Characterization of neuropeptide Y (NPY) receptors in human cerebral arteries with selective agonists and the new Y1 antagonist BIBP 3226.

1. We have characterized pharmacologically the receptor subtype(s) responsible for the neuropeptide Y (NPY)-induced vasoconstriction in human cerebral arteries. NPY, PYY and several of their derivatives with well defined affinities at the known Y1 and Y2 receptor subtypes were used. Moreover, we tested the ability of the new Y1 receptor antagonist, BIBP 3226, to antagonize the NPY-induced cerebral vasoconstriction. 2. NPY, PYY and their agonists with high affinities at the Y1 receptor subtype ([Leu31-Pro34]-NPY and [Leu31-Pro34]-PYY) elicited strong, long lasting and concentration-dependent contractions of human cerebral arteries. Compounds with Y2 affinity such as PYY3-36 or NPY13-36 either elicited a submaximal contraction at high concentrations or failed to induce any significant vasomotor response. Also, the application of NPY or the specific Y1 agonist, [Leu31-Pro34]-NPY, to human cerebral vessels pretreated with the Y1 agonist, NPY13-36, resulted in contractile responses identical to those obtained when these compounds were tested without prior application of NPY13-36. 3. The order of agonist potency at the human cerebrovascular receptor was: [Leu31-Pro34]-NPY = [Leu31-Pro34]-PYY > or = NPY > PYY > PYY3-36 > > > NPY13-36, which corresponded to that reported previously at the neuronal and vascular Y1 receptors. 4. Increasing concentrations (10(-9)-10(-6) M) of the Y1 receptor antagonist, BIBP 3226, to human cerebral vessels caused a parallel and rightward shift in the NPY dose-response curves without any significant change in the maximal contractile response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuropeptide Y (NPY) suppresses yohimbine-induced reinstatement of alcohol seeking

Introduction  

Reinstatement of responding to a previously alcohol-associated lever following extinction is an established model of relapse-like behavior and can be triggered by stress exposure. Here, we examined whether neuropeptide Y (NPY), an endogenous anti-stress mediator, blocks reinstatement of alcohol-seeking induced by the pharmacological stressor yohimbine.     

Effects of a selective neuropeptide Y Y(1) receptor antagonist BIBP 3226 on double peaked vasoconstrictor responses to periarterial nerve stimulation in canine splenic arteries

The periarterial electrical nerve stimulation (30 s trains of pulses at a frequency of 1, 4 or 10 Hz) induced a double peaked vasoconstriction consisting of an initial transient constriction (first peak) followed by a prolonged response (second peak) in the isolated, perfused canine splenic artery. At low frequencies (1 and 4 Hz), a neuropeptide Y (NPY) Y(1) receptor antagonist BIBP 3226 (0.1-1 microM) produced a dose-dependent inhibitory effect on the second peak, but did not modify the first peak. At a high frequency (10 Hz), 1 microM BIBP 3226 induced a slight, but significant inhibition on both the first and second peaked responses. At a low frequency (1 Hz), the first peak was not influenced by blockade of alpha(1)-adrenoceptors or NPY Y(1) receptors with prazosin (0.1 microM) or BIBP 3226 (1 microM), respectively, but abolished by P2X receptor desensitization with alpha,beta-methylene ATP (alphabeta-m ATP, 1 microM). At a high frequency (10 Hz), the first peak was mostly inhibited by alphabeta-m ATP and partially by prazosin and BIBP 3226. On the other hand, the second peak at a low frequency was largely decreased by BIBP 3226 and partially by prazosin and alphabeta-m ATP, whereas at a high frequency, it was largely attenuated by prazosin and partially by alphabeta-m ATP and BIBP 3226. The results suggest that at a low frequency, the firstly transient constriction of double peaked responses is mainly induced via an activation of P2X-receptors, whereas at a high frequency, it is mostly mediated by the P2X-receptors, and partially by alpha(1)-receptors and NPY Y(1)-receptors. The secondary prolonged vasoconstriction at frequencies used is predominantly mediated via both alpha(1)-receptor and NPY Y(1) receptor activations, and in part by P2X-receptors. Furthermore, an activation of NPY Y(1) receptors may play an important role in evoking the prolonged vasoconstrictor response to longer pulse trains of stimulation at a low frequency, whereas an alpha(1)-adrenoceptor activation exerts a main vasomotor effect for the prolonged response at a high frequency.     

