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(Hypertension. 1996;28:483-487.)
© 1996 American Heart Association, Inc.

Articles

Subconstrictor Doses of Neuropeptide Y Potentiate ₁-Adrenergic Venoconstriction In Vivo

Lilly Linder; Brigitte M. Lautenschlager; Walter E. Haefeli

the Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital Basel (Switzerland).

Correspondence to Walter E. Haefeli, MD, Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail haefeli@ubaclu.unibas.ch.

	Abstract

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The 36–amino acid human neuropeptide Y is a vasoactive compound released after stimulation of the sympathetic nervous system. In addition to its direct and long-lasting vasopressor effects, it may potentiate the constrictor action of catecholamines and other vasoconstrictors at doses that do not per se exert vascular effects. Using the hand vein compliance technique, we have previously shown that neuropeptide Y also constricts superficial hand veins and that its effects may last for several hours. In this study, we investigated the local effect of neuropeptide Y on ₁-adrenergic venoconstriction in nine healthy volunteers at dose rates that did not affect venous compliance. On separate days, cumulative dose-response curves to phenylephrine alone and with coadministration of 1 or 30 pmol neuropeptide Y per minute were constructed, and the responses were fitted to a four-parameter logistic equation. Neuropeptide Y dose dependently shifted the phenylephrine curves toward lower dose rates without affecting maximal effects. ED₅₀ values for phenylephrine alone and with 1 or 30 pmol/min neuropeptide Y were 4.0, 4.9 (P=NS versus control), and 1.2 (P<.005) nmol/min, respectively. Comparison with neuropeptide Y dose-response curves revealed that the interaction was synergistic. These are the first data in humans to show that small dose rates of neuropeptide Y may potentiate -adrenergic effects in vivo. Because this interaction occurs at estimated local concentrations nearly achieved in humans, these studies suggest that neuropeptide Y might modulate the filling of this capacitance system in vivo.

Key Words: adrenergic receptor agonists • neuropeptides • vasoconstriction • human

	Introduction

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Human neuropeptide Y (h-NPY), an endogenous 36–amino acid peptide discovered in 1982,¹ is costored with norepinephrine in perivascular sympathetic nerves and released together with the catecholamine after sympathetic nerve stimulation in animals.² In vitro, it is a potent, endothelium-independent^{2 3 4} vasoconstrictor with variable contractile effects in a variety of species, including humans.² In arteries, its efficacy is similar to that of other vasoconstrictors such as phenylephrine or norepinephrine, but its potency is higher than that of -adrenoceptor agonists and approximately 10-fold lower than endothelin-1.^{2 4}

Thus far, only limited information concerning the in vivo effects of h-NPY in the human vasculature is available. When administered topically, h-NPY constricts the vessels of the nasal mucosa,⁵ and local intravascular administration of h-NPY in the arterial^{6 7} or venous⁸ system of the human forearm causes potent and long-lasting constriction. When infused into coronary arteries of individuals with angina pectoris, h-NPY induces a transient myocardial ischemia that is mainly due to constriction of small vessels rather than to constriction of epicardial coronary arteries.⁹ In addition to its direct vasoconstrictor action, h-NPY at concentrations that per se have no constrictor effect has also been shown to modulate the pressor effects of catecholamines and histamine.^{2 10 11 12 13 14 15}

The role of circulating h-NPY is largely unknown. Elevated concentrations of plasma h-NPY have been found in numerous physiological and pathophysiological conditions that involve the sympathetic nervous system or modulate its activity. Increasing age, physical exercise, cold pressor testing, myocardial infarction, heart failure, and cigarette smoking all have been associated with increased circulating h-NPY concentrations.^{2 16 17 18 19 20 21 22 23} Plasma concentrations may often reach levels of 0.05 to 0.1 pmol/mL, and in a group of individuals with pheochromocytoma and ganglioneuroblastoma, concentrations of up to 2.3 pmol/mL have been reported.^{2 23 24} Hence, certain pathological conditions may be associated with h-NPY concentrations as high as those required for -adrenergic potentiation in vitro.

