bibo-3457 and Disease-Models--Animal

Memory is the ability to store, retrieve and use information that requires a progressive time-dependent stabilization process known as consolidation to be established. The hippocampus is essential for processing all the information that forms memory, especially spatial memory. Neuropeptide Y (NPY) affects memory, so in this study we investigated the participation and recruitment of NPY receptors during spatial memory consolidation in rats. Using the water maze test, we show that NPY (1 pmol) injected into the dorsal hippocampus impaired memory consolidation and that previous restraint stress (30 min) potentiates NPY effects, i.e. further impaired memory consolidation. Using selective antagonists for NPY Y

Topics: Animals; Arginine; Behavior, Animal; Benzazepines; Disease Models, Animal; Male; Memory Disorders; Neuropeptide Y; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Restraint, Physical; Spatial Memory; Stress, Psychological

Obesity is caused by an imbalance between food intake and energy expenditure (EE). Here we identify a conserved pathway that links signalling through peripheral Y1 receptors (Y1R) to the control of EE. Selective antagonism of peripheral Y1R, via the non-brain penetrable antagonist BIBO3304, leads to a significant reduction in body weight gain due to enhanced EE thereby reducing fat mass. Specifically thermogenesis in brown adipose tissue (BAT) due to elevated UCP1 is enhanced accompanied by extensive browning of white adipose tissue both in mice and humans. Importantly, selective ablation of Y1R from adipocytes protects against diet-induced obesity. Furthermore, peripheral specific Y1R antagonism also improves glucose homeostasis mainly driven by dynamic changes in Akt activity in BAT. Together, these data suggest that selective peripheral only Y1R antagonism via BIBO3304, or a functional analogue, could be developed as a safer and more effective treatment option to mitigate diet-induced obesity.

Topics: Adipocytes; Adipose Tissue, Brown; Adult; Animals; Arginine; Biopsy; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Energy Metabolism; Female; Humans; Male; Mice; Middle Aged; Obesity; Primary Cell Culture; Receptors, Neuropeptide Y; Thermogenesis

The sympathetic nervous system plays an important role in the occurrence of ventricular tachycardia (VT). Many patients, however, experience VT despite maximal doses of beta blocker therapy, possibly due to the effects of sympathetic cotransmitters such as neuropeptide Y (NPY). The purpose of this study was to determine, in a porcine model, whether propranolol at doses higher than clinically recommended could block ventricular electrophysiological effects of sympathoexcitation via stellate ganglia stimulation, and if any residual effects are mediated by NPY. Greater release of cardiac NPY was observed at higher sympathetic stimulation frequencies (10 and 20 vs. 4 Hz). Despite treatment with even higher doses of propranolol (1.0 mg/kg), electrophysiological effects of sympathetic stimulation remained, with residual shortening of activation recovery interval (ARI), a surrogate of action potential duration (APD). Adjuvant treatment with the NPY Y1 receptor antagonist BIBO 3304, however, reduced these electrophysiological effects while augmenting inotropy. These data demonstrate that high-dose beta blocker therapy is insufficient to block electrophysiological effects of sympathoexcitation, and a portion of these electrical effects in vivo are mediated by NPY. Y1 receptor blockade may represent a promising adjuvant therapy to beta-adrenergic receptor blockade.

Topics: Action Potentials; Adrenergic beta-Antagonists; Animals; Arginine; Disease Models, Animal; Neuropeptide Y; Receptors, Neuropeptide Y; Sus scrofa; Sympathetic Nervous System; Tachycardia, Ventricular

