Affiliation:
1. Department of Physiology, Second Medical School, Charles University, Prague, Czech Republic
Abstract
Chronic hypoxia induces an increased production of nitric oxide (NO) in pulmonary prealveolar arterioles. Bioavailability of the NO in the pulmonary vessels correlates with concentration of L-arginine as well as activity of phosphodiesterase-5 enzyme (PDE-5). We tested a hypothesis whether a combination of L-arginine and PDE-5 inhibitor sildenafil has an additive effect in reduction of the hypoxic pulmonary hypertension (HPH) in rats. Animals were exposed to chronic normobaric hypoxia for 3 weeks. In the AH group, rats were administered L-arginine during chronic hypoxic exposure. In the SH group, rats were administered sildenafil during chronic hypoxic exposure. In the SAH group, rats were treated by the combination of L-arginine as well as sildenafil during exposure to chronic hypoxia. Mean PAP, structural remodeling of peripheral pulmonary arterioles (%DL) and RV/LV+S ratio was significantly decreased in the SAH group compared to hypoxic controls even decreased compared to the AH and the SH groups in first two measured parameters. Plasmatic concentration of cGMP and NOx were significantly lower in the SAH group compared to hypoxic controls. We demonstrate that NO synthase substrate L-arginine and phosphodiesterase-5 inhibitor sildenafil administered in combination are more potent in attenuation of the HPH compared to a treatment by substances given alone.
Publisher
Institute of Physiology of the Czech Academy of Sciences
Subject
General Medicine,Physiology
Reference36 articles.
1. ADAMS MR, FORSYTH CJ, JESSUP W, ROBINSON J, CELERMAJER DS: Oral L-arginine inhibits platelet aggregation but does not enhance endothelium-dependent dilation in healthy young men. J Am Coll Cardiol 26: 1054-1061, 1995.
2. ARCHER SL, HUANG JM, HAMPL V, NELSON DP, SHULTZ PJ, WEIR EK: Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proc Natl Acad Sci U S A 91: 7583-7587, 1994.
3. CLOZEL M, HESS P, REY M, IGLARZ M, BINKERT C, QIU C: Bosentan, sildenafil, and their combination in the monocrotaline model of pulmonary hypertension in rats. Exp Biol Med (Maywood) 231: 967-973, 2006.
4. COHEN AH, HANSON K, MORRIS K, FOUTY B, MCMURTY IF, CLARKE W, RODMAN DM: Inhibition of cyclic 3'-5'-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxic rats. J Clin Invest 97: 172-179, 1996.
5. D'ALONZO GE, BARST RJ, AYRES SM, BERGOFSKY EH, BRUNDAGE BH, DETRE KM, FISHMAN AP, GOLDRING RM, GROVES BM, KERNIS JT, ET AL.: Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 115: 343-349, 1991.
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