Pulmonary hypertension (PH) is a debilitating and potentially fatal disease in humans, also reported in animals. Among many etiologies, the hypoxia-induced PH is the one most studied. It can be experimentally induced and produces characteristic thickening of pulmonary arteries and right ventricular hypertrophy. Studies to date have focused upon the effect of vasoactive substances and the influence of the autonomic nervous system. However, most of the pulmonary pressor response to hypoxia begins and ends within the lung, suggesting influence of local factors, for example the diffuse neuroendocrine system involved in peptide hormone mediated regulatory function. Although this new concept has received great interest over the last decade, its role in PH has been little studied. This proposal uses a rat model of hypoxia-induced PH to investigate the role of regulatory lung peptides in the etiology and development of the disease. I. Peptide screening for potential involvement in PH. Test rats will be exposed to hypobaric hypoxia (P 380 mmHg) for 14-21 days to create graded responses. After that time, right ventricular blood pressures (PRV) will be recorded and peptide levels quantitated in lung tissue extract and left ventricular plasma. Peptide levels in test an control rats will be correlated (regression analysis) with time spent in hypoxia, lung water, PRV, medial thickness index of small pulmonary arteries and RV hypertrophy index. II. Peptides which correlated with two or more of these indicators of PH in a previous study (SOM, PYY, CGRP, gamma-2 MSH), and their antibodies or antagonists, will be continuously infused for 14 days to the heart and lungs via a right side jugular vein cannula attached to a SQ osmotic minipump. Normoxic rats and hypoxia pre-treated (14 days) rats infused in hypoxia or normoxia, and their time-matched vehicle-infused controls, will be evaluated for signs of PH to determine the ability of peptide or antibody initiate, exacerbate or ameliorate PH.
| Tjen-A-Looi, S; Kraiczi, H; Ekman, R et al. (1998) Sensory CGRP depletion by capsaicin exacerbates hypoxia-induced pulmonary hypertension in rats. Regul Pept 74:1-10 |
| Tjen-A-Looi, S; Ekman, R; Osborn, J et al. (1996) Pulmonary vascular pressure effects by endothelin-1 in normoxia and chronic hypoxia: a longitudinal study. Am J Physiol 271:H2246-53 |
| Keith, I M; Ekman, R (1992) Dynamic aspects of regulatory lung peptides in chronic hypoxic pulmonary hypertension. Exp Lung Res 18:205-24 |
| Tjen-A-Looi, S; Ekman, R; Lippton, H et al. (1992) CGRP and somatostatin modulate chronic hypoxic pulmonary hypertension. Am J Physiol 263:H681-90 |
| Keith, I M; Pelto-Huikko, M; Schalling, M et al. (1991) Calcitonin gene-related peptide and its mRNA in pulmonary neuroendocrine cells and ganglia. Histochemistry 96:311-5 |
