Urocortin正性频率和正性肌力作用以及心脏CRF-R2β mRNA表达的研究
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摘要
Urocotin(Ucn)属于促肾上腺皮质激素释放激素(corticotropin-releasing factor, CRF)家族,由40个氨基酸组成,与CRF享有45%的同源性?CRF对心血管的作用曾被广泛研究,研究人员发现脑室内注射CRF可加快心率,增加心输出量和升高血压;相反,静脉注射CRF却降低平均动脉压?CRF作用于CRF受体(CRF-R1和CRF-R2)产生生理作用,CRF-R1主要分布于脑和垂体,CRF-R2除了分布于中枢神经系统外,还分布于包括心脏在内的外周组织?据报道,与CRF相比较,Ucn对CRF受体有更高的亲和力和内在活性,对于CRF-R2 Ucn表现出很高的亲和力,提示Ucn可能是CRF-R2的天然配体,对心血管系统有较高的选择性作用?
清醒大鼠静脉注射Ucn可缓慢而持久地降低平均动脉血压,同时伴有心率加快和心输出量增加。羊静脉注射Ucn可明显升高升主动脉血流量和升主动脉dF/dt值,提示Ucn对羊心脏具有正性肌力作用。大鼠侧脑室内注射Ucn则使动物血压轻微升高,但不影响心肌收缩力。最近,研究人员在大鼠离体心脏观察到Ucn的正性肌力作用。为了进一步明确Ucn对心脏的作用,我们观察了Ucn对大鼠和兔离体右心房、心室乳头肌和大鼠右心室肌的作用,并研究了Ucn对大鼠心室乳头肌和左心房肌细胞动作电位的影响。通过比较Ucn对SHR和Wistar大鼠离体心肌的作用,我们还观察了Ucn在病理情况下对心脏的作用。
据报道,在大鼠离体心脏β受体阻断药对Ucn的正性频率和正性肌力作用无明显影响;CRF-R2阻断药α-helical CRH 9-41能阻断Ucn对大鼠离体心脏的作用;敲除小鼠CRF-R2可完全消除Ucn的正性肌力作用和降血压作用;这些结果提示Ucn的作用可能通过激动CRF-R2所产生。为了进一步揭示Ucn对心脏的作用机制,我们使用小鼠离体心房肌标本,观察了阿托品、普萘洛尔、吲哚美辛、酚妥拉明、TTX及α-helical CRH 9-41对Ucn作用的影响;并观察了CRF受体的mRNA在大鼠、小鼠心肌的表达。
Urocortin (Ucn), a 40 amino acid peptide, belongs to the corticotropin -releasing factor (CRF) family and displays 45% amino acid sequence homology to CRF. Effects of CRF on the cardiovascular system have been extensively studied. It has been shown that CRF administered into the cerebral ventricles increases the heart rate, cardiac output and mean arterial blood pressure, intravenous administration of CRF, however, decreases the mean arterial blood pressure. CRF plays biological roles by acting on CRF receptors (CRF-R1 and CRF-R2), and CRF-R1 is expressed in brain and pituitary. However, CRF-R2 is expressed not only in the central nervous system but also in peripheral tissues, including the heart. Ucn is reported to bind and activate CRF-R to a greater extent than CRF, and Ucn has much greater affinity for CRF-R2. It is therefore suggested that Ucn may be a nature ligand for CRF-R2, and its cardiovascular effects might be more potent than those of CRF.
