1.
Grundemar, L, et al.
(författare)
Long-lasting inhibition of the cardiovascular responses to glutamate and the baroreceptor reflex elicited by neuropeptide Y injected into the nucleus tractus solitarius of the rat
1991
Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940. ; 122:1, s. 135-139
Tidskriftsartikel (refereegranskat) abstract
Neuropeptide Y (NPY) microinjected unilaterally into the nucleus tractus solitarii (NTS) of anesthetized paralyzed rats elicits a gradual dose-dependent and reversible fall in arterial pressure (AP) and heart rate (HR) lasting 20 min. It also abolished the brief (less than 1 min) dose-dependent and reversible fall of AP and HR elicited by L-glutamate (L-Glu) injected into the nucleus. The blockade of L-Glu by NPY appeared gradually and was prolonged, lasting over 2 h, and recovering by 24 h. It was not replicated by desamido-NPY or galanin. Unlike 2% lidocaine it did not block the hypotension elicited by focal electrical stimulation at the injection site indicating the response was not that of a local anesthetic. Bilateral injection of NPY into the NTS resulted, after an initial fall, in an elevation of AP (+48 +/- 10.6 mmHg). At this time the reflex bradycardia evoked by elevating AP with phenylephrine was markedly reduced. We conclude that in the NTS, NPY antagonizes the actions of L-Glu and may attenuate baroreceptor reflexes. Since the NTS is richly innervated by NPY neurons and contains many NPY binding sites and since primary baroreceptor afferents appear to be glutamatergic the results suggested that NPY may serve in NTS as a long-term regulator of baroreceptor reflex activity.
2.
Grundemar, L, et al.
(författare)
Activation of neuropeptide Y1 and neuropeptide Y2 receptors by substituted and truncated neuropeptide Y analogs : identification of signal epitopes
1993
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 232:2-3, s. 271-278
Tidskriftsartikel (refereegranskat) abstract
Neuropeptide Y (NPY-(1-36)) acts on Y1 and Y2 receptors at the sympathetic neuroeffector junction. Various truncated NPY analogs were tested in the isolated guinea-pig caval vein where NPY is a vasoconstrictor (Y1 receptors) and in isolated rat vas deferens, by monitoring the suppression of electrically evoked contractions (Y2 receptors). The aim of this study was to define which parts of the NPY-(1-36) molecule were required to activate these receptors. NPY-(1-36), [Pro34]NPY and [Glu16,Ser18,Ala22,Leu28,31]NPY (ESALL-NPY), the latter being an analog with increased alpha-helicity in the 14-31 region, evoked vasoconstriction with similar potency and efficacy. Cyclic as well as linear NPY analogs having the 4 to 7 N-terminal amino acid residues linked to the 9 to 19 C-terminal residues by an 8-aminooctanoic acid (Aoc) residue were 25-50 times less potent than NPY-(1-36) itself. In the cyclic analogs, a disulfide bond was introduced to bring the N- and C-termini close together. Linear Aoc-2-27-NPY was virtually inactive. The Y1 receptor needs an intact N-terminal end of NPY in order to become fully activated. The requirements for the C-terminus are less stringent, since substitutions in this part of the molecule resulted in fully active analogs. The central portion of the molecule may impose steric constraints on the N- and C-terminal ends, thereby facilitating Y1 receptor activation, but it does not seem to be essential for receptor recognition. NPY-(2-36) and NPY-(5-36) were only slightly less potent than the parent molecule in suppressing electrically evoked twitches in the vas deferens.(ABSTRACT TRUNCATED AT 250 WORDS)
3.
Grundemar, L, et al.
(författare)
Biphasic blood pressure response to neuropeptide Y in anesthetized rats
1990
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 179:1-2, s. 83-87
Tidskriftsartikel (refereegranskat) abstract
The effects of neuropeptide Y (NPY) on systemic arterial blood pressure and heart rate were studied in anesthetized intact and pithed rats. I.v. doses of NPY (0.3-30 nmol/kg) raised the mean arterial blood pressure dose dependently. At doses of greater than or equal to 3.0 nmol/kg, the initial pressor response was followed by a dose-dependent fall in blood pressure in intact and pithed rats. The depressor response was accompanied 1-2 min after the NPY injection by a slight increase in heart rate in pithed rats but not in intact rats, and 10 min after the injection by a decrease in heart rate in intact rats. After repeated injections of NPY, the depressor effect vanished, whereas the integrated pressor response over time was markedly enhanced. After pretreatment with the histamine H1-receptor antagonist, mepyramine, or with the histamine liberator, compound 48/80, the pressor response to NPY remained but the depressor response disappeared. We suggest that the marked fall in blood pressure can be attributed to NPY-evoked histamine release from mast cells.
