MECHANISMS OF LUNG POLYAMINE ACCUMULATION IN CHRONIC HYPOXIC PULMONARY-HYPERTENSION

Chronic hypoxia causes polyamine-dependent hypertensive pulmonary vascular remodeling (J.E. Atkinson, J.W. Olson, R.J. Altierre, and M.N. Gillespie. J. Appl. Physiol. 62:1562-1568, 1987), but mechanisms by which lung polyamine contents are elevated have not been established. This study measured polyamine contents, biosynthetic activities, and transport in lungs of rats exposed to hypobaric hypoxia (simulated altitude: 4,570 m) for 4-14 days. Hypoxia increased lung contents of spermidine and spermine within 40 h and of putrescine within 4 days. These changes preceded hypoxia-induced increases in pulmonary arterial pressure and development of right ventricular hypertrophy. Additional experiments determined whether increased lung polyamine contents could be ascribed to elevated activity of ornithine decarboxylase (ODC), the rate-limiting enzyme in conversion of ornithine to putrescine. Lung ODC activity did not differ from controls at 40 h posthypoxia and was reduced below control levels from 4-14 days of exposure. Putrescine transport kinetics were assessed in isolated, salt solution-perfused lungs. Apparent K(m) for putrescine uptake was increased from 10.4-mu-M in control lungs to 16.9-mu-M in lungs from rats maintained for 7 days in an hypoxic environment. Maximal velocity (V(max)) of lung putrescine transport was increased from 1.67 nmol.g-1.min-1 in controls to 2.65 in hypoxic lungs. Putrescine efflux also was altered by hypoxic exposure; T1/2 for loss of diamine from a slowly effluxing pool was increased from 60.6 min in controls to 91.5 min in hypoxic lungs. Impaired degradation did not seem to contribute to increased lung putrescine content since lung activity of diamine oxidase was increased with 40 h of hypoxia and declined gradually to control levels over the remainder of 14-day exposure period. Hypoxia was associated with sustained increases in lung S-adenosylmethionine decarboxylase (AdoMet-DC) activity and promoted polyamine interconversion through acetylated intermediates as evidenced by increased activity of spermidine-spermine actyltransferase (SAT) and increased lung contents of N1-acetylspermidine. These observations suggest that elevation of polyamines in hypoxic rat lungs does not require increased lung ODC activity. Instead, accentuated uptake and decreased efflux may provide sufficient quantities of putrescine that, in concert with elevated AdoMet-DC and SAT activities, regulates increases in lung spermidine and spermine contents.