Effects of Low-dose Morphine on Nitric Oxide Concentration and Angiogenesis in Two-kidney One Clip Hypertensive Rats

Document Type: Original Article

Authors

1 Physiology and Pharmacology Research Centre, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

2 Molecular Medicine Research Centre, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

Abstract

Objective(s)
We investigated the effects of low-dose morphine on nitric oxide (NO) and angiogenesis in two-kidney one clip hypertensive (2K1C) rats.
Materials and Methods
Male rats were divided into two groups: sham-clip operated and 2K1C. Each group subdivided into saline and morphine (3 mg/kg i.p. 8 weeks) groups. Blood pressure, heart rate, plasma renin activity (PRA), NO concentration and murine matrigel angiogenesis were evaluated.
Results
Morphine had no effects on blood pressures and HR in sham normotensive rats but attenuated diastolic blood pressure (DBP) (P< 0.01) and mean arterial pressure (MAP) (P< 0.01) in 2K1C compared with saline. PRA level was significantly higher in 2K1C compared with sham groups (P< 0.01) but morphine decreased it in 2K1C compared with saline (P< 0.01). After clipping, NO in 2K1C hypertensive rats was decreased (P< 0.01) and morphine increased it compared with saline (P< 0.01). Morphine promoted angiogenesis in both sham (P< 0.01) and 2K1C (P< 0.0001) groups.
Conclusion
Low-dose morphine stimulated angiogenesis in two-kidney one clip hypertensive rats probably via NO pathways.

Keywords


1.Viazzi F, Leoncini G, Ratto E, Parodi A, Falqui V, Conti N, et al. Vascular permeability, blood pressure, and organ damage in primary hypertension. Hypertens Res 2008; 31:873-879.

2.Kilarski WW, Samolov B, Petersson L, Kvanta A, Gerwins P. Biomechanical regulation of blood vessel growth during tissue vascularization. Natur Med 2009; 15:657-664.

3.Bian K, Doursout MF, Murad F. Vascular system: role of nitric oxide in cardiovascular diseases. J Clin Hypertens 2008; 10:304-310.

4.Tatemoto K, Takayama K, Zou MX, Kumaki I, Zhang W, Kumano K, et al. The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regul Pept 2001; 99:87-92.

5.Stefano GB, Hartman A, Bilfinger TV, Magazine HI, Liu Y, Casares F, et al. Presence of theopiate receptor in endothelial cells. J Biol Chem 1995; 270:30290. 

6.Arendt RM, Schmoeckel M, Wilbert-Lampen U, Plasse A, Heucke L, Werdan K. Bidirectional effects of endogenous opioid peptides on endothelin release rates in porcine aortic endothelial cell culture: mediation by delta opioid receptor and opioid receptor antagonist-insensitive mechanisms. J Pharmacol Exp Ther 1995; 272:1.

7.Toda N, Kishioka S, Hatano Y, Toda H. Modulation of opioid actions by nitric oxide signaling. Anesthesiology 2009; 110:166.

8.Toda N, Kishioka S, Hatano Y, Toda H. Interactions between morphine and nitric oxide in various organs. J Anesth 2009; 23:554-68.

9.Banach M, Casares F, Kream R, Gluba A, Rysz J, Stefano G. Morphine-mediated alteration of hypertension- related gene expression in human white blood cells and multilineage progenitor cells. J Hum Hypertens 2010; 24:713-720.

10.Ustun F, Durmus-Altun G, Altaner S, Tuncbilek N, Uzal C, Berkarda S. Evaluation of morphine effect on tumour angiogenesis in mouse breast tumour model, EATC. Med Oncol 2010; 22:1-9.

11.Komjati K, Greenberg JH, Reivich M, Sandor P. Interactions between the endothelium-derived relaxing factor/nitric oxide system and the endogenous opiate system in the modulation of cerebral and spinal vascular CO2 responsiveness. J Cereb Blood Flow Metab 2001; 21:937-944.

12.Lam CF, Chang PJ, Huang YS, Sung YH, Huang CC, Lin MW, et al. Prolonged use of high-dose morphine impairs angiogenesis and mobilization of endothelial progenitor cells in mice. Anesth Analg 2008; 107:686.

13.Peart JN, Gross GJ. Adenosine and opioid receptor-mediated cardioprotection in the rat: evidence for cross-talk between receptors.Am J Physiol Heart Circ Physiol 2003; 285:H81.

14.Gross ER, Hsu AK, Gross GJ. Opioid-induced cardioprotection occurs via glycogen synthase kinase {beta} inhibition during reperfusion in intact rat hearts. Circ Res 2004; 94:960.

15.Pasi A, Qu B, Steiner R, Senn HJ, Bar W, Messiha FS. Angiogenesis: modulation with opioids. Gen Pharmacol 1991; 22:1077-1079.

16.Bhat RS, Bhaskaran M, Mongia A, Hitosugi N, Singhal PC. Morphine-induced macrophage apoptosis: oxidative stress and strategies for modulation. J leukocyte biology? 2004; 75:1131.

17.Pacifici R, di Carlo S, Bacosi A, Pichini S, Zuccaro P. Pharmacokinetics and cytokine production in heroin and morphine-treated mice. Int J Immunopharmacol 2000; 22:603-614.