4.
Grundemar, L, et al.
(författare)
Characterization of vascular neuropeptide Y receptors
1992
Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188. ; 105:1, s. 45-50
Tidskriftsartikel (refereegranskat) abstract
1. In the present study we compared neuropeptide Y (NPY) and NPY-related analogues for their ability to activate or bind to vascular NPY receptors in four experimental set-ups. Previous results have suggested the existence of different receptor subtypes, Y1 receptors requiring full-length NPY (1-36) or [Pro34]-NPY, and Y2 receptors recognizing also N-terminally truncated forms of NPY but not [Pro34]-NPY. 2. NPY 1-36 and [Pro34]-NPY dose-dependently increased arterial pressure in the anaesthetized rat with a similar magnitude and potency. NPY 2-36 was much less potent than NPY 1-36. NPY 4-36 and NPY 11-36 were inactive even at a dose as high as 10 nmol kg-1. 3. NPY 1-36, [Pro34]-NPY, NPY 2-36 and NPY 5-36 concentration-dependently increased the coronary resistance in the Langendorff preparation of the rat. NPY 1-36 and [Pro34]-NPY were equipotent, while NPY 2-36 and NPY 5-36 were about 7 and 20 times less potent. At 0.3 microM, NPY 11-36, NPY 20-36 and NPY 22-36 induced a slight contraction while NPY 23-36 was inactive. 4. NPY 1-36, [Pro34]-NPY, NPY 2-36, NPY 4-36, NPY 5-36 and NPY 11-36 evoked concentration-dependent contractions in the isolated inferior caval vein of the rat and guinea-pig. [Pro34]-NPY was more potent than NPY 1-36. NPY 2-36 was equipotent with NPY 1-36, while NPY 4-36, NPY 5-36 and NPY 11-36 were approximately 30 times less potent.5. [Pro34]-NPY was equipotent with NPY 1-36 in displacing the '25I-labelled gut hormone peptide([1251]-PYY) from rat aortic smooth muscle cells, while NPY 2-36 and shorter forms of NPY were much less potent or inactive.6. In caval vein smooth muscle cells of the rat, the displacement pattern was more complex than in aortic smooth muscle cells, in that both [Pro34]-NPY and NPY 13-36 effectively displaced the radioligand,albeit none of them completely.7. In conclusion, the NPY-evoked pressor response in the whole rat and coronary vessels seems to be mediated by vascular Y1 receptors and the binding characteristics of the NPY-related peptides in the aortic smooth muscle cells correspond to a population of such receptors. In the caval vein, the profile of the bioactivity and the binding affinity of the NPY-related peptides suggest a mixed population of Y1/Y2 receptors.
5.
Grundemar, L, et al.
(författare)
Effects of various neuropeptide Y/peptide YY fragments on electrically-evoked contractions of the rat vas deferens
1990
Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188. ; 100:1, s. 190-192
Tidskriftsartikel (refereegranskat) abstract
1. The effects of various neuropeptide Y (NPY) and peptide YY (PYY) fragments on electrically-evoked twitches in the rat isolated vas deferens were studied and compared with the effects of full length NPY and PYY. The aim was to identify the shortest NPY/PYY fragments that are capable of suppressing the contractions. 2. NPY (1-36) and C-terminal fragments of NPY (from 11-36 to 22-36) suppressed the electrically-evoked twitches in a concentration-dependent manner. On the whole there seemed to be a gradual lowering of the pIC50 values with progressive shortening of the NPY fragments (except for fragments 16-36 and 22-36 that had rather high pIC50 values). NPY 23-36, 24-36 and 25-36 suppressed the twitches at high concentrations (3 microM). NPY 26-36 was without effect as were C-terminal carboxy-deaminated NPY and glycine extended NPY (NPY-Gly-Lys-Arg). 3. PYY (1-36) and C-terminal fragments of PYY (from 11-36 to 23-36) suppressed the electrically-evoked twitches in a concentration-dependent manner. PYY 1-36 was more potent than any of the fragments. There was a tendency for shorter fragments to have lower pIC50 values. PYY 24-36 and 25-36 suppressed the twitches at high concentrations (3 microM). PYY 26-36 was without effect. 4. The findings suggest that the 12 C-terminal amino acid residues of NPY and PYY are the minimum length required to activate the Y2-receptor.
