Published online before print September 22, 2003, doi: 10.1161/01.HYP.0000094980.67417.58
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(Hypertension. 2003;42:e13.)
© 2003 American Heart Association, Inc.
Letters to the Editor |
Neuropeptide Y and Sympathetic Nervous System in Blood Pressure Regulation
Division of Cardiology, Department of Medicine, Wakayama Medical University, Wakayama, Japan
To the Editor:
We read with great interest the recent article by Dr Michalkiewicz and his colleagues1 dealing with a possible link between neuropeptide Y (NPY) and sympathetic nervous system in the NPY-transgenic rats. The results of their presented study demonstrated that overexpression of endogenous NPY in the transgenic rats was associated with lower blood pressure in baseline and during stress. Dr Michalkiewicz proposed that the antiadrenergic action of NPY within the sympathetic nervous system may protect the cardiovascular system from excessive adrenergic excitations.
Several studies have reported the influences of NPY on sympathetic neurotransmission in both the central and peripheral nervous systems.2–7 In a study we presented earlier, the change in norepinephrine (NE) release induced by NPY was investigated in rat hypothalamus and medulla oblongata.2,3 In an in vitro study using rat brain slices, we showed that NPY inhibited the stimulation-evoked NE release in a dose-dependent manner. It was also demonstrated that NPY potentiated the inhibitory effect of the 
2-adrenergic receptor agonists on NE release. In contrast, blockade of the 2-adrenergic receptors or pretreatment of pertussis toxin (a potent inhibitor of the Gi-proteins) diminished the inhibitory effects of NPY on NE release. It would be possible that NPY might reduce NE release in the central nervous system partially mediated by the 2-adrenergic receptors and the pertussis toxin–sensitive Gi-proteins. In addition, the inhibitory effect of NPY on NE release was impaired in spontaneously hypertensive rats (SHR).3 It was reported that NPY increased the number of the 2-adrenergic receptor binding sites in medulla oblongata of normotensive Wistar-Kyoto rats, whereas NPY failed to increase the 2-adrenergic receptor binding sites in medulla oblongata of SHR,8 indicating that the interactions between NPY and 2-adrenergic receptors might be disturbed in hypertension.
In the separate series of the experiments, Dr Michalkiewicz9 showed that the pressor responses to exogenous NE were significantly increased in the NPY-transgenic rats. The finding might be consistent with the hypothesis that genetic upregulation of NPY could enhance the -adrenergic receptor sensitivity. Therefore, we would like to know whether the 2-adrenergic receptor function might be altered in the NPY-transgenic rats. In this context, it can be speculated that, because central stimulation of the 2-adrenergic receptors might markedly reduce blood pressure,10 the changes in the 2-adrenergic receptors might partially explain the blood pressure–lowering effect of NPY in this type of transgenic rats. Further studies should be performed to assess more thoroughly the relationships between NPY and sympathetic nervous system and their role in the blood pressure regulation.
References
1. Michalkiewicz M, Knestaut KM, Bytchkova EY, Michalkiewicz T. Hypotension and reduced catecholamines in neuropeptide Y transgenic rats. Hypertension. 2003; 41: 1056–1062.
2. Tsuda K, Yokoo H, Goldstein M. Neuropeptide Y and galanin in norepinephrine release in hypothalamic slices. Hypertension. 1989; 14: 81–86.
3. Tsuda K, Tsuda S, Masuyama Y, Goldstein M. Norepinephrine release and neuropeptide Y in medulla oblongata of spontaneously hypertensive rats. Hypertension. 1990; 15: 784–790.
4. Dahlöf C, Dahlöf P, Tatemoto K, Lundberg JM. Neuropeptide Y (NPY) reduces field stimulation-evoked release of noradrenaline and enhances force of contraction in the rat portal vein. Naunyn Schmiedebergs Arch Pharmacol. 1985; 328: 327–330.[Medline] [Order article via Infotrieve]
5. Tsuda K, Masuyama Y. Presynaptic regulation of neurotransmitter release in hypertension. Clin Exp Pharmacol Physiol. 1991; 18: 455–467.[CrossRef][Medline] [Order article via Infotrieve]
6. Tsuda K, Tsuda S, Goldstein M, Masuyama Y. Sodium ions attenuate the inhibitory effects of neuropeptide Y on norepinephrine release in rat hypothalamus. Am J Hypertens. 1995; 8: 1135–1140.[Medline] [Order article via Infotrieve]
7. Bacci A, Huguenard JR, Price DA. Differential modulation of synaptic transmission by neuropeptide Y in rat neocortical neurons. Proc Natl Acad Sci U S A. 2002; 99: 17125–17130.
8. Agnati LF, Fuxe K, Benfenati F, Battistini N, Harfstrand A, Hökfelt T, Cavicchioli L, Tatemoto K, Mutt V. Failure of neuropeptide Y in vitro to increase the number of 2-adrenergic binding sites in membranes of medulla oblongata of the spontaneously hypertensive rat. Acta Physiol Scand. 1983; 119: 309–312.[CrossRef][Medline]
[Order article via Infotrieve]
9. Michalkiewicz M, Michalkiewicz T, Kreulen D, McDougall S. Increased vascular responses in neuropeptide Y transgenic rats. Am J Physiol. 2001; 281: R417–R426.