Ucn administered intravenously to the conscious rats produces a slow and long-lasting decrease in mean arterial blood pressure, which parallels with a rise in heart rate and cardiac output. A significant increase in cardiac contractility was speculated after intravenous administration of Ucn to the sheep as reflected by elevation in both maximal ascending aortic blood flow and ascending aortic dF/dt. However, Ucn injected into the lateral cerebral ventricle in rats increases blood pressure slightly and has no effect in myocardial contractility. A recent study in isolated rat hearts showed a direct evidence of positive inotropic action induced by Ucn. The purpose of this study was to investigate the effects of Ucn on the rat and rabbit right atrium, papillary muscles and rat right ventricle strip, and the effects of Ucn on action potentials of the rat papillary muscles and left atrium. We also compared the
清醒大鼠静脉注射Ucn可缓慢而持久地降低平均动脉血压,同时伴有心率加快和心输出量增加。羊静脉注射Ucn可明显升高升主动脉血流量和升主动脉dF/dt值,提示Ucn对羊心脏具有正性肌力作用。大鼠侧脑室内注射Ucn则使动物血压轻微升高,但不影响心肌收缩力。最近,研究人员在大鼠离体心脏观察到Ucn的正性肌力作用。为了进一步明确Ucn对心脏的作用,我们观察了Ucn对大鼠和兔离体右心房、心室乳头肌和大鼠右心室肌的作用,并研究了Ucn对大鼠心室乳头肌和左心房肌细胞动作电位的影响。通过比较Ucn对SHR和Wistar大鼠离体心肌的作用,我们还观察了Ucn在病理情况下对心脏的作用。
据报道,在大鼠离体心脏β受体阻断药对Ucn的正性频率和正性肌力作用无明显影响;CRF-R2阻断药α-helical CRH 9-41能阻断Ucn对大鼠离体心脏的作用;敲除小鼠CRF-R2可完全消除Ucn的正性肌力作用和降血压作用;这些结果提示Ucn的作用可能通过激动CRF-R2所产生。为了进一步揭示Ucn对心脏的作用机制,我们使用小鼠离体心房肌标本,观察了阿托品、普萘洛尔、吲哚美辛、酚妥拉明、TTX及α-helical CRH 9-41对Ucn作用的影响;并观察了CRF受体的mRNA在大鼠、小鼠心肌的表达。
Urocortin (Ucn), a 40 amino acid peptide, belongs to the corticotropin -releasing factor (CRF) family and displays 45% amino acid sequence homology to CRF. Effects of CRF on the cardiovascular system have been extensively studied. It has been shown that CRF administered into the cerebral ventricles increases the heart rate, cardiac output and mean arterial blood pressure, intravenous administration of CRF, however, decreases the mean arterial blood pressure. CRF plays biological roles by acting on CRF receptors (CRF-R1 and CRF-R2), and CRF-R1 is expressed in brain and pituitary. However, CRF-R2 is expressed not only in the central nervous system but also in peripheral tissues, including the heart. Ucn is reported to bind and activate CRF-R to a greater extent than CRF, and Ucn has much greater affinity for CRF-R2. It is therefore suggested that Ucn may be a nature ligand for CRF-R2, and its cardiovascular effects might be more potent than those of CRF.
Ucn administered intravenously to the conscious rats produces a slow and long-lasting decrease in mean arterial blood pressure, which parallels with a rise in heart rate and cardiac output. A significant increase in cardiac contractility was speculated after intravenous administration of Ucn to the sheep as reflected by elevation in both maximal ascending aortic blood flow and ascending aortic dF/dt. However, Ucn injected into the lateral cerebral ventricle in rats increases blood pressure slightly and has no effect in myocardial contractility. A recent study in isolated rat hearts showed a direct evidence of positive inotropic action induced by Ucn. The purpose of this study was to investigate the effects of Ucn on the rat and rabbit right atrium, papillary muscles and rat right ventricle strip, and the effects of Ucn on action potentials of the rat papillary muscles and left atrium. We also compared the
引文
1 Huang Y, Yao XY, Lau YC, et al. Urocortin and cardiovascular protection. Acta Pharmacol Sin, 2004, 25(3): 257-265
2 丛海滨,倪鑫. Urocortin的心血管作用. 生理科学进展,2005,36(4):349-352
3 Schiling L, Kanzler C, Schmiedek P, et al. Characterization of the relaxant action of urocortin, a new peptide related to corticotropin-releasing factor in the rat isolated basilar artery. Br J Pharmacol, 1998, 125 (6): 1164-1171
4 Vaughan J, Donaldson C, Bittencourt J, et al. Urocortin, a mammalian neuropeptide related to fish urotensin Ⅰand to corticotrophin-releasing factor. Nature, 1995, 378 (1): 287-292
5 David GP, Clive NM. Urocortin: A novel player in cardiac control. News in Physiological Sciences, 2000, 15 (5): 264-268
6 Parkes DG, Joan V, Jean R, et al. Cardiac inotropic action of urocortin in conscious sheep. Am J Physiol Heart Circ Physiol, 1997, 272 (41): H2115-H2122
