Thickening of the media with intrusion on the vascular lumen contributes substantially to the pulmonary hypertension seen in primary or secondary pulmonary hypertension. Heparin has been shown to be antiproliferate and antihypertrophic for systemic and pulmonary smooth muscle cells in vitro and has been variably effective at inhibiting in vivo remodelling in several systemic and pulmonary models. Commercial heparin lots are a mixture of proteogly can chains ranging from 3,000 to 30,00 daltons and we have found the lots vary widely in their antiproliferative activity. We have shown, however, that an effective heparin in vitro for SMC proliferation can prevent hypoxic pulmonary hypertension in mice, rats and guinea pigs and can reverse it in guinea pigs even in the presence of continued hypoxia. We have also shown that heparin's ability to inhibit SMC proliferation and in vivo pulmonary hypertension correlates with its ability to prevent cytokine stimulation of the Na+ H+ antiporter. We are continuing to dissect the chemistry of antiproliferative heparins and have shown the protein core is unimportant and that 3-0-sulfate thought important in synthetic heparin pentasaccharide is not the important feature in full length heparin which is more potent. With this progress we hope to continue our pursuit of an effective treatment for pulmonary hypertension with the following specific aims: 1) Determine in the pig, as a preclinical trial in a large mammal, if heparin is effective at preventing hypoxic and monocrotaline induced pulmonary hypertension. 2) Continue our biochemical dissection of strongly versus weakly antiproliferative heparin, including pulmonary artery endothelial derived heparin, in order to discover the reason for the differences with a goal of amplifying the antiproliferative potency and perhaps divorcing it from the anticoagulative and osteopenic properties. 3) Completing pilot data on the Na+/H+ inhibitors dimithyl amiloride and ethyl isopropyl ameloride showing they block hypoxic pulmonary hypertension and extend these studies to the pig. Thus, this proposal may lead to novel therapeutic trials in humans with certain commercial heparins, pulmonary artery derived heparin or Na+/H+ antiporter inhibitors.
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