The involvement of neuropeptide Y Y1 receptors in the blood pressure baroreflex: studies with BIBP 3226 and BIBO 3304.

To ascertain the role of the neuropeptide Y Y1 receptors in the vascular manifestations of the sympathetic baroreflex, 10-s bilateral carotid occlusions were performed in anesthetized cats; systemic blood pressure was monitored continually. This maneuver rose systolic blood pressure in 23 +/- 2 mmHg. Following 100 microg/kg BIBP 3226 or BIBO 3304 i.v., the increase in blood pressure elicited by the occlusions was only 14 +/- 1 and 15 mmHg, respectively. Both BIBP 3226 and BIBO 3304 displaced significantly 5.5 fold rightward the pressor dose-response curve elicited by exogenous neuropeptide Y, without altering the norepinephrine curve. Prazosin (10 microg/kg) reduced the pressor response elicited by the carotid occlusion to 12 +/- 4 mmHg. The simultaneous administration of BIBP 3226 plus prazosin rose the systemic blood pressure following the occlusion only 9 +/- 2 mmHg, supporting the involvement of neuropeptide Y in vascular sympathetic reflexes.     

Neuropeptide Y (NPY) Y4 receptor selective agonists based on NPY(32-36): development of an anorectic Y4 receptor selective agonist with picomolar affinity

We have previously shown [Cys-Trp-Arg-Nva-Arg-Tyr-NH(2)](2), 1, to be a moderately selective neuropeptide Y (NPY) Y(4) receptor agonist. Toward improving the selectivity and potency for Y(4) receptors, we studied the effects of dimerizing H-Trp-Arg-Nva-Arg-Tyr-NH(2) using various diamino-dicarboxylic acids containing either di-, tri-, or tetramethylene spacers. These parallel dimers, 2A, 2B, 3, 4A, and 4B, and the corresponding linear tandem dimer and trimer analogues, 5 and 6, had enhanced selectivity and affinity for Y(4) receptors compared to 1 (Table 1). Substitution of Trp and Nva with Tyr and Leu, respectively, as in 2,7-d/l-diaminosuberic acid derivatized dimer, 7, resulted in a superior Y(4) selective agonist with picomolar affinity. Intraperitoneal (ip) injection of 7 potently inhibited food intake in fasted mice. Moreover, 7 (ip) inhibited the food intake in wild-type mice and not in Y(4)(-/-) knock-out mice, confirming that the actions of 7 on food intake are not due to global effects, but specifically mediated Y(4) receptors.     

Neuropeptide Y (NPY) inhibits spontaneous contraction of the mouse atrium by possible activation of the NPY1 receptor

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Neuropeptide Y (NPY) metabolism by endopeptidase-2 hinders characterization of NPY receptors in rat kidney.

1. Despite the observation of pharmacological responses to neuropeptide Y (NPY) in mammalian kidneys, there are species differences in the ease with which specific NPY binding sites can be demonstrated; we have investigated whether this can be explained by differential metabolism of NPY by a membrane-bound peptidase. 2. NPY receptors were identified on cell membranes isolated from the rabbit kidney (KD = 97 +/- 16 pM, Bmax = 290 +/- 30 fmol mg-1 protein), and this preparation did not degrade [125I]-NPY. However, a similar preparation of cell membranes from the rat kidney exhibited a much lower apparent receptor affinity (IC50 approximately 30 nM); these membranes rapidly degraded [125I]-NPY to fragments which did not bind NPY receptors in either tissue. 3. [125I]-NPY binding sites were revealed in the rat kidney when degradation was inhibited by insulin B chain. Chelating agents also inhibited degradation, but interfered with receptor binding. Binding sites could not be demonstrated in sections of rat kidney, even in the presence of insulin B chain. 4. The difference in degradative activity between rat and rabbit renal cell membranes, inhibition of degradation by chelating agents and insulin B chain, and insensitivity to phosphoramidon suggest that the enzyme responsible was endopeptidase-2, and this was confirmed by comparing the hydrolysis of [125I]-NPY by purified enzyme with rat renal tissue. Activity of this enzyme explains the difficulties encountered demonstrating receptors in the rat kidney. 5. Renal cell membranes from the mouse digested [125I]-NPY in a similar manner and this may be due to the closely related enzyme, meprin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for involvement of neuropeptide Y receptors in the regulation of food intake: studies with Y1-selective antagonist BIBP3226

