Effect of thoracic epidural blockade on hypoxia-induced pulmonary arterial hypertension in rats

Document Type : Original Article

Authors

1 Institute of Pulmonary Disease, the First Hospital of China Medical University, Shenyang, China, 110001First Hospital of Harbin Medical University, Harbin, China, 150001

2 First Hospital of Harbin Medical University, Harbin, China, 150001

Abstract

Objective(s): The present study was aimed to investigate the influence of thoracic epidural blockade on hypoxia-induced pulmonary hypertension in rats.
Materials and Methods: Forty eight Wistar rats were randomly divided into 4 equal groups, named normoxia hypoxia hypoxia/ ropivacaine and hypoxia/saline. Animals were placed in a hypoxia chamber and instrumented with epidural catheters at the thoracic level. Rats were injected with saline or ropivacaine. Haemodynamic measurements included pulmonary artery pressure and right ventricular hypertrophy. Degree of pulmonary vascular remodeling was determined by Hematoxylin and Eosin (HE) staining. Serum cyclic GMP (cGMP) and TNF-α were measured using radioimmuno assay. Real-time PCR and western boltting were employed to examine the expression of cAMP responding-element binding protein (CREB).
Results: We found that the thoracic epidural blockade significantly decreased chronic hypoxia-induced pulmonary hypertension and vascular remodeling in rats. Ropivacaine-treated rats exhibited significantly lower mean pulmonary artery pressure (mPAP), ratio of right ventricular weight to left ventricular plus septal weight (RV/(LV+S)) and wall thickness of pulmonary artery compared with those of control rats. Hypoxia-induced increase in levels of serum cGMP and TNF-α was reversed by thoracic epidural blockade. Moreover, hypoxia increased expression of CREB at mRNA and protein levels which could be suppressed by thoracic epidural blockade.
Conclusion:Thoracic epidural blockade reduced mPAP and serum level of TNF-α and increased cGMP. The treatment reversed upregulated expression of CREB at mRNA and protein production.