10. van Zwieten PA, Thoolen MJMC, Timmermans PBMWM. The hypotensive activity and side effects of methyldopa, clonidine, and guanfacine. Hypertension. 1984; 6 (suppl 2): 28–33.
Response: Hypotension and Reduced Catecholamines in Neuropeptide Y Transgenic Rats
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
We appreciate Dr Tsuda’s interest and enriching comments regarding our recently published paper.1 The correspondent’s comments are very insightful and point to the 2-adrenergic signaling as the most likely mechanism of the hypotensive and sympatholytic effects of the genetic upregulation of neuropeptide Y (NPY). Indeed NPY appears as a potent presynaptic inhibitor of norepinephrine (NE) release in the brain centers involved in regulation of blood pressure. This suggestion is supported by Dr Tsuda’s own extensive work assessing the physiological importance of the coexistence of NPY with NE in sympathetic nervous system (for the references see the correspondent’s letter). This notion is also in line with the findings of others.2 It is important to emphasize that our observations of the sympatholytic and hypotensive effects of long-term genetic upregulation of NPY in transgenic rat are in agreement with the correspondent’s findings obtained by using isolated cerebral slices models. Unfortunately, the stated space limitations of the journal did not allowed us to discuss all of his interesting and very relevant findings more extensively in our report.
We entirely agree with Dr Tsuda’s suggestion that this transgenic rat provides a unique model to determine the physiological importance of functional cooperation between endogenous NPY and NE in the sympathetic nervous system. In particular, this transgenic rat will allow us to determine whether the hypotensive responses to increased NPY signaling are a consequence of enhanced 2-adrenergic functions. It is particularly difficult to determine such interreceptor interactions using a short-term model. Therefore, availability of a genetic model allowing long-term, whole-animal manipulation is advantageous. Indeed, there are data to suggest the importance of endogenous NPY in regulation of the function of the 2-adrenoceptor. Like the 2-agonist clonidine, NPY inhibits NE release in synaptosomes from the medulla oblongata, and it potentiates clonidine-induced inhibition of NE release.2,3 Along with hypotension, stimulation of the central 2-adrenoceptor leads to sedation.4,5 We have reported anxiolysis and behavioral insensitivity to restraint stress in this transgenic rat.6 This peptide has also been suggested to be involved in the enhanced stress resilience in humans.7 These anxiolytic effects of NPY could reflect an enhanced 2-adrenoceptor signaling due to NPY upregulation. Thus, indeed, as the correspondent suggests, NPY transgenic rat provides an appropriate model to study the modulatory role of NPY in the regulation of adrenergic signaling.
In summary, we agree with Dr Tsuda that NPY appears as an important endogenous modulator of the 2-adrenoceptor and that NPY transgenic rat provides a useful model to assess many functional aspects of the interactions between NPY and the 2-adrenergic signaling implicated in the regulation of blood pressure by the sympathetic nervous system.
References
1. Michalkiewicz M, Knestaut KM, Bytchkova EY, Michalkiewicz T. Hypotension and reduced catecholamines in neuropeptide Y transgenic rats. Hypertension. 2003; 41: 1056–1062.
2. Martire M, Pistritto G. Neuropeptide Y interaction with the adrenergic transmission line: a study of its effect on alpha-2 adrenergic receptors. Pharmacol Res. 1992; 25: 203–215.[CrossRef][Medline] [Order article via Infotrieve]
3. Tsuda K, Tsuda S, Masuyama Y, Goldstein M. Norepinephrine release and neuropeptide Y in medulla oblongata of spontaneously hypertensive rats. Hypertension. 1990; 15: 784–790.
4. Donnelly CL. Pharmacologic treatment approaches for children and adolescents with posttraumatic stress disorder. Child Adolesc Psychiatr Clin N Am. 2003; 12: 251–269.[Medline] [Order article via Infotrieve]
5. Wolkowitz OM, Paul SM. Neural and molecular mechanisms in anxiety. Psychiatr Clin North Am. 1985; 8: 145–158.[Medline] [Order article via Infotrieve]
6. Thorsell A, Michalkiewicz M, Dumont Y, Quirion R, Caberlotto L, Rimondini R, Mathé A, Heilig M. Behavioral insensitivity to restraint stress, absent fear suppression of behavior and impaired spatial learning in NPY transgenic rats. Proc Natl Acad Sci U S A. 2000; 97: 12852–12857.
7. Morgan CA 3rd, Wang S, Southwick SM, Rasmusson A, Hazlett G, Hauger RL, Charney DS. Plasma neuropeptide-Y concentrations in humans exposed to military survival training. Biol Psychiatry. 2000; 47: 902–909.[CrossRef][Medline] [Order article via Infotrieve]
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