REDUCTION OF CHRONIC HYPOXIC PULMONARY-HYPERTENSION IN THE RAT BY AN INHIBITOR OF COLLAGEN PRODUCTION

Chronic hypoxic pulmonary hypertension in the rat is associated with increased collagen and elastin in the pulmonary artery. We investigated whether excess vascular collagen contributes to chronic hypoxic pulmonary hypretension by administering the proline analogue cis-4-hydroxy-L-proline (cHyp), an agent relatively specific for inhibitig collagen production, to rats exposed to chronic hypoxia. Sprague-Dawley rats (weighting 200 g) were exposed to air or hypoxia (10% O2-90% N2) for 3 wk. Groups studied were: air-exposed injected with saline, air-exposed injected with cHyp, hypoxic injected with saline, and hypoxic injected with cHyp. At the end of 3 wk, we measured mean right ventricular pressure (RVP) of aimals breathing room air and hydroxyproline and desmosine contents of the main pulmonary artery trunk. Hypoxia increased RVP from 13 .+-. 1 to 27 .+-. 1 mm Hg (p < 0.05); cHyp partially prevented this increase since RVP was 17 .+-. 1 mm Hg (p < 0.05). There was no effect of cHyp on cardiac output. Hypoxia increased collagen from 0.9 .+-. 1.0 to 2.0 .+-. 0.3 mg/artery (p < 0.05); cHyp completely prevented this increase since collagen was 1.0 .+-. 0.2 mg/artery (p < 0.05). Hypoxia increased elastin from 1.1 .+-. 0.1 to 2.4 .+-. 0.2 mg/artery (p < 0.05); cHyp had no apparent effect since elastin was 2.1 .+-. 0.1 mg/artery. Also, cHyp did not affect RVP or vascular collagen or elastin in air-breathing animals. The cHyp treatment prevented luminal narrowing and thickening of arteriolar walls by hypoxia. These results show that cHyp ameliorates chronic hypoxic hypertension and accumulation of vascular colagen, but ot elastin, in the main pulmonary artery trunk. We conclude that there is a relationship between pulmonary hypertension and pulmonary artery collagen. It remains to be established whether this relationship is causal.