1. Experiments were conducted to evaluate the effects of the novel non-peptide neuropeptide Y Y₁ receptor antagonist, BIBP3226 (N²-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]-D-arginine amide) on spontaneous, fasting-induced and NPY-induced food intake in rats. In addition to consumption of regular chow, the effects of BIBP3226 on consumption of highly palatable sweetened mash were monitored in a 1 h test on first exposure and after familiarization with novel food.
2. BIBP3226 (10.0 nmol, i.c.v.) had no effect on the consumption of regular chow, but reduced significantly the intake of highly palatable diet and the food intake stimulated by fasting (24 h). Neuropeptide Y (NPY, 1.0 nmol, i.c.v.) significantly increased the consumption of regular rat chow. This orexigenic effect of NPY was blocked by BIBP3226 (10.0 nmol, administered i.c.v. 5 min before NPY) at 30  min and 4  h, but not at 1 and 2  h. When animals were pretreated with diazepam (0.5 mg kg⁻¹, i.p., 20 min before NPY), BIBP3226 failed to suppress NPY-induced feeding.
3. An NPY Y₁ and Y₃ receptor agonist, [Leu³¹,Pro³⁴]NPY and a Y₅ receptor agonist human peptide YY_3–36 (hPYY_3–36, both 30 pmol), microinjected into the paraventricular nucleus of the hypothalamus (PVN) increased the consumption of regular rat chow. BIBP3226 (0.4 nmol, into the PVN) completely blocked the stimulatory effect of [Leu³¹,Pro³⁴]NPY but not that of hPYY_3–36. BIBP3226 (0.4 nmol) alone failed to modify the consumption of the regular chow. Higher doses of BIBP3226 (1.0 and 2.0 nmol) injected into the vicinity of the PVN reduced the consumption of the sweetened mash.
4. These results suggest that both the NPY Y₁ and Y₅ receptors in the PVN are involved in the regulation of food intake. The stimulatory effect of exogenous NPY is probably mediated through an NPY receptor subtype that is not identical with the Y₁ receptor (possibly Y₅ receptor). However, the NPY Y₁ receptors may mediate the effect of endogenous NPY in conditions of increased energy demand or on intake of highly palatable diets.

     

Neuropeptide Y (NPY)-induced suppression of activity in the rat: evidence for NPY receptor heterogeneity and for interaction with alpha-adrenoceptors

The receptor mechanisms mediating the neuropeptide Y (NPY)-induced suppression of behavioural activity have been examined in the rat. The interaction of NPY with central noradrenergic mechanisms was also studied. The non-selective alpha-adrenoceptor antagonist, phentolamine (15-60 nmol intracerebroventricularly, i.c.v.), caused a dose-related antagonism (up to 50%) of the NPY-induced suppression of activity. The selective alpha 2-adrenoceptor antagonist, idazoxan (0.125 mg/kg intraperitoneally, i.p.), was even more effective, while the selective alpha 1-adrenoceptor antagonist, prazosin, was without effect. In addition, we examined whether the recently postulated subdivision of peripheral NPY receptors was also applicable to the brain. The ability of the C-terminal 13-36 amino acid fragment of NPY (postulated to activate NPY-Y2 receptors) to reproduce the effects of the full molecule (postulated to activate both NPY-Y1 and -Y2 receptors) was tested. NPY-(13-36) (0.4-10.0 nmol i.c.v.) failed to produce any suppression of activity. On the contrary, it produced an increase in locomotor activity and rearings at low doses. This effect was not blocked by phentolamine. We conclude that the NPY-induced suppression of activity is produced to a large extent by modulation of alpha 2-adrenergic transmission. Our results also provide evidence for heterogeneity among the central NPY receptors, with the NPY-induced suppression of activity being mediated by the NPY-Y1 receptor subtype.     

