David M. Kaye

Effects of Aging on the Responsiveness of the Human Cardiac Sympathetic Nerves to Stressors

BACKGROUNDnAging increases human sympathetic nervous activity at rest. Beause of the probable importance of neural stress responses in the heart as triggers for clinical end points of coronary artery disease, it is pertinent to investigate whether sympathetic nervous responses to stresses are increased by aging.nnnMETHODS AND RESULTSnWe applied kinetic methods for measuring the fluxes to plasma of neurochemicals relevant to sympathetic neurotransmission in younger (aged 20 to 30 years) and older (aged 60 to 75 years) healthy men during mental stress (difficult mental arithmetic), isometric exercise (sustained handgrip), and dynamic exercise (supine cycling). The increase in total norepinephrine spillover to plasma with mental stress was unaffected by age. In contrast, the increase in cardiac norepinephrine spillover was two to three times higher in the older subjects (P < .05). The probable mechanism of this higher cardiac norepinephrine spillover was reduced neuronal reuptake of the transmitter, because age had no influence on the overflow of the norepinephrine precursor, dihydroxyphenylalanine, or intraneuronal metabolite, dihydroxyphenylglycol (levels of these two substances reflect rates of cardiac norepinephrine synthesis and intraneuronal metabolism), and the transcardiac extraction of plasma radiolabeled norepinephrine was lower in the older subjects (P < .05). An almost identical pattern of neurochemical response was seen with isometric exercise. During cycling, total norepinephrine spillover was 16% lower in the older men, but cardiac norepinephrine spillover was 53% higher.nnnCONCLUSIONSnReduced norepinephrine reuptake increases the overflow of the neurotransmitter to plasma from the aging heart during stimulation of the cardiac sympathetic outflow. Failure of transmitter inactivation at postjunctional receptors with aging would amplify the neural signal, and in the presence of myocardial disease could trigger adverse stress-induced cardiovascular events, particularly when accompanied by an age-dependent reduction in vagal tone. Reduction of postsynaptic adrenergic responsiveness with aging, however, might protect against this, as indicated by our finding that in no case was the heart rate increase during stress greater in older men, despite their having larger increases in cardiac norepinephrine spillover.

Phenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension

Previous reports suggest that neuronal norepinephrine (NE) reuptake may be impaired in essential hypertension, perhaps because of dysfunction of the NE transporter, although the evidence is inconclusive. To further test this proposition, we applied phenotypically relevant radiotracer methodology, infusion of tritiated NE and quantification of NE metabolites, to 34 healthy lean subjects (body mass index <27.0 kg/m2), 19 overweight (body mass index >28.0 kg/m2) but otherwise healthy normotensive subjects, 13 untreated lean patients with essential hypertension, and 14 obesity-related hypertensives. Spillover of NE from the heart was increased in lean hypertensives only (mean±SD 33.4±20.6 versus 16.1±11.7 ng/min in lean normotensives, P <0.05), but this could have resulted from high cardiac sympathetic nerve firing rates, faulty NE reuptake, or both. The arterial plasma concentration of 3-methoxy-4-hydroxylphenylglycol, an extraneuronal metabolite of NE, was elevated in lean hypertensives only (3942±1068 versus 3055±888 pg/mL in healthy subjects, P <0.05). The fractional extraction of plasma tritiated NE in passage through the heart, determined on the basis of neuronal NE uptake, was reduced in lean essential hypertensives (0.65±0.19 versus 0.81±0.11 in healthy subjects, P <0.05). Cardiac release of the tritiated NE metabolite [3H]dihydroxylphenylglycol, produced intraneuronally by monoamine oxidase after uptake of [3H]NE by the transporter, was reduced in lean hypertensives only (992±1435 versus 4588±3189 dpm/min in healthy subjects, P <0.01) These findings suggest that neuronal reuptake of NE is impaired in essential hypertension. Through amplification of the neural signal, such a defect could constitute a neurogenic variant of essential hypertension. In obesity-related hypertension, there was no phenotypic evidence of NE transporter dysfunction.

Region-Specific Neuropeptide Y Overflows at Rest and During Sympathetic Activation in Humans