We conducted these studies to address the question of whether h-NPY modulates ₁-adrenergic effects in vivo in hand veins, which are part of the venous capacitance system and are known to be under close sympathetic control. In this vasculature, small changes in the compliance and tone of subcutaneous veins may significantly modify the filling state of the venous system and thereby the blood distribution and subsequent volume load of the heart.²⁵

	Methods

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Subjects
Nine healthy nonsmokers (four women, five men) with a mean age of 31 years (range, 20 to 40 years) and mean weight of 70 kg (54 to 90 kg) entered the study after having given written informed consent. No subject was taking any medication other than oral contraceptives. The protocol was reviewed and approved by the Ethics Committee of the University Hospital of Basel (Switzerland). The volunteers were allowed to eat a light breakfast but were asked to refrain from all methylxanthine- and alcohol-containing beverages for at least 12 hours before the study. They remained semirecumbent in a quiet room with a constant temperature of 22±1°C throughout the study.

Materials
h-NPY was purchased from Clinalfa AG and phenylephrine (Neo-Synephrine) from Sanofi Winthrop. To prevent the peptide from sticking to tubing, 4% gelatin (Physiogel, SRK) solutions were used for all studies as solvent.

Hand Vein Compliance Technique
Hand vein experiments were performed as previously described.^{26 27} In brief, a continuous infusion of 4% gelatin solution (0.25 mL/min) was delivered through a 23-gauge needle into a suitable vein on the dorsal surface of the hand with a high-precision infusion pump (Harvard Apparatus Inc). The arm was placed on a vacuum pillow above heart level sloping upward at an angle of 30° to allow for complete emptying of the vein. A tripod holding a linear variable differential transformer (LVDT, Schaevitz Engineering) was mounted on the top of the vein approximately 10 mm downstream from the tip of the needle. The freely movable core of the LVDT, weighing 5 g, was placed over the center of the vein under investigation. The vertical movement of the core is directly proportional to the signal output of the LVDT, which is recorded on a strip-chart recorder after amplification by a signal conditioner (Schaevitz ATA 101). The difference between the position of the core before and during inflation of a sphygmomanometer cuff on the same arm to 40 mm Hg gives a measure of the diameter changes under a given congestion pressure. Once a stable initial baseline with the gelatin solution was established, the vein was studied according to one of the protocols described below. Different studies in any given volunteer were separated by at least 6 days. To allow sufficient time for a maximal response to be reached, we measured the effects of h-NPY and phenylephrine not earlier than 8 and 6 minutes, respectively, after infusion of a given dose was started.

Protocols
We performed a series of experiments that addressed the question of whether h-NPY interacts with ₁-adrenergic venous responses and evaluated whether such an interaction is additive or synergistic. As interindividual variability in venous ₁-adrenergic effects is large,²⁸ a complete dose-response curve to phenylephrine (0.001 to 40 nmol/min) was constructed in every volunteer. This allowed assessment of net ₁-adrenergic effects and a comparison with dose-response curves modulated by h-NPY with the first ₁-adrenergic dose-response curve used as an individual control. After at least 6 days, the ₁-adrenergic dose-response curves were repeated with coadministration of small doses of h-NPY (1 or 30 pmol/min). In these coadministration studies, peptide administration was started at least 10 minutes before the first dose of phenylephrine and was maintained throughout the study. The dose rate of 1 pmol/min was chosen because it produces estimated local concentrations of less than 1 nmol/L, which do not potentiate effects mediated by ₁-adrenoceptors in vitro.¹⁰ Moreover, in previous experiments, this dose rate has not been found to evoke direct venoconstrictor effects.⁸ The dose rate of 30 pmol/min was selected because it produces local concentrations in a range close to circulating NPY levels under certain pathological conditions^{20 23 24} and because this concentration has been reported to exert synergistic effects in vitro.¹⁰

