İntraserebroventriküler olarak uygulanan Exendin-(9-39) santral "Glucagon-like peptide-1"in kardiyovasküler etkilerini önler mi?

Bu çalışmada uyanık, serbestçe hareket edebilen sıçanlara İntraserebroventriküler (i.c.v.) olarak enjekte edilen "glucagon-like peptide-1" (GLP-l)'in kan basıncı ve kalp hızı üzerine olan etkileri ve bu etkilerine santral spesifik reseptörlerinin aracılık edip etmediğinin belirlenmesi amaçlandı. Deneylerde kullanılan erkek Wistar albino sıçanlara eter anestezisi altında, sağ femoral artere kateter ve i.c.v. enjeksiyonlar,için sağ lateral ventriküle kanül yerleştirildi. Arteriyel kan basıncı ve kalp hızı, "TDA96 Transducer Data Acquisition System" aracılığıyla kaydedildi. Sıçanların ilaç enjeksiyonlarından önce ve enjeksiyonları takiben 30 dakika süresince kan basınçları ve kalp hızlan kaydedildi. İ.c.v. yolla verilen GLP-I (100, 500 ve 1000 ng/10$mu$l) kan basıncı ve kalp hızında doza bağlı olarak artış oluşturdu. GLP-I'in bu etkilerini i.c.v. olarak enjekte edilen reseptör antagonisti exendin-(9-39) (2500ng/10 $mu$l) inhibe etti. Bulgularımız i.c.v. GLP-I'in kan basıncı ve kalp hızını yükselttiğini, bu etkilerine santral spesifik reseptörlerinin aracılık ettiğini göstermektedir.

Does intracerebroventricularly-injected Exendin-(9-39) prevent the cardiovascular effects of central glucagon-like peptide-17

In this study, we aimed to investigate the effects of intracerebroventricularly (i.c.v.)-injected glucagon-like peptide-1 (GLP-I) on blood pressures and heart rates of conscious, freely-moving rats, and whether specific receptors mediate these effects. Male Wistar albino rats used throughout the experiments were implanted with a cathether through the right femoral artery and with a cannula into the right lateral ventricle for i.c.v. injections, under ether anesthesia. Blood pressure and heart rate were recorded by a "TDA96 Transducer DataAcquisi-tion System". Blood pressures and heart rates of rats were observed before and for 30 minutes following drug injections. I.c.v. GLP-I (100, 500 and 1000 ng/10 $mu$l) caused a dose-dependent increase in both blood pressure and heart rate. The effects of GLP-I on blood pressure and heart rate were inhibited by i.c.v. receptor antagonist exendin-(9-39) (2500 ng/$mu$l). Our data indicate that i.c.v. GLP-I in-creases blood pressure and heart rate, and that activation of central specific receptors mediate these effects.