Neuropeptide Y (NPY), a 36 aa peptide, regulates stress and emotional behaviors. Preclinical and clinical studies support an association of NPY with trauma-evoked syndromes such as posttraumatic stress disorder (PTSD), although the exact contribution of NPY is not clear. In the current study, we examined functional attributes of NPY in the infralimbic (IL) cortex, an area that regulates fear memories and is reported to be hypoactive in PTSD. Carriers of NPY gene polymorphism rs16147 have been reported to have elevated prefrontal NPY expression. Infusion of NPY into the IL cortex in rats significantly impaired fear extinction memory without affecting conditioned fear expression or acquisition of extinction. Neuroendocrine stress response, depression-like behavior, and working memory performance were not affected by NPY infusion into the IL. The NPY Y1 receptor antagonist BIBO3304 completely abolished NPY effects on fear extinction retrieval. Y1 receptor expression was localized on CaMKII-positive pyramidal projection neurons and GAD67-positive interneurons in the IL. Patch-clamp recordings revealed increased inhibitory synaptic transmission onto IL projection neurons in the presence of NPY. Thus, NPY dampens excitability of IL projection neurons and impairs retrieval of extinction memory by inhibiting consolidation of extinction. Of relevance to PTSD, elevation of prefrontal NPY attributable to the genetic polymorphism rs16147 may contribute to IL hypoactivity, resulting in impaired extinction memory and susceptibility to the disorder.. Neuropeptide Y (NPY), a stress modulatory transmitter, is associated with posttraumatic stress disorder (PTSD). Contribution of NPY to PTSD symptomology is unclear. PTSD patients have reduced activity in the infralimbic (IL) subdivision of the medial prefrontal cortex (mPFC), associated with compromised extinction memory. No information exists on fear modulation by NPY in the IL cortex, although NPY and NPY receptors are abundant in these areas. This study shows that IL NPY inhibits consolidation of extinction, resulting in impaired retrieval of extinction memory and modulates excitability of IL projection neurons. In addition to providing a novel perspective on extinction memory modulation by NPY, our findings suggest that elevated mPFC NPY in gene polymorphism rs16147 carriers or after chronic stress could increase susceptibility to PTSD.

Topics: Animals; Arginine; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Corticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Extinction, Psychological; Fear; Glutamate Decarboxylase; Learning Disabilities; Male; Mental Recall; Neurons; Neuropeptide Y; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Synaptic Potentials

Accumulated evidence suggests that neuropeptide Y (NPY) is involved in emotional disorders by acting on Y(1) and Y(2) receptors. This hypothesis is based on animal studies carried out in naïve normal animals but not in animal models of depression, including the olfactory bulbectomized (OBX) rat. The OBX rat produces a wide array of symptoms that mimic several aspects of human depression and anxiety disorders. In the present study, we aimed to investigate the effects of sustained (2 weeks) intracerebroventricular administration of NPY Y(1) and Y(2) agonists and antagonists in a battery of behavioral tests including the open field, forced swim test (FST) and social interaction (SI) tests in OBX rats. The levels of Y(1) and Y(2) receptors in the hippocampus and basolateral amygdala (BLA) were also evaluated. Treatment with the Y(1)-like receptor agonist, [Leu(31)Pro(34)]PYY, decreased both depressive- and anxiogenic-like behaviors. The Y(2) receptor antagonist, BIIE0246, decreased the immobility time in the FST in OBX animals and increased active contacts in the SI test in sham rats. The Y(2) agonist, PYY3-36, increased the immobility time in the FST in OBX rats. Additionally, increased levels of Y(2) receptor binding were quantified in the dorsal hippocampus and BLA in OBX rats. Taken together, the autoradiographic results add further evidence that the NPYergic system is altered in disturbed emotional states. Moreover, we demonstrate a differential role for NPY Y(1) and Y(2) receptors in emotional processes under control and challenged conditions. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Topics: Amygdala; Analysis of Variance; Animals; Anxiety; Arginine; Autoradiography; Benzazepines; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Delivery Systems; Exploratory Behavior; Hippocampus; Interpersonal Relations; Male; Neuropeptide Y; Olfactory Bulb; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Swimming; Time Factors