To control for the reproducibility of dose-response curves to ₁-adrenergic stimulation, we assessed phenylephrine (in gelatin solution) dose-response curves in four volunteers, each on two separate occasions separated by at least 1 week. The mean maximal effects (E_max) and mean dose rates eliciting 50% of E_max (ED₅₀) values were comparable in all these control volunteers (data not shown). In another subset of volunteers, we also constructed dose-response curves to h-NPY alone to quantify net h-NPY effects. These were necessary, as we have previously shown that interindividual variability in NPY responses is quite large.⁸ Moreover, these control dose-response curves to phenylephrine alone and h-NPY alone enabled us to graphically evaluate the interaction between the two vasoconstrictors to define whether the interaction was synergistic or purely additive.²⁹

Side Effects
h-NPY and phenylephrine were well tolerated in all volunteers, and no side effects were noted.

Data Analysis
Unless indicated otherwise, data are expressed as mean±SE. Individual dose-response curves to phenylephrine and h-NPY were fitted to a four-parameter logistic equation³⁰ by means of a computerized nonlinear regression analysis (Allfit, version 2.7; National Institutes of Health, Bethesda, Md). Pairs of curves were compared by F test as previously described.²⁷ Results of individual fits were compared by Student's t test for paired observations. A value of P<.05 was considered to indicate a statistically significant difference.

	Results

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Local Venous Effects
A series of dose-response curves constructed in the same volunteer in the absence of h-NPY and with coadministration of two different dose rates of h-NPY is shown in Fig 1. In this subject, a dose-response curve to h-NPY was also constructed. E_max and ED₅₀ values from individually fitted dose-response curves in all volunteers are shown in Table 1. The dose-response curves fitted after individual responses were averaged are shown in Fig 2. Whereas h-NPY did not affect E_max values, statistical analysis by t test (Table 1) and F test (Fig 2) revealed that the dose-response curves were significantly shifted to the left after coadministration of h-NPY at 30 pmol/min. Coadministration of h-NPY increased the potency of phenylephrine approximately fourfold, whereas E_max remained unchanged. The lower h-NPY dose rate (1 pmol/min) had no influence on the venoconstrictor effect of phenylephrine (Table 1, Fig 2).

View larger version (16K): [in this window] [in a new window]   Figure 1. Phenylephrine dose-response curves constructed in the same volunteer in the absence of human neuropeptide Y (h-NPY) () and during local coadministration of 1 () and 30 () pmol/min h-NPY. Respective individual ED50 values of phenylephrine alone and during 1 and 30 pmol/min were 8.7, 5.2, and 1.1 nmol/min. The fitted ED50 of h-NPY alone () was 0.23 nmol/min.

View this table: [in this window] [in a new window]   Table 1. Results of Individual Phenylephrine Dose-Response Curves Constructed in Hand Veins of Healthy Volunteers in the Absence and Presence of Small Doses of Human Neuropeptide Y

View larger version (15K): [in this window] [in a new window]   Figure 2. Dose-response relationships to phenylephrine fitted after data of all dose-response curves were averaged. ED50 values of these curves were 5.4, 5.1, and 1.7 nmol/min for phenylephrine alone () and in combination with 1 () and 30 () pmol/min human neuropeptide Y. Only the ED50 during administration of 30 pmol/min was significantly different from control values (P<.001, F test).

To determine whether the interaction between h-NPY and phenylephrine was synergistic (potentiation) or only additive, we constructed dose-response curves to h-NPY and phenylephrine alone as well as to phenylephrine with coadministration of a constant dose of h-NPY (30 pmol/min). Of the six subjects studied according to this protocol, two had no vasoconstrictor response to h-NPY up to dose rates of 2000 pmol/min. These were two volunteers who have been previously studied⁸ and in whom h-NPY was also found not to have a direct venoconstrictor effect. However, in all volunteers (including the two without direct venoconstrictor effects to h-NPY), the phenylephrine dose-response curve was shifted toward lower dose rates. Plots of isoboles (lines of drug combinations producing the same quantitative effect, Fig 3) according to the method of Berenbaum²⁹ revealed that the interaction was synergistic, indicating that small dose rates of h-NPY may potentiate ₁-mediated venoconstriction in humans in vivo.

