϪ7Ϯ6 and Ϫ9Ϯ7 ms/mm Hg, respectively; PϽ0.05). In conclusion, these data demonstrate that NO augments cardiac vagal control in humans. Key Words: nitric oxide Ⅲ heart rate Ⅲ baroreceptors Ⅲ autonomic nervous system Ⅲ blood pressure T he powerful influence of autonomic control on the natural history of cardiac disease is evidenced by large trials showing that reduced heart rate variability (HRV) and baroreflex sensitivity (BRS) are independent indicators of adverse prognosis. 1,2 However, the mechanisms controlling cardiovascular autonomic function remain poorly defined.The initial suggestion that nitric oxide (NO) may be an important mediator in cardiac autonomic control came from the demonstration of discrete neuronal populations that possess NO synthase at numerous sites within known cardiac autonomic pathways. 3 Animal evidence suggests that the NO synthesized at these sites is active in modulating activity within both limbs of the autonomic nervous system. NO appears to act as a sympatholytic agent, decreasing activity within sympathoexcitatory brain stem nuclei and reducing central ...

SUMMARY1. Subjects with active stretch reflexes responded to an imposed sinusoidal movement of the ankle joint with a reflex force whose amplitude and timing varied widely with changes in the frequency of movement.2. At some frequency between 6 and 8 Hz, the reflex force tended to offset the non-reflex component of resistance, and thus to reduce the total resistance to movement. At this frequency the reflex response was particularly vigorous, with a deep modulation of electromyogram (e.m.g.) activity and a displacement of the joint stiffness vectors far from their high frequency values. The total resistance to movement might then be small, or it might be zero, or the reflex might actually assist the movement.3. As the frequency of movement was decreased through this critical range, the timing of the reflex response to movement changed rapidly with an abrupt advancement of the triceps surae e.m.g. signal, and a wide separation of the joint stiffness vectors as they passed close to the origin.4. This result was attributed to a changing distribution of the movement between the muscle fibres and an elastic Achilles tendon. It was assumed that at most frequencies the muscle fibres resisted extension, so that a major part of the imposed movement went into stretching the tendon; when, however, at 6-8 Hz, the reflex response was so timed as to reduce or abolish the resistance of the muscle fibres, more ofthe movement would take place in them. The muscle spindles would 'see 'this larger movement of the muscle fibres, and generate correspondingly more reflex activity.5. A simplified model of the muscle-tendon combination behaves in a way that supports this view, and the available information about the human Achilles tendon indicates that it is sufficiently compliant for such an explanation.6. Therefore, movements imposed on the ankle joint would not necessarily be 'seen' by the muscle spindles, since they would be modified by transmission through a compliant tendon. By assuming a value for the tendon stiffness, it was possible to calculate the course of movements that actually occurred in the muscle fibres and spindles. Records of these spindle movements indicated how some non-linearities might arise.

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SUMMARY1. The mechanical resistance of the human forearm has been measured during imposed sinusoidal flexion-extension movements of the elbow joint.2. The force required to move the limb can be divided into components required to move the mass, and components required to overcome the resistance offered by elastic and frictional properties of the muscles and other soft tissues.3. When during a vigorous flexing effort the limb was subjected to a small amplitude sinusoidal movement each extension was followed by a considerable reflex contraction of the flexor muscles. At low frequencies of movement this reflex provided an added resistance to extension, but at 8-12 Hz the delay in the reflex pathway was such that the reflex response to extension occurred after the extension phase of the movement was over and during the subsequent flexion movement. The reflex activity then assisted the movement whereas at other frequencies it impeded it.4. The reflex response to movement increased as the subject exerted a greater flexing force.5. Small movements generated a relatively larger reflex response than big ones.6. Even with large amplitudes of movement when the reflex activity was relatively small, the limb resisted extension with a high level of stiffness; this was comparable with the short range stiffness of muscles in experimental animals.7. The fact that at some frequencies the reflex response assisted the movement implies that with appropriate loading the limb could undergo a self-sustaining oscillation at those frequencies.

Forces and electromyograms were recorded from patients with Parkinson's disease during imposed joint movements. Muscles which were stretched by 3 to 5 Hz sinusoidally alternating movements often showed vigorous bursts of EMG activity whose timing established that it was a reflex response to the movement. The same movements provoke no stretch reflex response from normal subjects. When resting tremor was present the driven movements sometimes entrained it, and the bursts of EMG activity then became locked to the imposed movement. On other occasions the tremor activity continued at its own rate; EMG bursts then occurred at times unrelated to the movement, and the irregular force records reflected a conflict between the movement and the muscle activity. Tremor was most consistently entrained when a large mass of muscle was driven through a large movement at a frequency that was close to the usual tremor frequency. Tremor which involved synchronous contractions of muscles at different joints was often resistant to the effects of our imposed movements, but it could sometimes also be entrained by large movements of a single joint. When tremor was entrained by a driving movement, the EMG discharge was indistinguishable from a reflex response, and the limb exerted forces on the machinery which had the timing and magnitude that would be expected of a reflex response. Spontaneous tremor in the same subjects had frequencies which altered in the predicted way with changes of mechanical load. We conclude that peripheral reflexes are more important in parkinsonian tremor than has often been supposed, although afferent activity from the moving limb probably interacts with other potentially oscillatory mechanisms.