Converging evidence implicates the regulatory neuropeptide Y (NPY) in anxiety- and depression-related behaviors. The present study sought to assess whether there is an association between the magnitude of behavioral responses to stress and patterns of NPY in selected brain areas, and subsequently, whether pharmacological manipulations of NPY levels affect behavior in an animal model of PTSD. Animals were exposed to predator-scent stress for 15 min. Behaviors were assessed with the elevated plus maze and acoustic startle response tests 7 days later. Preset cutoff criteria classified exposed animals according to their individual behavioral responses. NPY protein levels were assessed in specific brain regions 8 days after the exposure. The behavioral effects of NPY agonist, NPY-Y1-receptor antagonist, or placebo administered centrally 1 h post-exposure were evaluated in the same manner. Immunohistochemical technique was used to detect the expression of the NPY, NPY-Y1 receptor, brain-derived neurotrophic factor, and GR 1 day after the behavioral tests. Animals whose behavior was extremely disrupted (EBR) selectively displayed significant downregulation of NPY in the hippocampus, periaqueductal gray, and amygdala, compared with animals whose behavior was minimally (MBR) or partially (PBR) disrupted, and with unexposed controls. One-hour post-exposure treatment with NPY significantly reduced prevalence rates of EBR and reduced trauma-cue freezing responses, compared with vehicle controls. The distinctive pattern of NPY downregulation that correlated with EBR as well as the resounding behavioral effects of pharmacological manipulation of NPY indicates an intimate association between NPY and behavioral responses to stress, and potentially between molecular and psychopathological processes, which underlie the observed changes in behavior. The protective qualities attributed to NPY are supported by the extreme reduction of its expression in animals severely affected by the stressor and imply a role in promoting resilience and/or recovery.

Topics: Animals; Arginine; Brain; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Down-Regulation; Gene Expression Regulation; Humans; Male; Maze Learning; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Reflex, Startle; Resilience, Psychological; Stress Disorders, Post-Traumatic; Stress, Psychological

Neuropeptide Y (NPY) and Orexin-A (OX-A), well-known neuropeptides associated with feeding and arousal, show antidepressant-like properties via hippocampal cell proliferation. Previous studies have revealed that kososan, a Kampo (Japanese herbal) medicine, has an antidepressant-like effect in behavioral animal models of depression; the mechanisms underlying this effect may involve the orexinergic system and subsequent upregulation of hippocampal cell proliferation. However, the roles of NPY in kososan's antidepressant-like effect remain unclear. Here we investigated whether the regulation of the NPY system could play crucial roles in this effect in the stress-induced depression-like model mice. The antidepressant-like effect of kososan administered orally (1.0 g/kg) for 28 d was abolished by a continuous intracerebroventricular injection of BIBO3304, a neuropeptide Y1 receptor antagonist, for 7 d. Likewise, BIBO3304 injection blocked the kososan-induced increases in hippocampal cell proliferation and cluster formation of neural progenitor cells. On the other hand, BIBO3304 injection did not affect kososan-induced increases in hypothalamic OX-A-producing cells or in serum OX-A levels. These results suggest that the control of the NPY system in the brain plays an essential role in kososan's antidepressant-like effect and facilitates hippocampal cell proliferation, both of which could be attributed, at least in part, to the control of the NPY system subsequent to the control of the OX-A system.

Topics: Animals; Antidepressive Agents; Arginine; Cell Proliferation; Depression; Disease Models, Animal; Drugs, Chinese Herbal; Hippocampus; Intracellular Signaling Peptides and Proteins; Male; Medicine, Kampo; Mice; Neuropeptide Y; Neuropeptides; Orexins; Signal Transduction; Stress, Psychological

Neuropeptide Y (NPY) has an important but still insufficiently defined role in pain modulation. We therefore examined the ability of NPY to modulate experimentally induced neuropathic pain by injecting it directly into dorsal root ganglion (DRG) immediately following spinal nerve ligation (SNL) injury. We have found that this application exacerbates pain-related behavior induced by SNL in a modality-specific fashion. When saline was injected after SNL, the expected increase in hyperalgesia responses to needle stimulation was present on the 8th postoperative day. When we injected NPY, hyperalgesic responses were increased in a manner similar to the SNL/saline group. To characterize NPY action, specific Y1 and Y2 antagonists were also delivered directly to DRG, which revealed that behavioral actions of NPY were abolished by Y2 receptor antagonist. We tested whether NPY effects were the result of its role in immunity by immunohistochemical staining for glial fibrillary acidic protein, in order to identify activation of DRG satellite cells and dorsal horn astrocytes. Exacerbation of pain-related behavior following NPY injection was accompanied by astrocyte activation in ipsilateral dorsal horn and with satellite cells activation in the DRG proximal to injury. This activation was reduced following Y2 receptor antagonist application. These findings indicate an important link between pain-related behavior and neuroimmune activation by NPY through its Y2 receptor.