Neuropeptide Y (NPY): a coronary vasoconstrictor and potentiator of catecholamine-induced coronary constriction

The vasoactive effect of neuropeptide Y (NPY) a peptide commonly found in perivascular nerves, including those of the heart, was assessed in the coronary circulation of the isolated perfused dog heart and in superfused segments of isolated canine coronary arteries. The intracoronary administration of 0.7-23.5 nmol NPY to hearts during beta adrenergic blockade produced a dose-dependent increase in coronary vascular resistance ranging from 0.10 to 0.49 mmHg.min-1.ml-1.100 g-1 without changes in myocardial oxygen consumption. The potency of NPY as a coronary vasoconstrictor was about 250 times that of noradrenaline. Pretreating the coronary system of these hearts with NPY caused a marked potentiation of the vasocontractile effect of noradrenaline, displacing its dose-response curve to the left in a non-parallel fashion. The addition of 0.2-3.7 nmol NPY did not induce contraction in superfused helical segments of large coronary arteries but it potentiated the tension developed in response to 0.18 microM adrenaline in a concentration-dependent manner. Pretreatment of these arteries with 3.7 nmol NPY caused a significant leftward displacement of the adrenaline contractile effect. These results show that NPY is a potent coronary vasoconstrictor and a potentiator of the contractile effect of catecholamines and support the hypothesis that NPY may participate in the regulation of coronary vascular resistance.     

Neuropeptide Y (NPY): functions and biosynthesis as a peptidergic neurotransmitter and the regulation of neuron-specific expression of NPY gene

Neuropeptide Y (NPY) is widely distributed in the central and sympathetic nervous systems and has a variety of central actions including regulation of blood pressure and peripheral actions; e.g., continuous vasoconstriction and inhibition of catecholamine release. The NPY receptor can be divided into 2 subclasses (Y1, Y2), and these subclasses are coupled to GTP binding proteins (Gi, Go, Gp ......). Recently, human and rat prepro-NPY mRNA and NPY gene structures have been determined by cDNA and genomic cloning and sequencing. The strong evolutionary conservation of these structures suggested that NPY is an essential peptidergic neurotransmitter. Little is known about the biosynthesis, processing, degradation of NPY and NPY gene expression. We showed that NPY gene expression and NPY biosynthesis are regulated by neural activity, hormone, and intracellular second messengers via neurotransmitter receptors. The change of NPY gene expression by these neural factors is considered to be a good model for a synaptic plasticity, because these changes cause the changes of synaptic transmission. Furthermore, because NPY is expressed in sympathetic neurons and its gene expression increased markedly on the differentiation of adrenergic cells, this study about NPY gene expression could provide good clues for elucidating the differentiation of sympathetic neurons.     

Neuropeptide Y (NPY) gene: Impact on emotional processing and treatment response in anxious depression

Neuropeptide Y (NPY) has been found to play a role in the pathomechanism of both anxiety and depression. Thus, NPY is a promising candidate in the investigation of the clinical phenotype of “anxious depression”.Five NPY gene variants were investigated for an influence on antidepressant treatment response in a sample of 256 patients with depression. Additionally, NPY gene impact on amygdala activation during facial emotion processing was analyzed in a subsample of 35 depressed patients.Particularly in anxious depression, the less active NPY rs16147 −399C allele conferred slow response after 2 weeks and failure to achieve remission after four weeks of treatment. The rs16147 C allele was further associated with stronger bilateral amygdala activation in response to threatening faces in an allele-dose fashion.The present results point towards a possible influence of functional NPY gene variation on antidepressant treatment response in anxious depression, potentially conveyed by altered emotional processing.     

