To study the molecular basis of vascular remodeling in pulmonary hypertension, we developed an experimental system in which male Sprague-Dawley rats were exposed to hypoxia for up to 3 wk. Both the right ventricular systolic pressure and gravimetric index for right ventricular hypertrophy were higher in rats exposed to hypoxia for 3 wk than those of age-matched control rats (P < 0.01), indicating that pulmonary hypertension was established under conditions used. To examine the possible involvement of platelet-derived growth factor (PDGF) in the pulmonary vascular remodeling caused by hypoxia, we cloned rat PDGF A- and B-chain cDNA and prepared specific cRNA probes. Northern blot analysis revealed that PDGF B-chain mRNA levels in the lungs were increased, reached a maximum of day 1, and were sustained at day 3, whereas PDGF A-chain mRNA levels reached a maximum on day 3. Thus the increase in the PDGF B-chain mRNA level precedes that in the PDGF A-chain mRNA level. These results suggest that the PDGF A- and B-chain products may be coordinately and sequentially involved in hypoxic pulmonary vascular remodeling.
To examine the hypothesis that suppression of basal release of endothelium-derived relaxing factor (EDRF) by hypoxia might be related to the mechanism of hypoxic pulmonary vasoconstriction, rings of porcine pulmonary artery (PA, 2 mm OD) were suspended in organ chambers and changes in isometric force were measured. Hypoxia significantly reduced endothelium-dependent relaxation induced by acetylcholine and augmented contractile response to phenylephrine. This augmentation by hypoxia was not seen in rings without endothelium. Contractile response to phenylephrine was also enhanced by removal of endothelium. With 15 min of hypoxia, PA contracted and guanosine 3',5'-cyclic monophosphate content decreased. Pretreatment with 10(-6) M methylene blue, 3 x 10(-7) M oxyhemoglobin, and 9.6 x 10(-5) M NG-monomethyl-L-arginine significantly enhanced hypoxic contraction. Furthermore, removal of endothelium also enhanced hypoxic contraction. These results suggest that suppression of basally released EDRF by hypoxia was not the cause of the contractile response to hypoxia and that EDRF modulates the hypoxic contraction of porcine PA in basal conditions at this diameter.
The intracellular recording of a single auricle fiber of frog or toad shows a spike-dip-plateau contour, suggesting two depolarizations are involved and two deflections comprise the action potential contour. Low oxygen reduces the plateau phase. Acetylcholine applied locally by microejection (or by vagal stimulation) acts specifically to cause plateau phase to be diminished or abolished and simultaneously affects the mechanical response in a like manner. The Q10 of the spike exposed alone by the acetylcholine effect is significantly different (1.2) from the Q10 value of the normal prolonged response (2.4) or the mechanogram (2.5). The evidence supports the idea that two ion carrier systems exist in the excitable membrane: one which reacts rapidly, the other more slowly. In cardiac muscle the fast one causes the spike depolarization, which itself is adequate to trigger the slow response. The slow system must react not specifically with potassium but with sodium also and causes the prolonged depolarization or plateau. Recovery is probably due to slow inactivation of this second process.
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