Topics: Analysis of Variance; Animals; Arginine; Benzazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Functional Laterality; Glial Fibrillary Acidic Protein; Hyperalgesia; Male; Motor Activity; Neuralgia; Neurons; Neuropeptide Y; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Rotarod Performance Test; Spinal Cord

Recent pharmacologic studies in our laboratory have suggested that the spinal neuropeptide Y (NPY) Y1 receptor contributes to pain inhibition and to the analgesic effects of NPY. To rule out off-target effects, the present study used Y1-receptor-deficient (-/-) mice to further explore the contribution of Y1 receptors to pain modulation.. Y1(-/-) mice exhibited reduced latency in the hotplate test of acute pain and a longer-lasting heat allodynia in the complete Freund's adjuvant (CFA) model of inflammatory pain. Y1 deletion did not change CFA-induced inflammation. Upon targeting the spinal NPY systems with intrathecal drug delivery, NPY reduced tactile and heat allodynia in the CFA model and the partial sciatic nerve ligation model of neuropathic pain. Importantly, we show for the first time that NPY does not exert these anti-allodynic effects in Y1(-/-) mice. Furthermore, in nerve-injured CD1 mice, concomitant injection of the potent Y1 antagonist BIBO3304 prevented the anti-allodynic actions of NPY. Neither NPY nor BIBO3304 altered performance on the Rotorod test, arguing against an indirect effect of motor function.. The Y1 receptor contributes to pain inhibition and to the analgesic effects of NPY.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Arginine; Behavior, Animal; Disease Models, Animal; Hot Temperature; Hyperalgesia; Inflammation; Male; Mice; Mice, Knockout; Neuropeptide Y; Pain; Pain Measurement; Receptors, Neuropeptide Y; Sciatic Neuropathy

The sympathetic nervous system and renin-angiotensin system are both thought to contribute to the development and maintenance of hypertension in experimental models such as the spontaneously hypertensive rat (SHR). We demonstrated that periarterial nerve stimulation (NS) increased the perfusion pressure (PP) and neuropeptide Y (NPY) overflow from perfused mesenteric arterial beds of SHRs at 4-6, 10-12, and 18-20 wk of age, which correspond to prehypertensive, developing hypertensive, and maintained hypertensive stages, respectively, in the SHR. NS also increased PP and NPY overflow from mesenteric beds of Wistar-Kyoto (WKY) normotensive rats. NS-induced increases in PP and NPY were greater in vessels obtained from SHRs of all three ages compared with WKY rats. ANG II produced a greater increase in PP in preparations taken from SHRs than WKY rats. ANG II also resulted in a greater increase in basal NPY overflow from 10- to 12-wk-old and 18- to 20-wk-old SHRs than age-matched WKY rats. ANG II enhanced the NS-induced overflow of NPY from SHR preparations more than WKY controls at all ages studied. The enhancement of NS-induced NPY overflow by ANG II was blocked by the AT1 receptor antagonist EMD-66684 and the angiotensin type 2 receptor antagonist PD-123319. In contrast, ANG II greatly enhanced norepinephrine overflow in the presence of PD-123319. Both captopril and EMD-66684 decreased neurotransmitter overflow from SHR mesenteric beds; therefore, we conclude that an endogenous renin-angiotensin system is active in this preparation. It is concluded that the ANG II-induced enhancement of sympathetic nerve stimulation may contribute to the development and maintenance of hypertension in the SHR.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Age Factors; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin II Type 2 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Blood Pressure; Captopril; Disease Models, Animal; Electric Stimulation; Hypertension; Imidazoles; Mesenteric Arteries; Neuropeptide Y; Prazosin; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 2; Receptors, Adrenergic, alpha-2; Receptors, Neuropeptide Y; Splanchnic Circulation; Sympathetic Nervous System