View larger version (23K): [in this window] [in a new window]   Figure 3. Individual isoboles of four subjects showing synergy between human neuropeptide Y (h-NPY) and phenylephrine. Isoboles were constructed for venoconstrictor effects of 15%. Lines connecting the x and y axes indicate the zero interaction isoboles (), ie, the locus of all drug combinations that would have produced purely additive effects. Combined administration of phenylephrine and h-NPY (30 pmol/min) () revealed responses that were shifted to the left and below the connecting lines of net responses to either agonist, confirming that in the presence of small amounts of h-NPY, markedly lower doses of phenylephrine were needed to produce the same response (potentiation).

Hemodynamic Effects
In agreement with earlier findings,⁸ administration of h-NPY alone did not change supine blood pressure values at dose rates up to 2000 pmol/min. Whereas systolic pressure was also unaffected during coadministration of phenylephrine and h-NPY, there was a slight but statistically significant increase in diastolic pressure (P=.016) during the potentiation experiments with 30 pmol/min h-NPY (Table 2).

View this table: [in this window] [in a new window]   Table 2. Hemodynamic Effects Before (Control) and at the End of Administration of Vasoactive Compounds in Healthy Volunteers

	Discussion

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The most outstanding role of the subcutaneous venous capacitance bed is its active involvement in temperature regulation of the body and volume control of the circulation. In these vessels, tone is largely controlled by the sympathetic nervous system, and stimulators of sympathetic activity readily decrease the compliance of superficial hand veins.^{31 32} Any compound constricting these highly compliant vessels may therefore reduce venous pooling, provoke shifts of intravascular volume, and increase the preload of the heart. As suggested by numerous animal experiments, at least two classes of constrictors may mediate sympathetic vasoconstriction, namely, ₁-agonists and h-NPY. During acute activation of the sympathetic nervous system in humans (eg, after cytokine exposure), the observed hand vein constriction is mainly mediated through norepinephrine since it is completely reversed by local administration of phentolamine.³¹ Phentolamine is an inhibitor of ₁- and ₂-adrenoceptors that does not affect h-NPY–induced vasoconstriction in vitro² or in vivo.⁸ Although a direct contribution of h-NPY to venous tone in these conditions can be excluded, a modulatory effect on ₁-adrenergic responsiveness is still possible. The potential involvement of h-NPY has not been thoroughly investigated in veins.

Recent studies in our group have revealed potent but only moderately efficacious venoconstrictor effects of h-NPY.⁸ The lack of specific Y₁-receptor antagonists available for human use has precluded a study of the role of h-NPY in physiological and pathological conditions. Our studies⁸ suggested that under conditions associated with unusually high levels of circulating h-NPY (eg, pheochromocytoma), the peptide might exert direct venopressor actions. h-NPY has been found both in vitro and in vivo to markedly enhance the constrictor effects of phenylephrine,¹³ norepinephrine,^{10 11 12 33} epinephrine,³⁴ and histamine.³⁵ However, this synergistic effect largely depends on the origin of the isolated vessel or vascular bed studied. In certain studies, a heterogeneity between veins and arteries with respect to this interaction has been reported; no cooperation between norepinephrine and h-NPY has been observed in peripheral rabbit veins^{10 36} or human veins.³⁵ We performed the present study to further evaluate the role of h-NPY in the human capacitance bed. Because of the large interindividual variability in both -adrenergic²⁸ and h-NPY⁸ responses, a potential interaction can be detected only with a study design in which each subject acts as his or her own control.

