Nitric Oxide and Cardiac Autonomic Control in Humans

Abstract

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 ...

Influence of Vitamin C on Baroreflex Sensitivity in Chronic Heart Failure

“…Accordingly, experimental evidence shows that a reduction in prostacyclin, an increase in free oxygen radicals, and the reduced endotheliumdependent synthesis of nitric oxide associated with endothelial dysfunction are all factors that reduce baroreflex sensitivity. 7,19,20 Vitamin C, a potent antioxidant, improves endothelial function. Besides reducing oxidative stress, 17 it acts also to suppress the induction of endothelial cell apoptosis by cytokines, tumor necrosis factor-␣, and angiotensin II.…”

“…18 Regardless of how it acts, by improving endothelial cell function, vitamin C could improve autonomic nervous system control through 2 mechanisms: indirectly, by improving hemodynamics, or directly, by acting on subendothelial nerve endings at the baroreceptor level (carotid, aortic, or cardiopulmonary). Possible support for a direct action comes from the recent observation that endothelium-derived nitric oxide increases vagal activity in patients with CHF 19,20 and that acute infusion of vitamin C influences nitric oxide-mediated vasodilation. 21 Acute administration of vitamin C might therefore improve local nitric oxide production, thus directly stimulating the vagus nerve.…”

Spironolactone impairs endothelial function and heart rate variability in patients with Type 2 diabetes

“…Although these small changes may not be of great clinical significance, the fact that heart rate variability also deteriorated with spironolactone treatment makes it unlikely that the worsening of endothelial function is due to chance, since heart rate variability has been shown to be closely associated with nitric oxide activity [35,36].…”

Nitric oxide and hypertension: not just an endothelium derived relaxing factor!

“…Conversely, during hypotension resulting from the NO donor sodium nitroprusside, there was relative preservation of indices of vagal activity compared to those produced by an equal fall in blood pressure with the non-NO dependent vasodilator, hydralazine. 93 …”