EFFECTS OF NITRENDIPINE AND HYPOXIA ON PULMONARY VASCULAR-RESISTANCE IN EXPERIMENTAL EMPHYSEMA

We evaluated the hemodynamic effects of nitrendipine, a dihydropyridine Ca2+ channel blocker, and hypoxia in intact dogs with emphysema produced by treatments with aerosolized papain. We also determined the effects of emphysema, chronic Ca2+ channel blocker treatment, and acute hypoxia on the distribution of vascular resistance in isolated left lower lobes. Pulmonary vascular resistance was increased (4 ± 1 mm Hg/L/min) in the animals studied 6 months after receiving 4 weekly treatments with papain compared with control animals (2.6 ± 0.6 mm Hg/L/min, p < 0.05), and this effect of emphysema was blunted with chronic nitrendipine, 3 mg/kg twice a day (3.1 ± 0.9 mm Hg/L/min). Both at baseline and at 6 months, hypoxia-induced increases in pulmonary vascular resistance were abolished by nitrendipine. The total pulmonary pressure gradient (ΔPt) was partitioned into pressure gradients across arterial (ΔPa), middle (ΔPm), and venous (ΔPv) vessels by occlusions performed during normoxia (P(IOO2) = 200 mm Hg) and hypoxia (P(IOO2 = 30 mm Hg). Papain-treated animals had elevated ΔPt compared with that in control animals because of an increased ΔPv (9.7 ± 1.1 mm Hg versus 5.2 ± 0.4 mm Hg in control animals, p < 0.05). In contrast, only ΔPm was increased with papain + nitrendipine (2.6 ± 1.0 mm Hg versus 0.2 ± 0.3 mm Hg in control animals, p < 0.05). An increase in the downstream pressure gradient was also observed when lobes from animals with emphysema were studied under conditions of reverse perfusion. Hypoxic responses were similar in the control and papain groups, with increases in ΔPa and ΔPm. In contrast, the relatively smaller increases in ΔPt with papain + nitrendipine occurred because the extent of hypoxic vasoconstriction in arteries was less, so that only ΔPm increased. Our data suggest that the increased pulmonary artery pressure that develops in papain-induced emphysema is due in part to the development of Zone II conditions. Active upstream vasoconstriction may also contribute to the increased pulmonary artery pressure, and it is attenuated during normoxia and hypoxia by nitrendipine.