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 ...

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The finding of no difference in insulin sensitivity between the two groups contrasts with, but does not entirely contradict, the results of previous epidemiological studies--perhaps suggesting that longer term changes such as liver enzyme induction may be important. The difference in insulin secretion questions the validity of previous studies of the influence of alcohol on insulin sensitivity, where insulin levels were used as a surrogate for insulin resistance.

1. We have previously shown that brief voluntary isometric contractions of upper arm flexor muscles performed for one respiratory cycle elicit a significant decrease in the R-R interval. The present study was designed to determine if similar changes are produced by non-voluntary electrically evoked contractions and, if so, to establish the consistency and repeatability of the associated changes in the R-R interval. 2. The heart rate (R-R interval) response to voluntary or non-voluntary brief isometric contraction equivalent to 40% of the maximum voluntary contraction was studied in 10 healthy young male subjects during controlled ventilation at supine rest. 3. The absolute values of R-R intervals occurring in any one of 10 arbitrary phases of a respiratory cycle were measured and plotted by a computer. 4. Both voluntary and non-voluntary contractions elicited similar changes in heart rate and R-R interval, which were greater during expiration than during inspiration. 5. This confirms our previous finding that the magnitude of the R-R interval changes, with brief isometric contraction, is positively related to the degree of cardiac vagal tone. 6. Analysis of the variability between repeated tests initiated in either inspiration or expiration revealed that there was significantly less variability with the electrically induced contraction. 7. It was concluded that electrically induced contractions of 40% maximal voluntary contraction are a viable alternative to voluntary contractions and provide a more controllable means of measuring cardiac vagal withdrawal.

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Objective-To investigate the eVects of angiotensin II in the absence of baroreflex activation. Design-Ten healthy male volunteers were studied in a single blind, randomised, crossover study of heart rate variability during intravenous angiotensin II infusion (5-20 ng/kg/min) compared with a control pressor infusion of phenylephrine (0.7-2.8 µg/kg/min). Each infusion was titrated to increase mean blood pressure by 20 mm Hg; sodium nitroprusside was then infused simultaneously to restore blood pressure to baseline values. Conclusions-When the pressor response is controlled by sodium nitroprusside, angiotensin II infusion is associated with tachycardia. Analysis of heart rate variability suggests that this reflects inhibition of cardiac vagal activity. (Heart 1998;80:127-133) Keywords:angiotensin II; heart rate variability; autonomic nervous system; parasympathetic nervous system Results-DuringThe important pathophysiological eVects of angiotensin II in congestive heart failure and after myocardial infarction have been amply demonstrated by the reduction in mortality seen in trials of angiotensin converting enzyme inhibitors and more recently, angiotensin II antagonists.1-3 The results cannot be explained by haemodynamic actions alone as other vasodilators are less eVective.4 5 We have previously suggested that the explanation may lie in the adverse eVects of angiotensin II on cardiac autonomic nervous control. There is strong evidence that impaired cardiac autonomic function is associated with an adverse prognosis after myocardial infarction and in heart failure, 8 9 and animal experiments have shown that angiotensin II has direct eVects on both vagal and sympathetic nervous control. Inhibition of cardiac vagal activity by circulating angiotensin II is mediated both centrally 10 and peripherally. 11 There is also evidence of facilitatory eVects on sympathetic nervous activity.12 Most of this work has been performed in anaesthetised animals, making it diYcult to draw conclusions which can be applied reliably to humans.Investigation of the eVect of angiotensin II on cardiac autonomic activity in intact conscious animals and in humans is hampered by baroreflex activation caused by its powerful pressor eVect. One approach has been to control for the pressor eVect by comparing the results of angiotensin II infusion with those resulting from a control pressor agent such as phenylephrine. In dogs, little increase in vagal activity occurred during angiotensin II infusion despite the rise in arterial pressure; in contrast there was a marked increase in vagal activity during control pressor infusion of phenylephrine. 13 In humans, the baroreceptor heart rate reflex is similarly inhibited by angiotensin II.7 14 This does not appear to result from facilitation of sympathetic tone, as tritiated noradrenaline kinetic studies showed no significant diVerence in sympathetic activity during angiotensin II infusion and during an equipressor infusion of phenylephrine. 15In a previous study using analysis of heart rate v...

1. Animal studies show that cardiac vagal tone can be modified by gamma-aminobutyric acid neurons acting at several sites in the central nervous system. The present study has attempted to determine whether similar control exists in humans by using midazolam, a benzodiazepine. Benzodiazepines exert their main actions on the central nervous system by interacting co-operatively at the gamma-aminobutyric acid receptor. 2. Twenty patients took part in the study before undergoing cardiac catheterization. After resting for 20 min in a semi-supine position on a couch, ECG, blood pressure and respiration were recorded for 5-min periods with either controlled (fixed) or free respiration. During this time a baroreceptor sensitivity test was conducted. 3. Doses of 1 mg and 5 mg of midazolam were administered intravenously. 4. Five-minute segments of data, before and after midazolam, were subjected to power spectral and time-domain analysis. 5. Midazolam caused a decrease in the high-frequency and an increase in the low-frequency components of the power spectral density plot, and in addition reduced the mean R-R interval and R-R variability expressed as the interquartile difference, and pNN50. There were no significant changes in the sensitivity of the baroreflex or in the systolic, diastolic and average blood pressures. 6. This decrease in variability of heart period, particularly at a controlled respiratory frequency, strongly suggests that cardiac vagal tone in man can be regulated by gamma-aminobutyric acid neurons.

Impaired renal function is associated with a striking clinical and economic burden among patients presenting to cardiac intensive care. As a marker for future risk, renal function accounts for a substantial proportion of the burden of late mortality. The burden of risk suggests a greater potential opportunity for improvement of outcomes through optimisation of therapeutic strategies.