Neuropeptide Y (NPY) family of hormones: progress in the development of receptor selective agonists and antagonists

Neuropeptide Y (NPY), the most abundant peptide present in the mammalian brain, exhibits a wide spectrum of central and peripheral activities mediated by at least six G-protein coupled receptors. The latter observation, and the implication of NPY in the pathophysiology of feeding, seizures, diabetes, intestinal dysfunction, cardiovascular diseases and respiratory disorders, have led to vigorous efforts to dissociate various effects of NPY and develop receptor selective ligands required for fundamental investigations, and possible clinical utility. These efforts have made significant advancement in the development of antagonists, especially for Y(1) and Y(5) receptors mediating NPY effects on feeding and/or thermogenesis. However, only a limited progress has been made in the case of Y(2) ligands, and none in the case of Y(4) ligands. Moreover, most of the nonpeptidic ligands developed to date have little use clinically because of their solubility and toxicity problems and their limited passage through blood-brain barrier. Furthermore, no progress has been made in developing lower molecular weight agonists, which may also have clinical potential in treating seizures, intestinal dysfunction, respiratory disorders, cachexia and anorexia. Thus, despite significant advances, NPY research is expected to attract scientists for years to come in the pursuit to develop clinically useful ligands. The recent advances in the peptide drug delivery techniques have given added impetus for these efforts. This article reviews the usefulness of widely used ligands as well as those developed more recently.     

α-Trinositol: A Functional (Non-receptor) Neuropeptide Y Antagonist in Vasculature

Neuropeptide Y is a sympathetic co-neurotransmitter released with noradrenaline upon sympathetic nerve stimulation. This study describes the ability of a synthetic inositol phosphate, α-trinositol (d-myo-inositol 1,2,6?triphosphate; PP 56) to antagonize vasoconstrictor responses to neuropeptide Y in-vitro as well as in-vivo. In human and guinea-pig isolated arteries α-trinositol potently (10 nM to 1 μM extracellular concentration) suppressed the constriction evoked by neuropeptide Y alone, the potentiation by neuropeptide Y of noradrenaline-evoked constriction, and the neuropeptide Y-induced inhibition of relaxation. Moreover, in the pithed (areflexive) rat, a non-adrenergic portion of the pressor response to preganglionic sympathetic nerve stimulation was sensitive to α-trinositol. As studied in the recently cloned human (vascular-type) Y1 receptor, the action of α-trinositol does not occur through antagonism at the neuropeptide Y recognition site nor does it induce allosteric changes of this receptor. However, we found α-trinositol to inhibit the rise in intracellular Ca²⁺ as well as inositol triphosphate concentrations induced by neuropeptide Y. It is, therefore, proposed that α-trinositol represents a non-receptor, but yet selective antagonist of neuropeptide Y in vasculature, opening up the possibility to investigate involvement of neuropeptide Y in sympathetic blood pressure control and in cardiovascular disorders.     

Neuropeptide Y (NPY) reduces field stimulation-evoked release of noradrenaline and enhances force of contraction in the rat portal vein

The effect of neuropeptide Y (NPY) on fractional tritium-noradrenaline (3H-NA) release and contractile activity was studied in the isolated portal vein of SHR and WKY rats. NPY (5 X 10(-7) M) enhanced the force of the spontaneous contractile activity by about 40%. The fractional 3H-release elicited by transmural nerve stimulation (TNS), which mainly reflects 3H-NA, was reduced by about 40% after preincubation with 5 X 10(-7) M NPY in portal veins from both SHR and WKY rats. The inhibitory effect of NPY on TNS-evoked 3H-release was more slowly reversed by washout than the facilitatory action on spontaneous contractile force. The contractile response to field stimulation was not reduced by NPY, but rather tended to be increased. It is concluded that NPY exerts a dual action in the SHR and WKY portal vein, thus enhancing the smooth muscle contractions and inhibiting sympathetic neurotransmission. The inhibitory effect of NPY on TNS-evoked NA efflux, which is present in both SHR and WKY rats, is most likely due to a presynaptic site of action.     

