Exogenous ghrelin improves blood flow distribution in pulmonary hypertension—assessed using synchrotron radiation microangiography
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Ghrelin has cardioprotective properties and, recently, has been shown to improve endothelial function and reduce endothelin-1 (ET-1)-mediated vasoconstriction in peripheral vascular disease. Recently, we reported that ghrelin attenuates pulmonary hypertension (PH) caused by chronic hypoxia (CH), which we hypothesized in this study may be via suppression of the ET-1 pathway. We also aimed to determine whether ghrelin’s ability to prevent alterations of the ET-1 pathway also prevented adverse changes in pulmonary blood flow distribution associated with PH. Sprague–Dawley rats were exposed to CH (10% O2 for 2 weeks) with daily subcutaneous injections of ghrelin (150 μg/kg) or saline. Utilizing synchrotron radiation microangiography, we assessed pulmonary vessel branching structure, which is indicative of blood flow distribution, and dynamic changes in vascular responsiveness to (1) ET-1 (1 nmol/kg), (2) the ET-1A receptor antagonist, BQ-123 (1 mg/kg), and (3) ACh (3.0 μg kg−1 min−1). CH impaired blood flow distribution throughout the lung. However, this vessel “rarefaction” was attenuated in ghrelin-treated CH-rats. Moreover, ghrelin (1) reduced the magnitude of endothelial dysfunction, (2) prevented an increase in ET-1-mediated vasoconstriction, and (3) reduced pulmonary vascular remodeling and right ventricular hypertrophy—all adverse consequences associated with CH. These results highlight the beneficial effects of ghrelin for maintaining optimal lung perfusion in the face of a hypoxic insult. Further research is now required to establish whether ghrelin is also an effective therapy for restoring normal pulmonary hemodynamics in patients that already have established PH.
KeywordsGhrelin Chronic hypoxia Pulmonary hypertension Endothelin-1 Rat
This study was supported in part by a University of Otago Research Grant, an Otago Medical Research Foundation Grant (AG293), a Grant in aid for Scientific Research (20590242) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Health and Labour Sciences Research Grants (research on intractable diseases, no. H22-Nanti-ippan-033), and the Monash Centre for Synchrotron Science. The synchrotron radiation experiments were performed at the BL28B2 at SPring-8 with the approval of the Japan Synchrotron Radiation Research Institute (proposal no. 2009B1328).
All experiments were approved by the local Animal Ethics Committee of SPring-8 and conducted in accordance with the guidelines of the Physiological Society of Japan.
Conflicts of interest
The authors declare that they have no conflicts of interest.
- 2.Baber SR, Deng W, Master RG, Bunnell BA, Taylor BK, Murthy SN, Hyman AL, Kadowitz PJ (2007) Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction. Am J Physiol Heart Circ Physiol 292:H1120–H1128PubMedCrossRefGoogle Scholar
- 6.Carville C, Raffestin B, Eddahibi S, Blouquit Y, Adnot S (1993) Loss of endothelium-dependent relaxation in proximal pulmonary arteries from rats exposed to chronic hypoxia: effects of in vivo and in vitro supplementation with l-arginine. J Cardiovasc Pharmacol 22:889–896PubMedCrossRefGoogle Scholar
- 7.Fike CD, Kaplowitz MR, Thomas CJ, Nelin LD (1998) Chronic hypoxia decreases nitric oxide production and endothelial nitric oxide synthase in newborn pig lungs. Am J Physiol (Lung Cell Mol Physiol) 274:L517–L526Google Scholar
- 9.Henriques-Coelho T, Roncon-Albuquerque R Jr, Lourenco AP, Baptista MJ, Oliveira SM, Brandao-Nogueira A, Correia-Pinto J, Leite-Moreira AF (2006) Ghrelin reverses molecular, structural and hemodynamic alterations of the right ventricle in pulmonary hypertension. Portuguese J Cardiol 25:55–63Google Scholar
- 12.Johnson W, Nohria A, Garrett L, Fang JC, Igo J, Katai M, Ganz P, Creager MA (2002) Contribution of endothelin to pulmonary vascular tone under normoxic and hypoxic conditions. Am J Physiol (Heart Circ Physiol) 283:H568–H575Google Scholar
- 15.Le Cras TD, McMurtry IF (2001) Nitric oxide production in the hypoxic lung. Am J Physiol (Lung Cell Mol Physiol) 280:L575–L582Google Scholar
- 21.Schwenke DO, Pearson JT, Shimochi A, Kangawa K, Tsuchimochi H, Umetani K, Shirai M, Cragg PA (2009) Changes in pulmonary blood flow distribution in monocrotaline compared with chronic hypoxia-induced models of pulmonary hypertension—assessed using synchrotron radiation microangiography. J Hyperten 27:1410–1419CrossRefGoogle Scholar