Current evidence suggests that hyperactivity of the sympathetic nervous system and endothelial dysfunction are important factors in the development and maintenance of hypertension. Under normal conditions the endothelial mediator nitric oxide (NO) negatively modulates the activity of the norepinephrine portion of sympathetic neurotransmission, thereby placing a "brake" on the vasoconstrictor ability of this transmitter. This property of NO is diminished in the isolated, perfused mesenteric arterial bed taken from the spontaneously hypertensive rat (SHR), resulting in greater nerve-stimulated norepinephrine and lower neuropeptide Y (NPY) overflow from this mesenteric preparation compared with that of the normotensive Wistar-Kyoto rat (WKY). We hypothesized that increased oxidative stress in the SHR contributes to the dysfunction in the NO modulation of sympathetic neurotransmission. Here we demonstrate that the antioxidant N-acetylcysteine reduced nerve-stimulated norepinephrine and increased NPY overflow in the mesenteric arterial bed taken from the SHR. Furthermore, this property of N-acetylcysteine was prevented by inhibiting nitric oxide synthase with N(omega)-nitro-l-arginine methyl ester, demonstrating that the effect of N-acetylcysteine was due to the preservation of NO from oxidation. Despite a reduction in norepinephrine overflow, the nerve-stimulated perfusion pressure response in the SHR mesenteric bed was not altered by the inclusion of N-acetylcysteine. Studies including the Y(1) antagonist BIBO 3304 with N-acetylcysteine demonstrated that this preservation of the perfusion pressure response was due to elevated NPY overflow. These results demonstrate that the reduction in the bioavailability of NO as a result of elevated oxidative stress contributes to the increase in norepinephrine overflow from the SHR mesenteric sympathetic neuroeffector junction.

Topics: Acetylcysteine; Animals; Antioxidants; Arginine; Blood Pressure; Disease Models, Animal; Electric Stimulation; Enzyme Inhibitors; Hypertension; Male; Mesenteric Arteries; Neuropeptide Y; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Norepinephrine; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Neuropeptide Y; Splanchnic Circulation; Superoxides; Sympathetic Nervous System

Prevention of nerve injury-induced tactile, but not thermal, hypersensitivity is achieved by ipsilateral lesions of the dorsal columns or lidocaine microinjection into the nucleus gracilis (n. gracilis). These and other data support the possibility that tactile hyperresponsiveness after nerve injury may be selectively mediated by a low-threshold myelinated fiber pathway to the n. gracilis. Here we identify a transmitter that might selectively mediate such injury-induced tactile hypersensitivity. Neuropeptide Y (NPY), normally not detected in the dorsal root ganglion (DRG) or in the n. gracilis of rats, became markedly upregulated at both sites and in the spinal cord after spinal nerve injury. Injury-induced NPY-IR occurred predominately in large-diameter DRG cells, and the NPY-IR in the n. gracilis was blocked by dorsal rhizotomy or dorsal column lesion. NPY microinjection into the n. gracilis of uninjured rats elicited reversible tactile, but not thermal, hypersensitivity only in the ipsilateral hindpaw. Administration of anti-NPY antiserum, but not control serum or preabsorbed serum, into the n. gracilis ipsilateral to nerve injury reversed tactile, but not thermal, hypersensitivity. Similarly, microinjection of the NPY antagonists NPY(18-36) and (R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N2-(diphenylacetyl)-argininamide trifluoroacetate, into the n. gracilis ipsilateral to the injury reversed tactile, but not thermal, hypersensitivity. Antagonist administration into the contralateral n. gracilis had no effect on injury-induced hypersensitivity. These data suggest the selective mediation of nerve injury-induced tactile hypersensitivity by upregulated NPY via large fiber input to n. gracilis. Selective reversal of injury-induced tactile allodynia by NPY receptor antagonists would have significant implications for human neuropathic conditions.

Topics: Animals; Arginine; Benzazepines; Disease Models, Animal; Disease Progression; Ganglia, Spinal; Hyperalgesia; Immune Sera; Ligation; Lumbosacral Region; Male; Medulla Oblongata; Microinjections; Nerve Crush; Neuropeptide Y; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Rhizotomy; Spinal Cord; Spinal Nerves