Neuropeptide Y (NPY) in the central nucleus of the amygdala (CeA) does not affect ethanol-reinforced responding in binge-drinking, nondependent rats

The central nucleus of the amygdala (CeA) has been implicated as having a significant role in mediating alcohol-drinking behavior. Neuropeptide Y (NPY) has been investigated as a potential pharmacotherapeutic due to its ability to attenuate ethanol intake, particularly when administered into the CeA. Previous research suggests, though the evidence is somewhat conflicting, that the efficacy of NPY is contingent upon genetic background and/or prior history of ethanol dependence in rats. However, studies looking at the effects of NPY in nonselected animals lacking a history of ethanol dependence have two factors that could impact the interpretation of the results: ethanol history/selection AND relatively low baseline ethanol intakes as compared to ethanol-dependent and/or genetically selected controls. The purpose of the present study was to generate higher baseline ethanol intakes upon which to examine the effects of NPY on ethanol and sucrose drinking in nonselected rats using a binge drinking model. Long Evans rats were trained to complete a single response requirement resulting in access to either 2% sucrose (Sucrose Group) or 2% sucrose/10% ethanol (Ethanol Group) for a 20-min drinking session. On treatment days, rats were bilaterally microinjected into the CeA with aCSF or one of three doses of NPY (0.25 μg, 0.50 μg, or 1.00 μg/.5 μL). Subjects in the Ethanol Group were consuming an average of 1.2 g/kg of ethanol (yielding BELs of ~ 90 mg%) during the 20 min access period following aCSF treatments. The results revealed that NPY had no effect on either sucrose or ethanol consumption or on appetitive responding (latency to respond). Overall, the findings indicate that even a history of binge-like ethanol consumption is not sufficient to recruit CeA NPY activity, and are consistent with previous studies showing that the role of NPY in regulating ethanol reinforcement in the CeA may be contingent upon a prior history of ethanol dependence.     

Relevance of neuropeptide Y (NPY) in psychiatry

Extensive preclinical studies suggest neuropeptide Y (NPY) to be involved in stress regulation and coping. NPY counteracts the behavioral consequences of stress and anxiety to maintain emotional homeostasis. NPY is also involved in learning, memory, and cognition, all of which are dysregulated in many psychiatric states. Dense localization of NPY and NPY receptors is found in brain areas implicated in psychopathology such as the amygdala, hippocampus, neocortex, septum, caudate-putamen, hypothalamus and locus coeruleus. Impaired central NPY signaling may therefore be involved in the pathophysiology of depression, anxiety, schizophrenia, alcoholism, and trauma-induced disorders like PTSD. Studies on the readily accessible plasma from psychiatric patients have provided some information on the relevance of NPY as a marker for sympathetic tone in certain conditions. Reports on cerebrospinal fluid (CSF) NPY in subjects with depression indicate a dysregulation of central NPY in this disorder, however, other conditions still need to be investigated.     

Neuropeptide Y (NPY): enhancement of blood pressure increase upon alpha-adrenoceptor activation and direct pressor effects in pithed rats

The effects of neuropeptide Y (NPY) on blood pressure and heart rate were studied in pithed rats. Systemic infusion of NPY in a dose (230 pmol X kg-1 X min-1) which per se did not affect blood pressure enhanced the pressor response to phenylephrine (50 nmol X kg-1 i.v.) and that to electrical stimulation of the sympathetic outflow. In higher doses, NPY caused a pressor effect per se, which was dose-dependently antagonized by nifedipine but not by adrenoceptor antagonists. In conclusion, NPY enhanced the alpha-adrenoceptor-mediated response and had Ca2+-dependent vasoconstrictor activity in vivo.