6.
Grundemar, L, et al.
(författare)
Multiple neuropeptide Y receptors are involved in cardiovascular regulation. Peripheral and central mechanisms
1993
Ingår i: General Pharamacology. - : Elsevier BV. - 0306-3623. ; 24:4, s. 785-796
Forskningsöversikt (refereegranskat) abstract
1. Neuropeptide Y (NPY) occurs in both the central and peripheral nervous system. In the periphery, NPY coexists with noradrenaline (NA) in perivascular sympathetic fibers. 2. NPY has a vasopressor effect, reflecting direct vasoconstriction of blood vessels and potentiation of the NA-evoked response. NPY also suppresses the release of NA from sympathetic fibers. 3. The post- and pre-junctional NPY receptors are referred to as Y1 and Y2, respectively. They recognize not only NPY but also the homologous gut hormone peptide YY (PYY). 4. The Y1 and Y2 receptors have been characterized in numerous test systems using analogs of NPY/PYY. Already the deletion of the first N-terminal amino acid (NPY 2-36) results in a marked loss of potency at the Y1 receptor. The Y2 receptor is much less dependent upon an intact N-terminus, and a wide range of C-terminal NPY fragments retain quite high potency. 5. Recently, yet another NPY receptor, Y3, that is distinct from Y1 and Y2 in that it recognizes PYY poorly, has been demonstrated in the brainstem and in the periphery. 6. Further attempts to characterize the various receptor types have relied on truncated and substituted analogs of NPY/PYY. Although such studies suggest the existence of at least three types of NPY receptors, the lack of antagonists has represented a problem. 7. Since NPY may regulate cardiovascular functions via peripheral and central receptors its physiological and possibly pathophysiological significance has attracted much attention. 8. The responsiveness to NPY seems to be altered in animal models of hypertension and elevated plasma levels of NPY have been found in patients under various conditions of stress and in primary hypertension. A number of studies have suggested that NPY may be a pathogenetic factor behind primary hypertension. 9. Antagonists for the various NPY receptors would be useful for an analysis of which effects of these peptides are physiologically relevant. It is tempting to predict that both agonists and antagonists of the NPY receptors could be useful as drugs, for instance, in the treatment of primary hypertension.
7.
Grundemar, L, et al.
(författare)
Neuropeptide Y acts at an atypical receptor to evoke cardiovascular depression and to inhibit glutamate responsiveness in the brainstem
1991
Ingår i: Journal of Pharmacology and Experimental Therapeutics. - 0022-3565. ; 258:2, s. 633-638
Tidskriftsartikel (refereegranskat) abstract
Microinjection of neuropeptide Y (NPY) into the nucleus tractus solitarius (NTS) induces an initial and reversible fall in arterial pressure (AP) and heart rate (HR), along with a delayed and long-lasting blockade of cardiovascular responses to L-glutamate (L-Glu) injected into the same site and an inhibition of the baroreflex arc. By injecting NPY-receptor subtype selective agonists and NPY-related peptides into NTS we have sought to characterize the receptors that mediate these responses. Unilateral injections into NTS (9-90 pmol) of NPY as well as the Y1 receptor selective agonist [34Pro]NPY and the Y2 receptor selective fragment NPY 13-36 evoked comparable dose-dependent falls of AP and HR in the anesthetized and paralyzed rat. Injections into NTS of peptide YY or pancreatic polypeptide had no effect. Preinjection of NPY, [34Pro]NPY, NPY 13-36 (all at 90 pmol) as well as norepinephrine (6.7 nmol) virtually abolished the fall in AP and HR evoked by subsequent injections of L-Glu into NTS. Injection of peptide YY or pancreatic polypeptide (both at 90 pmol) did not affect the cardiovascular responses evoked by L-Glu in NTS. Injection of NPY (90 pmol) into the caudal ventrolateral medulla induced a slight fall in AP of -17 +/- 5 mm Hg (P less than .05) and a sustained fall in HR of -44 +/- 8 beats per min (P less than .01). Injection of NPY also abolished the fall in HR and AP evoked by L-Glu in the caudal ventrolateral medulla. The profile of the cardiovascular effects elicited by the NPY-related peptides in NTS does not correspond to either of the Y1 or the Y2 receptor subtypes. The findings suggest that NPY acts on an atypical receptor in NTS to lower AP and HR. Moreover, this receptor may also interfere with the L-Glu-evoked neurotransmission in the NTS. Finally, norepinephrine shared with NPY the ability to inhibit L-Glu-evoked responses in NTS; however, a much higher dose of norepinephrine (than NPY) was required.