Neuropeptide Y coexists with norepinephrine in sympathetic nerves and is coreleased into the circulation on sympathetic activation. Little is known about the regional release of neuropeptide Y in humans under normal conditions or in pathophysiological situations of sympathetic activation or denervation. We measured plasma neuropeptide Y-like immunoreactivity and norepinephrine concentrations in samples taken from the brachial artery; coronary sinus; and internal jugular, antecubital, or hepatic veins in volunteers aged 20 to 64 years. Regional neuropeptide Y overflow at rest was calculated from venoarterial plasma concentration differences and plasma flow, and norepinephrine spillover was determined by [3H]norepinephrine infusion techniques. Cardiac release of neuropeptide Y and norepinephrine was examined in response to various stressors as well as in clinical models of sympathetic activation, cardiac failure, and denervation after cardiac transplantation. In healthy volunteers, cardiac, forearm, and jugular venous sample neuropeptide Y concentrations were similar to arterial levels. Hepatic vein plasma neuropeptide Y was greater than arterial both at rest (119 +/- 5% of arterial, n = 7) and after a meal (132 +/- 12%, n = 7), with neuropeptide Y overflows of 6 +/- 2 and 11 +/- 2 pmol/min, respectively. In contrast, hepatomesenteric norepinephrine spillover was not significantly increased by feeding. Although coronary sinus plasma norepinephrine concentrations increased significantly with the cardiac sympathetic activation accompanying mental arithmetic, coffee drinking, isotonic exercise, and bicycle exercise, only the latter powerful sympathetic stimulus increased neuropeptide Y overflow. Cardiac failure was associated with increased resting release of both norepinephrine and neuropeptide Y from the heart, whereas postcardiac transplant norepinephrine spillover from the heart was reduced. The net overflow of neuropeptide Y to plasma observed at rest across the hepatic circulation, but not the cardiac, forearm, or cerebral circulations, indicates that the gut, the liver, or both make a major contribution to systemic plasma neuropeptide Y levels in humans. Sympathetic activation by exercise produced a modest increase in cardiac neuropeptide Y overflow but to only approximately 25% of the resting input from the gut and without a change in arterial neuropeptide Y concentration. Plasma neuropeptide Y measurements are less sensitive than those of plasma norepinephrine concentrations as an index for quantifying sympathetic neural responses regulating the systemic circulation.

Regional Sympathetic Effects of Low-Dose Clonidine in Heart Failure

Abstract—This study examined the effects of low doses of intravenous clonidine on regional and global sympathetic nervous system activity in heart failure. In heart failure, adrenoceptor-blocking treatments have a limited sphere of activity. Centrally acting sympatholytic therapies should be further investigated, with a specific emphasis on targeting cardiac and renal sympathetic overactivity. In 10 patients with moderate-severe congestive heart failure, we examined the effect of intravenous clonidine on systemic, cardiac, and renal sympathetic activity and on brain monoamine turnover using the norepinephrine spillover method. In addition, we assessed the effect of clonidine on cardiac release of the sympathetic cotransmitter neuropeptide Y. A dose of 1 &mgr;g/kg of clonidine resulted in a fall in cardiac (326±73 to 160±40 pmol/min, P <0.001), renal (2.5±0.6 to 1.5±0.3 nmol/min, P =0.01), and global norepinephrine spillover (4.0±0.6 to 3.1±0.5 nmol/min, P <0.01), with a significantly disproportionate reduction in cardiac versus total-body sympathetic activity (P <0.05). No significant changes in cardiac neuropeptide Y release or in central monoamine turnover were demonstrated. Clonidine, at modest doses, significantly attenuates cardiac and renal sympathetic tone in heart failure. In addition to the beneficial effects of antiadrenergic therapy in the heart, the renal sympatholytic effect may counter the salt and water retention that is a hallmark of the condition.

Chapter 126 – Panic Disorder

Publisher Summary nThe chapter focuses on sympathetic nervous activity and epinephrine secretion rates and epinephrine cotransmission in sympathetic nerves. Multiunit sympathetic nerve firing rates measured directly by microneurography, in the sympathetic outflow to the skeletal muscle vasculature, and rates of norepinephrine spillover from the sympathetic nerves of the whole body are normal in untreated, resting patients with panic disorder, as is the spillover of norepinephrine measured selectively for the sympathetic nerves of the heart. Release of epinephrine from the sympathetic nerves of the heart, as an accessory neurotransmitter, has been demonstrated in patients with panic disorder. Heart rate and blood pressure increase during a panic attack, primarily due to sympathetic nervous system activation and adrenal medullary secretion of epinephrine. When recorded directly by microneurography, the size of sympathetic bursts increases remarkably during a panic attack, without any increase in firing rate. With the pronounced activation of the cardiac sympathetic outflow occurring during a panic attack, neuropeptide Y (NPY) is coreleased from the cardiac sympathetic nerves and appears in measurable quantities in coronary sinus venous blood.

106 – Panic Disorder

Publisher Summary nThere may be a precipitating cause of panic—such as being in a confining space (as in claustrophobia) or in public places (as in agoraphobia)—but in many cases, the occurrence of panic attacks is unexpected. Recurring attacks over a period of months or, in many cases, years, form the basis for the diagnosis of a panic disorder. This is a distressing and often very restricting condition, and it can lead to social avoidance behavior. Heart rate and blood pressure increase during a panic attack, primarily because of sympathetic nervous system (SNS) activation and adrenal medullary secretion of epinephrine (EPI). Affected individuals often fear that they have a heart disease because of the nature of their symptoms. Understanding autonomic nervous system (ANS) responses during a panic attack has been seen as relevant clinically because this might provide a rational basis for understanding the symptoms, and through this, for facilitating the treatment that can be based in part on patient self-knowledge as with cognitive behavior therapy. Clinical experience with the cardiologic management of patients with panic disorder has provided case material encompassing the range of cardiac complications that occur. A better understanding of the mechanism of coronary artery spasm in a panic disorder would facilitate therapeutic intervention.