Experimental pulmonary hypertension induced in a hypobaric hypoxic environment (HHE) is characterized by structural remodeling of the heart and pulmonary arteries. Adrenomedullin (AM) has diuretic, natriuretic, and hypotensive effects. To study the possible effects of HHE on the AM synthesis system, 150 male Wistar rats were housed in a chamber at the equivalent of a 5,500-m altitude level for 21 days. After 14 days of exposure to HHE, pulmonary arterial pressure (PAP) was significantly increased (compared with control rats). The plasma AM protein level was significantly increased on day 21 of exposure to HHE. In the right ventricle (RV), right atrium, and left atrium of the heart, the expressions of AM mRNA and protein were increased in the middle to late phase (5-21 days) of HHE, whereas in the brain and lung they were increased much earlier (0.5-5 days). In situ hybridization and immunohistochemistry showed AM mRNA and protein staining to be more intense in the RV in animals in the middle to late phase of HHE exposure than in the controls. During HHE, these changes in AM synthesis, which occurred strongly in the RV, occurred alongside the increase in PAP. Conceivably, AM may play a role in modulating pulmonary hypertension in HHE.

Experimental pulmonary hypertension induced in a hypobaric hypoxic environment (HHE) is characterized by structural remodelling of the heart. In rat cardiac ventricles, pressure and volume overload are well known to be associated with changes in cardiac myosin heavy chain (MHC) isoforms. To study the effects of HHE on the MHC profile in the ventricles, 83 male Wistar rats were housed in a chamber at the equivalent of 5500 m altitude for 1-8 weeks. Pulmonary arterial pressure, right ventricular free wall (RVFW) weight, the ratio of RVFW weight over body weight (BW), the ratio of left ventricular free wall (LVFW) weight over BW, and myocyte diameter in both ventricles showed significant increases after 1 week, 2 weeks, 1 week, 6 weeks, and 4 weeks of HHE, respectively. Semi-quantitative reverse transcriptase-polymerase chain reaction revealed that beta-MHC mRNA expression was increased significantly in both ventricles at 6 and 8 weeks of HHE, whereas alpha-MHC mRNA expression was decreased significantly at 6 and 8 weeks of HHE in the right ventricle (RV) and at 6 weeks of HHE in the left ventricle (LV). The percentage of myosin containing the beta-MHC isoform was increased significantly at 4-8 weeks of HHE in RV and at 6 weeks of HHE in LV. In situ hybridization showed that the area of strong staining for beta-MHC mRNA was increased in both ventricles at 8 weeks of HHE, and showed a decrease from RVFW to cardiac septum, and from cardiac septum to LVFW. These results suggest that HHE has a significant effect on the expression of both MHC mRNA and protein in the heart, particularly in RV. These changes may reflect a role for cardiac MHC in the response to pulmonary hypertension in HHE.

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp he pulmonary hypertension that develops in hypobaric hypoxia is characterized by structural remodeling of the heart (eg, right ventricular hypertrophy). 1-7 Over the past 20 years or so, various factors and influences, including the adrenergic-receptor system, have been shown to be involved in such cardiovascular remodeling processes. [8][9][10][11][12] It is well known that hypoxia stimulates endothelial cells to release adenosine triphosphate (ATP). Purinergic P2 nucleotide receptors on endothelial cells bind this ATP, triggering secretion of nitric oxide and consequent vasodilation. The P2 class of nucleotide receptors includes the P2X receptor, which is a ligand-gated receptor channel, and the G protein-coupled P2Y receptor. 13,14 Recently, the P2X4 receptor (P2X4R) has been reported to control vascular tone and vessel remodeling in at least some blood vessels. 15-19 Interestingly, P2X4R is an important subunit of the native cardiac myocyte P2X receptor, 17 and cardiac-restricted overexpression of P2X4R can induce an enhanced contractile state of the intact heart. 20 More recently, it was found that cardiac overexpression of P2X4R increased cardiac contractility and survival in a model of myocardial infarction-induced cardiac failure. 21 It has therefore emerged as a key factor in the enhancement of cardiac performance. However, no reports have been published of alterations in P2X4R expression in certain organs, especially the heart, upon exposure to hypobaric hypoxia, and little is known about any changes in P2X4R expression in hypoxia-induced pulmonary hypertension (in which only RV is exposed to pressure overload).Even if changes in P2X4R expression occur during exposure to hypobaric hypoxia and show an apparent relation to the pulmonary pressure overload, it needs to be firmly established: (1) whether the changes in P2X4R (at both the protein and mRNA levels) occurring in certain organs, especially the heart, are coupled to the elevation in pulmonary arterial pressure seen after exposure to hypobaric hypoxia; (2) whether the changes in P2X4R protein occurring in certain organs as an adaptation to hypobaric hypoxic exposure are mirrored by similar changes at the mRNA level; and (3) whether the dis- Expression of P2X4R mRNA and Protein in RatsWith Hypobaric Hypoxia-Induced Pulmonary HypertensionYuichiro Ohata, MD; Sho Ogata, MD; Kuniaki Nakanishi, MD; Fumiko Kanazawa; Maki Uenoyama; Sadayuki Hiroi, PhD; Susumu Tominaga; Toshiaki Kawai, MD Background: The experimental pulmonary hypertension that develops in hypobaric hypoxia is characterized by structural remodeling of the heart. The P2X4 receptor (P2X4R) controls vascular tone and vessel remodeling in several blood vessels, and it has emerged as a key factor in the enhancement of cardiovascular performance.

PKC-alpha may help to modulate the right ventricular hypertrophy caused by pulmonary hypertension in HHE.

No abstract