7 Bale TL, Hoshijima M, G Y, et al. The cardiovascular physiologic actions of urocortin Ⅱ: Acute effects in murine heart failure. Proc. Natl. Acad. Sci., USA, 2004, 101 (10): 3697-3702
8 Ding JX, Zhang SL, Wang RB. Effect of diacetyl guaufu base A on isolated atrial muscle. Chin Pharmacol Bull, 1997, 16 (6): 541-544
9 Wang LF, Yu GS, Zhang YY, et al. Effects of long-team atenolol trentment on β–adrenoceptor subtypes in rat heart. Acta Physiol Sin, 1995, 47 (4): 381-386
10 Zhao D, Ren LM. Electrophysiologic effect of moxonidine on action potential in rabbit sinoatrial node pacemaker cells. Chin J Pharmacol Toxicol, 2002, 16 (4): 250-254
11 Ren LM, Li JX, Shi CX, et al. Electrophysiologic effects of adenosine triphosphate on rabbit sinoatrial node pacemaker cells via P1 receptors. Acta Pharmacol Sin, 2003, 24 (9): 943-947
12 Kimura Y, Takahashi K, Totsune K, et al. Expression of urocortin and corticotrophin-releasing factor receptor subtypes in the human heart. J Clin Endocrinol & Metabol, 2002, 87(1): 340-346
13 Oki Y, Iwabuchi M, Masuzawa M, et al. Distribution and concentration of urocortin, and effect of adrenalectomy on its content in rat hypothalamus. Life Sci, 1998, 62(9): 807-812
14 Terui L, Higashiiyama A, Horiba N, et al. Coronary vasodilation and positive inotropism by urocortin in the isolated rat heart. J Endocrinol, 2001, 169 (1): 177-183
1 Mastorakos G, Bouzss EA, Sliver PB. Immune corticotropin-releasing hormone is present in the eyes of and promotes experimental autoimmune uveoretinitis in rodents. J Endocrinol, 1995, 136 (10): 4650-4658
2 Donaldson CJ, Sutton SW, Perrin MH, et al. Cloning and characterization of human urocortin. Endocrinol, 1996, 137 (5): 2167-2170
3 Vanghan J, Donaldson C, Bittencourt J, et al. Urocortin, a mammalian neuropeptide related to fish urotensin Ⅰ and to corticotropin-releasing factor. Nature, 1995, 378(1): 287-292
4 Rademaker MT, Charles CJ, Espiner EA, et al. Four-day urocortin-Ⅰ administration has sustained beneficial haemodynamic, hormonal, and renal effects in experimental heart failure. Eur Heart J, 2005,26(19): 2055-2062
5 Bale TL, Hoshijima M, Gu Y, et al. The cardiovascular physiologic actions of urocortin Ⅱ: Acute effects in murine heart failure. PNAS, 2004, 101(10): 3697 -3702
6 Nishikimi T, Miyata A, Horio T, et al. Urocortin, a member of the corticotrophin-releasing factor family, in normal and diseased heart. Am J Physiol Heart Circ Physiol, 2000, 279: H3031-H3039
7 Zhu ZN,Zhao D,Ren LM. Selective positive inotropic action of urocortin on rat and rabbit isolated heart tissues. Chin J Pharmacol Toxicol, 2005, 19(6): 428-435
8 Ding JX, Zhang SL, Wang RB. Effect of diacetyl guaufu base A on isolated atrial muscle. Chin Pharacol Bull, 1997, 16 (6): 541-544
9 Wang LF, Yu GS, Zhang YY, et al. Effects of long-team atenolol trentment on β–adrenoceptor subtypes in rat heart. Acta Physiol sini, 1995, 47 (4): 381-386
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5 Terui L, Higashiiyama A, Horiba N, et al. Coronary vasodilation and positive inotropism by urocortin in the isolated rat heart. J Endocrinol, 2001, 169 (1): 177-183
6 Bale TL, Hoshijima M, Gu Y, et al. The cardiovascular physiologic actions of urocortin Ⅱ: Acute effects in murine heart failure. PNAS, 2004, 101(10): 3697 –3702
7 Gardiner SM, March JE, Kemp PK, et al. Regional hemodynamic actions of selective corticotrophin-releasing factor type 2 receptor ligands in conscious rats. J Pharmacol Exp Ther, 2005, 312(1): 53-60
8 Parkes DG, Joan V, Jean R, et al. Cardiac inotropic action of urocortin in conscious sheep. Am J Physiol Heart Circ Physiol, 1997, 272 (41): H2115-H2122
9 Ding JX, Zhang SL, Wang RB. Effect of diacetyl guaufu base A on isolated atrial muscle. Chin Pharacol Bull, 1997, 16 (6): 541-544
10 Wang LF, Yu GS, Zhang YY, et al. Effects of long-team atenolol treatment on β-adrenoceptor subtypes in rat heart. Acta Physiol sin, 1995, 47 (4):381-386
11 Kimura Y, Takahashi K, Totsune K, et al. Expression of urocortin and corticotrophin-releasing factor receptor subtypes in the human heart. J Clin Endocrinol & Metabol, 2002, 87(1): 340-346
