Nifedipine Reduces Pulmonary Pressure and Vascular Tone during Short- but Not Long-term Treatment of Pulmonary Hypertension in Patients with Chronic Obstructive Pulmonary Disease

Abstract

We evaluated in patients suffering from COPD-related pulmonary hypertension whether nifedipine therapy lowers acutely and chronically pulmonary vascular pressure and resistance and whether pulmonary transmural pressure may be further lowered by the combined use of nifedipine and oxygen. Changes of the pulmonary vascular tone were determined on the pulmonary driving pressure/flow curve, which was generated by upright exercise. Fifteen patients with COPD and mean pulmonary pressure greater than or equal to 20 mm Hg were studied at control (Week 0) and after 1 wk of nifedipine treatment (180 mg daily, Week 1). It was possible to pursue the same nifedipine daily dosage for 2 months in 10 patients, who were re-evaluated after 8 wk of treatment and after nifedipine withdrawal the following week. At Week 1, mean pulmonary transmural pressure was reduced (32.8 +/- 4.1 versus 27.3 +/- 2.8 mm Hg, mean +/- SE, p less than 0.05) via active pulmonary vasodilation because the pulmonary driving pressure/flow curve was shifted right and downward. Both mean transmural pulmonary pressure lowering effect and active pulmonary vasodilatation regressed during long-term nifedipine treatment. Oxygen reduced pulmonary transmural pressure (32.8 +/- 4.1 versus 28.6 +/- 2.9 mm Hg, p less than 0.05, Week 0); however, this effect always disappeared during nifedipine treatment. We conclude that nifedipine should not be used as long-term treatment for COPD-related pulmonary hypertension and that nifedipine inhibits the oxygen capability to reduce pulmonary pressure.

Hypoxia-Induced Pulmonary Vascular Remodeling

“…147 However, other studies showed that the effects of calcium channel blockers are often only partial or temporary and are sometimes complicated by changes in cardiac output. 148 Interestingly, in chronically hypoxic rats, nifedipine was ineffective in reducing pulmonary hypertension, whereas another vasodilator, NIP121, caused significant reduction in PA pressure and vascular resistance. 149 More dramatically, the elevated resting [Ca 2ϩ ] i in PA SMCs of chronically hypoxic rats was unaffected by nifedipine but was reduced instantaneously to the level of control PA SMCs by the removal of extracellular Ca 2ϩ .…”

Enhanced store-operated Ca2+ entry and TRPC channel expression in pulmonary arteries of monocrotaline-induced pulmonary hypertensive rats

“…The hyperreactivity to ET-1 could be attributable to an increase in ET receptors (18,29) and their downstream signaling pathways involving SOCE. ET-1 binds to G proteincoupled ET receptors to activate phospholipase C to generate IP 3 and DAG, which can act synergistically to promote Ca 2ϩ entry through TRPC channels. IP 3 activates Ca 2ϩ release via IP 3 receptors and cross-activates neighboring ryanodine receptors through a Ca 2ϩ -induced Ca 2ϩ release mechanism (71), leading to the reduction of SR Ca 2ϩ to activate SOCE.…”

“…Ca 2ϩ influx in PASMCs is mainly regulated by voltage-dependent Ca 2ϩ channels and voltage-independent nonselective cation channels, such as store-operated Ca 2ϩ channels (SOCC) and receptor-operated Ca 2ϩ channels (ROCC). Blockers of voltage-gated Ca 2ϩ channel, however, are only effective in a small fraction of PAH patients, and the effect can be partial and temporary (2,3,10). Nifedipine is also ineffective in reducing pulmonary vascular resistance of chronic hypoxic rats (39).…”

Pulmonary hypertension in chronic obstructive pulmonary disease

“…Despite observation in some studies of slight haemodynamic improvement [101], other studies showed both pulmonary haemodynamics and clinical status either deteriorated or remained unchanged after several weeks or months of treatment [102,103].…”