18.Singhal PC, Pamarthi M, Shah R, Chandra D, Gibbons N. Morphine stimulates superoxide formation by glomerular mesangial cells. Inflammation 1994; 18:293-289.

19.Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric oxide 2001; 5:62-71.

20.Auerbach R, Lewis R, Shinners B, Kubai L, Akhtar N. Angiogenesis assays: a critical overview. Clin Chem 2003; 49:32.

21.Martinez-Maldonado M. Pathophysiology of renovascular hypertension. Hypertension 1991; 17:707.

22.NystrOm H, Jia J, Johansson M, Lambert G, BergstrOm G. Neurohormonal influences on maintenance and reversal of two kidney one clip renal hypertension. Acta Physiol Scand 2002; 175:245-251.

23.Delle M, Ricksten S, Haggendal J, Olsson K, Skarphedinsson J, Thoren P. Regional changes in sympathetic nerve activity and baroreceptor reflex function and arterial plasma levels of catecholamines, renin and vasopressin during naloxone-precipitated morphine withdrawal in rats. J Pharmacol Exp Ther 1990; 253:646.

24.Luscher T, Vanhoutte P, Raij L. Antihypertensive treatment normalizes decreased endothelium-dependent relaxations in rats with salt-induced hypertension. Hypertension 1987; 9:III193.

25.Wong WT, Wong SL, Tian XY, Huang Y. Endothelial dysfunction: the common consequence in diabetes and hypertension. J Cardiovasc Pharmacol 2010; 55:300-307.

26.Vanhoutte P, Shimokawa H, Tang E, Feletou M. Endothelial dysfunction and vascular disease. Acta Physiol 2009; 196:193-222.

27. Khazaei M, Zarei M, Sharifi M, Pourshanazari A. The effect of maintenance and reversal of DOCA-salt hypertension on extravasation of macromolecules and serum nitric oxide concentration in male rats. Pathophysiology 2011; 18:201-206.

28.Czernichow S, Bertrais S, Blacher J, Galan P, Briangon S, Favier A, et al. Effect of supplementation with antioxidants upon long-term risk of hypertension in the SU. VI. MAX study: association with plasma antioxidant levels. J Hypertens 2005; 23:2013.

29.Crabos M, Coste P, Paccalin M, Tariosse L, Daret D, Besse P, et al. Reduced basal NO-mediated dilation and decreased endothelial NO-synthase expression in coronary vessels of spontaneously hypertensive rats. J Mol Cell Cardiol 1997; 29:55-65.

30.de Gasparo M. Angiotensin II and nitric oxide interaction. Heart fail Rev 2002; 7:347-358.

31.Dortch-Carnes J, Russell KRM. Morphine-induced reduction of intraocular pressure and pupil diameter: role of nitric oxide. Pharmacology 2006; 77:17-24.

32.Dortch-Carnes J, Russell K. Morphine-stimulated nitric oxide release in rabbit aqueous humor. Exp Eye Res 2007; 84:185-190. 

33.Dortch-Carnes J, Russell Randall K. Morphine-induced nitric oxide production in isolated, iris-ciliary bodies. Exp Eye Res 2009; 89:660-664.

34.Zarei M, Khazaei M, Sharifi MR, Pourshanazari AA. Coronary angiogenesis during experimental hypertension: is it reversible? JRMS 2011; 16:269-275.

35.Felmeden DC, Spencer CGC, Belgore FM, Blann AD, Beevers DG, Lip GYH. Endothelial damage and angiogenesis in hypertensive patients: relationship to cardiovascular risk factors and risk factor management* 1. Am J Hypertens 2003; 16:11-20.

36.Sane DC, Anton L, Brosnihan KB. Angiogenic growth factors and hypertension. Angiogenesis 2004; 7:193¬201.

37.Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, Yee D, et al. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 2002; 62:4491.

38.Chen C, Farooqui M, Gupta K. Morphine stimulates vascular endothelial growth factor-like signaling in mouse retinal endothelial cells. Curr Neurovasc Res 2006; 3:171-180.

39.Polakiewicz RD, Schieferl SM, Gingras AC, Sonenberg N, Comb MJ. Opioid receptor activates signaling pathways implicated in cell survival and translational control. J Biol Chem 1998; 273:23534.

40.Polakiewicz RD, Schieferl SM, Dorner LF, Kansra V, Comb MJ. A mitogen-activated protein kinase pathway is required for -opioid receptor desensitization. J Biol Chem 1998; 273:12402.

41.Liu HC, Anday JK, House SD, Chang SL. Dual effects of morphine on permeability and apoptosis of vascular endothelial cells: morphine potentiates lipopolysaccharide-induced permeability and apoptosis of vascular endothelial cells. J Neuroimmunol 2004; 146:13-21.

42.Lam CF, Liu YC, Tseng FL, Sung YH, Huang CC, Jiang MJ, et al. High-dose morphine impairs vascular endothelial function by increased production of superoxide anions. Anesthesiology 2007; 106:532.

43.Roy S, Balasubramanian S, Wang J, Chandrashekhar Y, Charboneau R, Barke R. Morphine inhibits VEGF expression in myocardial ischemia. Surgery 2003; 134:336-44.