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40 Rademaker MT, Charles CJ, Espiner EA, et al. Four-day urocortin-Ⅰ administration has sustained beneficial haemodynamic, hormonal, and renal effects in experimental heart failure. Eur Heart J, 2005, 26(19): 2055-2062
41 Bale TL, Hoshijima M, Gu Y, et al. The cardiovascular physiologic actions of urocortin Ⅱ: Acute effects in murine heart failure. PNAS, 2004, 101(10):3697 -3702
42 Nishikimi T, Miyata A, Horio T, et al. Urocortin, a member of the corticotrophin-releasing factor family, in normal and diseased heart. Am J Physiol Heart Circ Physiol, 2000, 279: H3031-H3039
2 丛海滨,倪鑫. Urocortin的心血管作用. 生理科学进展,2005,36(4):349-352
3 Schiling L, Kanzler C, Schmiedek P, et al. Characterization of the relaxant action of urocortin, a new peptide related to corticotropin-releasing factor in the rat isolated basilar artery. Br J Pharmacol, 1998, 125 (6): 1164-1171
4 Vaughan J, Donaldson C, Bittencourt J, et al. Urocortin, a mammalian neuropeptide related to fish urotensin Ⅰand to corticotrophin-releasing factor. Nature, 1995, 378 (1): 287-292
5 David GP, Clive NM. Urocortin: A novel player in cardiac control. News in Physiological Sciences, 2000, 15 (5): 264-268
6 Parkes DG, Joan V, Jean R, et al. Cardiac inotropic action of urocortin in conscious sheep. Am J Physiol Heart Circ Physiol, 1997, 272 (41): H2115-H2122
7 Bale TL, Hoshijima M, G Y, et al. The cardiovascular physiologic actions of urocortin Ⅱ: Acute effects in murine heart failure. Proc. Natl. Acad. Sci., USA, 2004, 101 (10): 3697-3702
8 Ding JX, Zhang SL, Wang RB. Effect of diacetyl guaufu base A on isolated atrial muscle. Chin Pharmacol Bull, 1997, 16 (6): 541-544
9 Wang LF, Yu GS, Zhang YY, et al. Effects of long-team atenolol trentment on β–adrenoceptor subtypes in rat heart. Acta Physiol Sin, 1995, 47 (4): 381-386
10 Zhao D, Ren LM. Electrophysiologic effect of moxonidine on action potential in rabbit sinoatrial node pacemaker cells. Chin J Pharmacol Toxicol, 2002, 16 (4): 250-254
11 Ren LM, Li JX, Shi CX, et al. Electrophysiologic effects of adenosine triphosphate on rabbit sinoatrial node pacemaker cells via P1 receptors. Acta Pharmacol Sin, 2003, 24 (9): 943-947
12 Kimura Y, Takahashi K, Totsune K, et al. Expression of urocortin and corticotrophin-releasing factor receptor subtypes in the human heart. J Clin Endocrinol & Metabol, 2002, 87(1): 340-346
13 Oki Y, Iwabuchi M, Masuzawa M, et al. Distribution and concentration of urocortin, and effect of adrenalectomy on its content in rat hypothalamus. Life Sci, 1998, 62(9): 807-812
14 Terui L, Higashiiyama A, Horiba N, et al. Coronary vasodilation and positive inotropism by urocortin in the isolated rat heart. J Endocrinol, 2001, 169 (1): 177-183
1 Mastorakos G, Bouzss EA, Sliver PB. Immune corticotropin-releasing hormone is present in the eyes of and promotes experimental autoimmune uveoretinitis in rodents. J Endocrinol, 1995, 136 (10): 4650-4658
2 Donaldson CJ, Sutton SW, Perrin MH, et al. Cloning and characterization of human urocortin. Endocrinol, 1996, 137 (5): 2167-2170
3 Vanghan J, Donaldson C, Bittencourt J, et al. Urocortin, a mammalian neuropeptide related to fish urotensin Ⅰ and to corticotropin-releasing factor. Nature, 1995, 378(1): 287-292
4 Rademaker MT, Charles CJ, Espiner EA, et al. Four-day urocortin-Ⅰ administration has sustained beneficial haemodynamic, hormonal, and renal effects in experimental heart failure. Eur Heart J, 2005,26(19): 2055-2062
5 Bale TL, Hoshijima M, Gu Y, et al. The cardiovascular physiologic actions of urocortin Ⅱ: Acute effects in murine heart failure. PNAS, 2004, 101(10): 3697 -3702
6 Nishikimi T, Miyata A, Horio T, et al. Urocortin, a member of the corticotrophin-releasing factor family, in normal and diseased heart. Am J Physiol Heart Circ Physiol, 2000, 279: H3031-H3039
7 Zhu ZN,Zhao D,Ren LM. Selective positive inotropic action of urocortin on rat and rabbit isolated heart tissues. Chin J Pharmacol Toxicol, 2005, 19(6): 428-435
8 Ding JX, Zhang SL, Wang RB. Effect of diacetyl guaufu base A on isolated atrial muscle. Chin Pharacol Bull, 1997, 16 (6): 541-544
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