8.
Grundemar, L, et al.
(författare)
Neuropeptide Y and truncated neuropeptide Y analogs evoke histamine release from rat peritoneal mast cells. A direct effect on G proteins?
1994
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 258:1-2, s. 163-166
Tidskriftsartikel (refereegranskat) abstract
Several regulatory peptides, including neuropeptide Y, can release histamine from mast cells. In the present study we investigated which parts of the neuropeptide Y molecule are required to evoke the release of histamine from isolated rat peritoneal mast cells. In addition, we examined whether the histamine release evoked by neuropeptide Y (and by compound 48/80) is sensitive to the G protein inhibitors pertussis toxin and benzalkonium chloride. Neuropeptide Y released histamine in a concentration-dependent manner. Also a neuropeptide Y analog with the center part substituted by 8-aminooctanoic acid, [Aoc2-27]neuropeptide Y, and the cyclic form of the C-terminal hexapeptide, cyclic neuropeptide Y-(31-36), released histamine. The three peptides were equally effective and equally potent. Neuropeptide Y-(1-24)NH2 also released histamine, but its efficacy was low. The rank order of potency of the analogs tested did not agree with that of any of the previously known or postulated neuropeptide Y receptors. Pretreatment of mast cells with pertussis toxin or benzalkonium chloride markedly inhibited the histamine release evoked by neuropeptide Y, [Aoc2-27]neuropeptide Y and compound 48/80. In conclusion, most of the histamine-releasing activity of neuropeptide Y resides in the six C-terminal amino acid residues. The release appears to be G protein-dependent and is probably not receptor mediated.
9.
Grundemar, L, et al.
(författare)
Neuropeptide Y effector systems : perspectives for drug development
1994
Ingår i: Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147. ; 15:5, s. 153-159
Forskningsöversikt (refereegranskat) abstract
Neuropeptide Y was isolated in 1982 and has since attracted considerable interest. It is widely distributed in central and peripheral neurones and can produce a multitude of biological effects in the brain and the periphery. For example, the peptide has been associated with stimulation of food and water intake, control of mood, and regulation of central autonomic functions. In the periphery, sympathetic neuropeptide Y plays a role as a vasopressor and vasoconstrictor. Neuropeptide Y acts on at least three distinct receptor types, referred to a Y1, Y2 and Y3. This review by Lars Grundemar and Rolf Håkanson focuses on some neuropeptide Y-dependent mechanisms that may be implicated in certain disorders and may be promising targets for drugs active at neuropeptide Y receptors.
10.
Grundemar, L, et al.
(författare)
Neuropeptide Y, peptide YY and C-terminal fragments release histamine from rat peritoneal mast cells
1991
Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188. ; 104:4, s. 776-778
Tidskriftsartikel (refereegranskat) abstract
1. Neuropeptide Y (NPY) and peptide YY (PYY) seem to act on at least two receptor subtypes, Y1 and Y2. The Y1-receptor requires the whole C-terminally amidated NPY/PYY molecule whereas the Y2-receptor in addition recognizes C-terminal fragments of the two peptides. The present study was designed to elucidate whether NPY and related peptides were able to release histamine from isolated peritoneal mast cells of the rat. 2. NPY, NPY 15-36, NPY 22-36, NPY 26-36 and desamido-NPY evoked a concentration-dependent release of mast-cell histamine. The pEC15 values for NPY 15-36 and NPY 22-36 were higher, while the pEC15 value for NPY 26-36 was lower than that for NPY. At the highest concentration tested (0.1 mM), NPY and its C-terminal fragments released between 30 and 40% of the total histamine content. At the same concentration desamido-NPY released about 20%. 3. PYY and PYY 15-36 also evoked a concentration-dependent release of mast-cell histamine. PYY was more effective than PYY 15-36 since, at 0.1 mM, PYY released about 33%, while PYY 15-36 released about 15% of the total histamine content. Pancreatic polypeptide (PP) and the Y1-receptor-selective agonist [Pro34]NPY were virtually inactive. 4. The effect profile of the NPY/PYY-related peptides suggests that they act on the mast cells by a mechanism that does not involve either of the receptor subtypes hitherto described. The kinetics of the NPY-evoked histamine release may suggest that positively charged amino acid residues of NPY/PYY release mast-cell histamine by a non-receptor mechanism, as has been suggested for substance P and other basic peptides.