Keywords

References

1.   Lin MJ, Leung GP, Zhang WM, Yang XR, Yip KP, Tse CM, Sham JS: Chronic hypoxia-induced upregulation of store-operated and receptor-operated ca2+ channels in pulmonary arterial smooth muscle cells: A novel mechanism of hypoxic pulmonary hypertension. Circ Res 2004; 95:496-505.
2.   Yu L, Quinn DA, Garg HG, Hales CA: Cyclin-dependent kinase inhibitor p27kip1, but not p21waf1/cip1, is required for inhibition of hypoxia-induced pulmonary hypertension and remodeling by heparin in mice. Circ Res 2005; 97:937-945.
3.   Soon E, Holmes AM, Treacy CM, Doughty NJ, Southgate L, Machado RD, Trembath RC, Jennings S, Barker L, Nicklin P, Walker C, Budd DC, Pepke-Zaba J, Morrell NW: Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 2010; 122:920-927.
4.   Murray F, MacLean MR, Pyne NJ: Increased expression of the cgmp-inhibited camp-specific (pde3) and cgmp binding cgmp-specific (pde5) phosphodiesterases in models of pulmonary hypertension. Br J Pharmacol 2002; 137:1187-1194.
5.   Yu L, Hales CA: Effect of chemokine receptor cxcr4 on hypoxia-induced pulmonary hypertension and vascular remodeling in rats. Respir Res 2011; 12:21.
6.   Kanazawa H, Asai K, Nomura S: Vascular endothelial growth factor as a non-invasive marker of pulmonary vascular remodeling in patients with bronchitis-type of copd. Respir Res 2007; 8:22.
7.   Calbet JA: Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans. J Physiol 2003; 551:379-386.
8.   Arias-Stella J, Saldana M: The terminal portion of the pulmonary arterial tree in people native to high altitudes. Circulation 1963; 28:915-925.
9.   Stenmark KR, Fagan KA, Frid MG: Hypoxia-induced pulmonary vascular remodeling: Cellular and molecular mechanisms. Circ Res 2006; 99:675-691.
10. Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Reeves JT, Roedersheimer MT, van Rooijen N, Stenmark KR: Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol 2006; 168:659-669.
11. Fahim M: Cardiovascular sensory receptors and their regulatory mechanisms. Indian J Physiol Pharmacol 2003; 47:124-146.
12. Noll G, Wenzel RR, Binggeli C, Corti C, Luscher TF: Role of sympathetic nervous system in hypertension and effects of cardiovascular drugs. Eur Heart J 1998; 19 Suppl F:F32-38.
13. Ainslie PN, Ogoh S: Regulation of cerebral blood flow in mammals during chronic hypoxia: A matter of balance. Exp Physiol 2010; 95:251-262.
14. Hainsworth R, Drinkhill MJ: Cardiovascular adjustments for life at high altitude. Respir Physiol Neurobiol 2007; 158:204-211.
15. Neubauer JA, Sunderram J: Oxygen-sensing neurons in the central nervous system. J Appl Physiol 2004; 96:367-374.
16. Xie A, Skatrud JB, Puleo DS, Morgan BJ: Exposure to hypoxia produces long-lasting sympathetic activation in humans. J Appl Physiol 2001; 91:1555-1562.
17. Velez-Roa S, Ciarka A, Najem B, Vachiery JL, Naeije R, van de Borne P: Increased sympathetic nerve activity in pulmonary artery hypertension. Circulation 2004; 110:1308-1312.
18. Missant C, Rex S, Claus P, Derde S, Wouters PF: Thoracic epidural anaesthesia disrupts the protective mechanism of homeometric autoregulation during right ventricular pressure overload by cardiac sympathetic blockade: A randomised controlled animal study. Eur J Anaesthesiol 2011; 28:535-543.
19. Premkumar DR, Mishra RR, Overholt JL, Simonson MS, Cherniack NS, Prabhakar NR: L-type ca(2+) channel activation regulates induction of c-fos transcription by hypoxia. J Appl Physiol 2000; 88:1898-1906.
20. Rowell LB, Johnson DG, Chase PB, Comess KA, Seals DR: Hypoxemia raises muscle sympathetic activity but not norepinephrine in resting humans. J Appl Physiol 1989; 66:1736-1743.
21. Missant C, Rex S, Claus P, Derde S, Wouters PF: Thoracic epidural anaesthesia disrupts the protective mechanism of homeometric autoregulation during
right ventricular pressure overload by cardiac sympathetic blockade: A randomised controlled animal study. Eur J Anaesthesiol 2011; 28:535-543.
22. Svorkdal N: Treatment of inoperable coronary disease and refractory angina: Spinal stimulators, epidurals, gene therapy, transmyocardial laser, and counterpulsation. Semin Cardiothorac Vasc Anesth 2004; 8:43-58.
23. Kock M, Blomberg S, Emanuelsson H, Lomsky M, Stromblad SO, Ricksten SE: Thoracic epidural anesthesia improves global and regional left ventricular function during stress-induced myocardial ischemia in patients with coronary artery disease. Anesth Analg 1990; 71:625-630.
24. Ishibe Y, Shiokawa Y, Umeda T, Uno H, Nakamura M, Izumi T: The effect of thoracic epidural anesthesia on hypoxic pulmonary vasoconstriction in dogs: An analysis of the pressure-flow curve. Anesth Analg 1996; 82:1049-1055.
25. Rex S, Missant C, Segers P, Wouters PF: Thoracic epidural anesthesia impairs the hemodynamic response to acute pulmonary hypertension by deteriorating right ventricular-pulmonary arterial coupling. Crit Care Med 2007; 35:222-229.
26. Brimioulle S, Vachiery JL, Brichant JF, Delcroix M, Lejeune P, Naeije R: Sympathetic modulation of hypoxic pulmonary vasoconstriction in intact dogs. Cardiovasc Res 1997; 34:384-392.
 
Iranian Journal of Basic Medical Sciences
Volume 17, Issue 9 - Serial Number 9
September 2014
Pages 710-715

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