These are the first studies providing evidence for a synergistic interaction between low concentrations of h-NPY and ₁-adrenoceptor agonists in humans in vivo. In keeping with animal experiments,¹⁰ h-NPY dose dependently interacted with the ₁-agonist. Whereas dose rates of 1 pmol/min had no effect, the dose-response relationship of phenylephrine was shifted to the left after coadministration with 30 pmol/min h-NPY. The extent of the shift (fourfold) is well within the range observed previously.^{10 12 33} Similarly to most in vitro findings,^{10 14 33} h-NPY did not affect the E_max of the phenylephrine dose-response relationship. Assuming a local flow in a human hand vein of 0.5 to 2.5 mL/min,^{37 38} the local concentration of h-NPY is estimated to be 12 to 60 pmol/mL. Circulating concentrations only slightly below this range have been reported in patients with congestive heart failure²⁰ and with pheochromocytoma.^{2 23} Since h-NPY is released from nerve endings located in the adventitia of the vessel, the peptide exerts its effect in a paracrine fashion. Thus, assumptions based on circulating levels may underestimate the effect on vascular smooth muscle.

As graphically presented in Fig 3, the interaction between phenylephrine and h-NPY was clearly synergistic. Interestingly, the phenylephrine dose-response curve was also shifted to the left in the two subjects in whom h-NPY alone had no effect on hand vein compliance. Synergy between phenylephrine and h-NPY is also evident from changes in diastolic pressure (Table 2). Although no change in this parameter was observed during the construction of either the h-NPY dose-response curve or the phenylephrine dose-response curve with coadministration of 1 pmol/min h-NPY, diastolic pressure was significantly higher during coinfusion experiments with 30 pmol/min h-NPY. This difference is not due to differences in total amounts of h-NPY administered in these experiments, as 14-fold higher doses were administered to construct the h-NPY dose-response curve (approximately 31.2 nmol per experiment) compared with approximately 2.3 nmol required for potentiation experiments with 30 pmol/min h-NPY. In the arterial circulation of the human forearm, h-NPY at 50 pmol/min was reported not to affect the response to norepinephrine.⁷ However, in this previous study,⁷ sequential dose-response curves to h-NPY, norepinephrine, and a combination of norepinephrine and h-NPY were constructed. Washout periods between each dose-response profile were only 30 minutes. Under these conditions, the vasoconstrictor effects of h-NPY in the human forearm persist at the time norepinephrine is administered.⁶ It is therefore likely that the potentiation experiments were performed⁷ when h-NPY effects were still present. Studies using such a sequential design cannot exclude the possibility that the initial norepinephrine dose-response relationship was already shifted toward lower dose rates.

Although the potentiation of vasoconstrictor effects by h-NPY is a widely accepted phenomenon, the mechanism by which synergistic effects occur remains unclear. Recent studies imply that the potentiation of vascular effects does not occur via a presynaptic mechanism³⁶ and that the vascular Y₁-receptor is involved.³⁹ Moreover, as h-NPY may also potentiate the effect of noradrenergic vasoconstrictors,^{10 40} interaction between h-NPY and other constrictors may occur at the postreceptor rather than the receptor level. Indeed, phenylephrine-induced accumulation of inositol phosphates has been shown to be markedly increased by h-NPY concentrations that per se do not affect this second messenger system.⁴¹ It therefore appears possible that h-NPY might modulate the action of other compounds that exert vasoconstriction through the same second messenger system (eg, endothelin-1).

In conclusion, these in vivo experiments in human hand veins provide the first direct evidence for a synergistic interaction between the two main mediators of sympathetic vasoconstriction, ₁-adrenoceptor agonists and h-NPY. Since interaction occurred at estimated local concentrations that can be achieved in patients with heart failure,²⁰ h-NPY might substantially modulate the venous tone of superficial hand veins in vivo and thereby modify the filling of this capacitance system.

	Acknowledgments

 
These studies were supported in part by grants from the Swiss National Research Foundation (Nos. 32-36575.92 and 3200-036575.92/2). We would like to thank Dr Therese Resink for helpful comments and discussions.

Received November 13, 1995; first decision December 18, 1995; accepted April 4, 1996.

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