Chronic renal failure may be accompanied by reversible sympathetic activation, which appears to be mediated by an afferent signal arising in the failing kidneys.

Acute hypotension is an important complication of hemodialysis, but the underlying mechanisms remain poorly understood. Because hemorrhage-induced hypovolemia can trigger a sudden decrease in sympathetic activity resulting in bradycardia and vasodilation, we hypothesized that hemodialysis-induced hypovolemia also can trigger the same type of vasodepressor reaction, which would exacerbate the volume-dependent fall in blood pressure. We therefore measured blood pressure, vascular resistance, and sympathetic nerve activity (intraneural microelectrodes) during sessions of maintenance hemodialysis in 7 patients with and 16 patients without a history of hemodialysis-induced hypotension. During hemodialysis, blood pressure at first remained unchanged as calf resistance increased in both hypotension-resistant (from 37±4 to 49±5 U, P < 0.05) and hypotension-prone (from 42±6 to 66±12 U, P < 0.05) patients; sympathetic activity increased comparably in the subset of patients in whom it could be measured. With continued hemodialysis, calf resistance and sympathetic activity increased further in the hypotension-resistant patients, but in the hypotensionprone patients the precipitous decrease in blood pressure was accompanied by decreases in sympathetic activity, vascular resistance, and heart rate as well as symptoms of vasodepressor syncope. On an interdialysis day, both groups of patients increased vascular resistance normally during unloading ofcardiopulmonary baroreceptors with lower body negative pressure and increased heart rate normally during unloading of arterial baroreceptors with infusion of nitroprusside. These findings indicate that in a group of hemodialysis patients without diabetes or other conditions known to impair autonomic reflexes, hemodialysis-induced hypotension is not caused by chronic uremic impairment in arterial or cardiopulmonary baroreflexes but rather by acute, paradoxical withdrawal of sympathetic vasoconstrictor drive producing vasodepressor syncope. (J. Clin.

Activation of a metabolically generated reflex in exercising skeletal muscle (muscle metaboreflex) in humans is known to trigger increases in sympathetic nerve activity (SNA) to resting skeletal muscles. In seven healthy human subjects, to determine whether this reflex mechanism also increases SNA to the exercising muscles, we recorded muscle SNA with microelectrodes in the right peroneal nerve and in fascicles of the left peroneal nerve selectively innervating the exercising muscles of the left foot. Subjects performed static toe extension at 20% maximal voluntary contraction alone or in combination with foot ischemia. Only static toe extension at 20% MVC during ischemia activated the muscle metaboreflex. This paradigm caused increases in SNA to exercising muscle that paralleled those to the resting muscles: during the first minute of exercise SNA was unchanged, but during the second minute SNA increased from 29 +/- 2 to 38 +/- 2 bursts/min (P < 0.05) to the exercising muscles and from 30 +/- 3 to 40 +/- 2 bursts/min (P < 0.05) to the resting muscles. These bilateral increases in SNA were maintained when metaboreflex activation was sustained by postexercise foot ischemia. In conclusion, these data provide neurophysiological evidence that the muscle metaboreflex evokes parallel sympathetic activation in exercising and resting human skeletal muscle.

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...

The aim of this study was to reexamine the hypothesis that cardiopulmonary baroreflexes are more important than sinoaortic baroreflexes in causing vasoconstriction in the skeletal muscle circulation during orthostatic stress. We recorded muscle sympathetic nerve activity (MSNA) with microelectrodes in the peroneal nerve (and forearm blood flow with venous occlusion plethysmography) in normal subjects (innervated ventricles) and in heart transplant recipients (denervated ventricles) during graded lower body negative pressure (LBNP) performed alone and in combination with intravenous infusion of phenylephrine, which was titrated to eliminate the orthostatically induced fall in blood pressure and thus the unloading of both carotid and aortic baroreceptors. The principal new findings are as follows: (1) The increases in both MSNA and forearm vascular resistance during multiple levels of LBNP were not attenuated by heart transplantation, which causes ventricular but not sinoaortic deafferentation. (2) In heart transplant recipients, a small increase in MSNA during mild LBNP was dependent on a decrease in arterial pressure, but in normal subjects, a similar increase in MSNA occurred in the absence of any detectable decrease in the aortic pressure stimulus to the sinoaortic baroreceptors. (3) In normal subjects, the large increase in MSNA during a high level of LBNP was dependent on a decrease in arterial pressure and could be dissociated from the decrease in central venous pressure. Taken together, the findings strongly suggest that sinoaortic baroreflexes are much more important and ventricular baroreflexes are much less important than previously thought in causing reflex sympathetic activation and vasoconstriction in the human skeletal muscle circulation during orthostatic stress. (Circulation Research 1993;73:367-378) KEY WORDS * sympathetic nervous system rentricular mechanoreceptors with C-fiber vagal afferents have been firmly established to reflexly inhibit sympathetic vasomotor outflow in experimental animals,1 but the role played by these afferents in the reflex control of the human cardiovascular system remains incompletely understood.Previous hemodynamic studies in humans have suggested that cardiac filling pressure and contractility, the primary determinants of ventricular mechanoreceptor C-fiber discharge in experimental animals,2,3 also are primary determinants of efferent sympathetic vasomoReceived August 6, 1991; accepted April 21, 1993. From the Department of Internal Medicine, Cardiology Division (T.N.J., B.J.M., U.S., S.F.V., R.A.L., R.G.V.), and the Department of Thoracic ventricular sensory receptors * baroreceptor reflexes tor activation during orthostatic stress.4-6 During simulated orthostatic stress with lower body negative pressure (LBNP), ,B-adrenergic blockade, which decreases ventricular contractility in normal humans, and heart transplantation, which produces ventricular deafferentation, each were found to greatly attenuate the increase in forearm vascular resistance induced by a gi...