Inflammation induces an up-regulation of neuropeptide tyrosine (NPY) and its receptors in the dorsal horn, suggesting an important role in nociceptive transmission. Our initial studies revealed that NPY dose-dependently increased hotplate response latency, and to a lesser degree, thermal paw withdrawal latency (PWL); these effects occurred at doses that affect neither motor coordination (as assessed by the rotarod test) nor paw skin temperature. We next evaluated the behavioral effects of intrathecal administration of NPY and NPY antagonists with the aim of assessing the contribution of NPY to correlates of persistent nociception associated with the unilateral plantar injection of carrageenan or complete Freund's adjuvant (CFA). NPY robustly and dose-dependently increased PWL on the side ipsilateral to carrageenan injection, with only a small effect on the contralateral side. Similarly, NPY (30 microg) produced a large and long-lasting increase in PWL on the side ipsilateral to CFA injection (140% change), with only a small effect on the contralateral side (25% change). The ipsilateral effect of NPY was completely inhibited with the potent Y1 antagonist, BIBO 3304 (3 microg), but not the Y2 antagonist, BIIE 0246. When administered alone, BIBO 3304 (but not BIIE 0246) slightly decreased thermal PWL on the side ipsilateral (25% change), but not contralateral, to CFA injection; this suggests that inflammation strengthens inhibitory NPY tone. We conclude that spinal Y1 receptors contribute to the inhibitory effects of NPY on thermal hypersensitivity in the awake rat. Further studies are necessary to determine whether enhanced release of NPY and Y1-mediated inhibition of spinal nociceptive transmission ultimately results in a compensatory, adaptive inhibition of thermal hypersensitivity in the setting of inflammation.

Topics: Acute Disease; Animals; Arginine; Body Temperature; Carrageenan; Disease Models, Animal; Freund's Adjuvant; Hot Temperature; Hyperalgesia; Injections, Spinal; Male; Motor Activity; Neurogenic Inflammation; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Spinal Cord

Along with the renin-angiotensin system, sympathetic stimulation may contribute to renovascular hypertension. The vasoactive peptide neuropeptide Y (NPY) is co-released with and potentiates the pressor effects of norepinephrine through the Y-1 receptor. NPY, by exaggerating sympathetic activity, may contribute to renovascular hypertension, possibly by augmenting adrenergic-mediated renin release. This was studied by determining the effect of continuous Y-1 blockade on the development of two-kidney, one-clip renovascular hypertension and the effect of NPY on in vitro renin release.. Mean arterial pressure and renal blood flow responses to NPY (10 microg/kg, administered intravenously) were measured in five anesthetized Sprague-Dawley rats before and after BIBO3304TF administration to test the Y-1 antagonist BIBO3304TF. In hypertension studies, 28 rats underwent left renal artery clipping. Of these, 13 were implanted with a mini-osmotic pump for continuous BIBO3304TF infusion (0.3 microg/h, administered intravenously); the other 15 underwent sham implantation. Systolic blood pressure was then monitored for 4 weeks. Finally, in vitro renin release was measured from renal cortical slices (n = 6-12) incubated with NPY (10(-8) to 10(-6) mol/L) or NPY plus the adrenergic agonist isoproterenol (10(-4) mol/L).. BIBO3304TF attenuated the NPY-induced increase in mean arterial pressure by 54% (P <.02) and the NPY-induced decrease in renal blood flow by 38% (P <.05). In 4-week hypertension studies, systolic blood pressure in clipped controls increased from 130 +/- 3 mm Hg to 167 +/- 6 mm Hg (P <.01), whereas BIBO3304TF-treated rats had no significant increase (125 +/- 3 mm Hg to 141 +/- 8 mm Hg). Final systolic blood pressure was 26 mm Hg lower in BIBO3304TF-treated rats than in controls (P <.01). In renal cortical slices, no NPY effect was observed in basal or isoproterenol-stimulated renin release.. The Y-1 receptor antagonist BIBO3304TF attenuated acute pressor responses to NPY and blunted the development of two-kidney, one-clip renovascular hypertension in rats. NPY may contribute to the hypertensive response in this renovascular hypertension model. Our in vitro data do not suggest that this is due to NPY enhancement of renin release.

Topics: Animals; Arginine; Blood Pressure Determination; Disease Models, Animal; Hemodynamics; Hypertension, Renal; Injections, Intravenous; Kidney; Male; Neuropeptide Y; Probability; Rats; Rats, Sprague-Dawley; Reference Values; Renin