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  • 1. Fehmann HC, Habener JF. Insulinotropic glucagon-like peptide-1 (7-37)/(7-36) amide: a new incretin hormone. Trends Endocrinol Metab 1992;3:158-63.
  • 2. Mojsov S, Heinrich G, Wilson IB, et al. Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing. J Biol Chem 1986;261:11880-9.
  • 3. Jin SL, Han VKM, Simmons JG, et al. Distribution of glucagon-like peptide-1 (GLP-1), glucagon, and glisentin in the rat brain: an immunocytochemical study. J Comp Neurol 1988;271:519-32.
  • 4. Kreymann B, Ghatei MA, Burnet P, et al. Characterisation of glucagon-like peptide-1 (7-36) amide in the rat hypothalamus. Brain Res 1989;502:325-31.
  • 5. Elliot RM, Morgan LM, Tredger S, et al. Glucagon-like peptide-1 (7-36) amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h patterns. J Endocrinol 1993;138:159-66.
  • 6. Wei Y, Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide-1: brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Lett 1995;358:219-24.
  • 7. Edwards CMB, Edwards AV, Bloom R. Cardiovascular and pancreatic endocrine responses to glucagon-like peptide-1-(7-36) amide in the conscious calf. Exp Physiol 1997;82:709-16.
  • 8. Edwards CMB, Todd JF, Ghatei MA. Subcutaneous glucagon-ike peptide-I (7-36) amide is insulinotropic and can cause hypoglycaemia in fasted healthy subjects. Clin Sci 1998;96:719-24.
  • 9. O’Halloran DJ, Nikou GC, Kreymann B, et al. Glucagon-like peptide-1 (7-36)-NH2: a physiological inhibitor of gastric acid secretion in man. J Endocrinol 1990;126:169-73.
  • 10. Wettergren A, Wqjdemann M, Holst JJ. Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow. Am J Physiol (Gastrointest Liver Physiol) 1998;275(38):984-92.
  • 11. Barragan JM, Rodriguez RE, Blazquez E. Changes in arterial blood pressure and heart rate induced by glucagon-like peptide-1-(7-36) amide in rats. Am J Physiol (Endocrinol Metab) 1994;266 (29):456-66.
  • 12. Barragan JM, Rodriguez RE, Eng J, Blazquez E. Interaction of exendin-(9-39) with the effects of glucagon-like peptide-1-(7-36) amide and of exendin-4 on arterial blood pressure and heart rate in rats. Regul Pept 1996;67:63-8.
  • 13. Barragan JM, Eng J, Rodriguez R, Blazquez E. Neural contribution to the effect of glucagon-like peptide-1-(7-36) amide on arterial blood pressure in rats. Am J Physiol (Endocrinol Metab) 1999;277 (40):784-91.
  • 14. Bojanovska E, Stempniak B. Effects of centrally or systemically injected glucagon-like peptide-1-(7-36) amide on release of neurohypophysial hormones and blood pressure in the rat. Regul Pept 2000;91:75-81.
  • 15. Göke R, Fehmann HC, Linn T, et al. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting β-cells. J Biol Chem 1993;268(26):19650-5.
  • 16. Kollgs F, Fehmann HC, Göke R, Göke B. Reduction of the incretin effect in rats by the glucagon-like peptide 1 receptor antagonist exendin (9-39) amide. Diabetes 1995;44(1):16-9.
  • 17. Cancelas J, Villanueva-Penacarrillo ML, Valverde I, Malaisse WJ. Supression by exendin(9-39) amide of glucagon-like peptide-1 insulinotropic action in rats infused with dimethyl ester of succinic acid. Endocrine 2001;15(3):283-5.
  • 18. Daniel EE, Anvari M, Fox-Threlkeld JE, McDonald TJ. Local, exendin-(9-39)-insensitive, site of action of GLP-1 in canine ileum. Am J Physiol (Gastrointest Liver Physiol) 2002;283(3):595-602.
  • 19. Eng J, Kleiman WA, Singh L, et al. Isolation and characterization of exendin-4, and exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 1992;267:7402-5.
  • 20. Bullock BP, Heller RS, Habener JF. Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology 1996;137:2968-78.
  • 21. Merchenthaler I, Lane M, Shughrue P. Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. J Comp Neurol 1999;403:261-80.
  • 22. Goke R, Larsen PJ, Mikkelsen JD, Sheikh SP. Distribution of GLP-1 binding sites in the rat brain: evidence that exendin-4 is a ligand of brain GLP-1 binding sites. Eur J Neurosci 1995;7:2294-300.
  • 23. Yamamoto H, Kishi T, Lee CE, et al. Glucagon-like peptide-1 responsive catecholamine neurons in the area postrema link peripheral glucagon-like peptid-1 with central autonomic control sites. J Neurosci 2003;23(7):2939-46.
  • 24. Turton MD, O’Shea DO, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996;379:69-72.
  • 25. Meeran K, O’Shea D, Edwards CM, et al. Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat. Endocrinology 1999;140:244-50.
  • 26. Yamamoto H, Lee CH, Marcus JN, et al. Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons. J Clin Invest 2002;110:43-52.
  • 27. Bachelard H, Gardiner SM, Bennett T. Cardiovascular responses elicited by chemical stimulation of the rostral ventrolateral medulla in conscious, unrestrained rats. J Auton Nerv Syst 1990;31:185-90.