Cardiovascular trophic effects from the sympathetic nerve cotransmitter neuropeptide Y in end-stage renal disease?

Subsequent to von Euler's identification of noradrenaline as the major sympathetic nerve neurotransmitter [1], a variety of substances have been found to be coreleased with noradrenaline during sympathetic transmission. Some, including chromogranin A [2] and dopamine-β-hydroxlase (DβH) [3], which are both constituents of sympathetic nerve vesicles, are coreleased from the vesicles with noradrenaline during sympathetic nerve firing but do not serve a transmitter function. Other substances, such as adrenaline and neuropeptide Y (NPY) also are released with noradrenaline, but function as cotransmitters, either commonly as for NPY [4], or in special circumstances, as for adrenaline [5,6]. Efforts have been made to use the rates of release of DβH, chromogranin A and NPY as clinical and experimental neurochemical indices of sympathetic nerve firing rates [2–4]. The theoretical backdrop to these efforts has been the difficulty of quantifying rates of release of noradrenaline from sympathetic nerves. Measurement of the overflow (`spillover') of noradrenaline from individual organs to estimate regional sympathetic nervous system activity is both possible, using isotope dilution methodology [7], and useful, but this technique does not measure actual release rates of the transmitter because the extent of neuronal reuptake of noradrenaline is usually not known. It was hoped that DβH, chromogranin A and NPY measurements, being free of this confounding by neuronal reuptake, would have greater validity than noradrenaline measurements. It turns out that plasma DβH measurements are not valid for this purpose because plasma DβH concentration in humans is bimodally distributed under a genetic influence independent of sympathetic nervous system activity [3]. Measurement of plasma chromogranin concentrations is more helpful [2], although as yet not widely adopted, with increased values being described in patients with essential hypertension. Plasma NPY measurements have found wider application [8] and are featured in the study by Zoccali et al. [9] on patients with end-stage renal disease in this issue of the journal. NPY is a cotransmitter in sympathetic nerves, particularly in those distributed to the cardiovascular system, and is most strikingly evident in the sympathetic innervation of the arterial wall [10]. NPY, in appearing to be disproportionately released at very high rates of sympathetic nerve firing [4] might be particularly suited to detecting sympathetic nervous activation in conditions such as end-stage renal disease, where sympathetic nervous system stimulation has been well documented in sympathetic nerve recordings provided by clinical microneurography [11,12]. Zoccali et al. [9] describe a broad spread of NPY plasma concentrations in patients with renal failure. Although the results from a reference population of healthy people is not provided for comparison, in the patient tertile with highest NPY values, the NPY plasma concentration is clearly elevated, and accompanied by a high plasma noradrenaline concentration, an elevated heart rate and more pronounced left ventricular hypertrophy. End-stage renal disease (ESRD) is associated with an extraordinarily high incidence of cardiovascular mortality [13]. This has previously been tentatively attributed to the high level of sympathetic tone [11,12] which, in other contexts such as cardiac failure [14], has been demonstrated to contribute directly to myocardial damage and to the development of ventricular dysrhythmias. Zoccali et al. [9] make a very plausible, if perhaps not conclusive, case for NPY released from sympathetic nerves having a specific trophic effect, beyond that resulting from high exposure to noradrenaline, in contributing directly to myocyte growth, for which there is independent experimental evidence [15], and to the development of left ventricular hypertrophy. Cardiac hypertrophy is so prevalent in ESRD as to strongly suggest the presence of important trophic influences acting in concert with the elevated blood pressure. What might be the origins of the chronic sympathetic activation of ESRD? Perhaps the elevated plasma concentration of the adipocyte hormone, leptin, reported previously in ESRD [16], and noted here, might be contributing. However, in the study by Zoccali et al. [9], leptin and indices of sympathetic activity were not closely linked. This lack of a relationship between plasma NPY and leptin concentrations is not surprising on two grounds. First, although there is a direct stimulatory influence of leptin on the sympathetic nervous system, demonstrable in rodents [17], this remains unproven in humans [18]. Second, leptin plasma concentration is very sensitive to renal clearance, and is elevated in renal insufficiency patients largely due to a reduction in leptin plasma clearance; most plasma clearance of leptin is renal [19]. Recent evidence suggests afferent neural signals from the diseased kidneys underly the sympathetic activation of ESRD [11,20]. Nephrectomy, by removing this input to the brain, normalizes sympathetic outflow in ESRD [11]. It might be said that the authors are perhaps too trusting in their acceptance of plasma NPY concentrations as a quantitative marker of sympathetic nervous system activity. Although NPY is released from sympathetic nerves at high rates of nerve firing, NPY in systemic plasma primarily derives from the gut, with the input via the hepatic vein to the central plasma pool being much greater than from all other regional venous drainages [21]. Although the elevated plasma NPY concentration of ESRD is probably due in part to increased sympathetic nerve firing in sympathetic outflows other than the sympathetic innervation of the gastrointestinal tract, cardiac sympathetic activation would make a small contribution only to the systemic plasma NPY concentration [21]. If coronary sinus sampling had been performed to directly estimate release of NPY by the cardiac sympathetic nerves (and the failure to make this measurement in the present study is of course understandable), the present uncertainties that still remain concerning the possible direct relationship of high intra-cardiac concentrations of NPY with stimulation of cardiomyocyte growth and the development of left ventricular hypertrophy in ESRD possibly would have been resolved.