Thomas P. Kennedy

Inhibition of hypoxic pulmonary vasoconstriction by nifedipine

Nifedipine is a potent slow channel calcium antagonist and systemic vasodilator recently reported to attenuate hypoxic pulmonary vasoconstriction in man. Other systemic vasodilators have also been shown to attenuate hypoxic pulmonary vasoconstriction, but their effects in some species may be mediated by reflex beta-adrenergic discharge. We evaluated the effect of nifedipine on the relation between pulmonary arterial pressure and blood flow during hyperoxia (inspired partial pressure of oxygen [PO2] 200 mm Hg) and hypoxia (inspired PO2 50 mm Hg) in denervated ventilated pig lungs perfused in situ with the animals own blood. Ten lungs were ventilated with alternating 15 minute periods of hyperoxia and hypoxia. Hypoxia shifted the pulmonary artery pressure (x axis)-blood flow (y axis) relationship to the right and decreased its slope, indicating vasoconstriction. Nifedipine, given as a 0.1, 1, or 10 microgram/kg bolus into the pulmonary artery, caused a dose-dependent reduction of hypoxic pulmonary vasoconstriction. It is concluded that nifedipine is a potent pulmonary vasodilator acting locally within the lung and that it might be useful in the therapy of hypoxic pulmonary hypertension from chronic lung disease in man.

Amiodarone causes acute oxidant lung injury in ventilated and perfused rabbit lungs

Amiodarone (ADR), a new antiarrhythmic drug for life-threatening cardiac arrhythmias, causes pneumonitis or lung fibrosis in a sizeable minority of patients. The cause of lung damage is not known. We have shown that infusion of 10 mg amiodarone into the inflow circuit of ventilated and perfused rabbit lungs causes immediate increase in pulmonary artery pressure (mean ± SEM) (from 13.6 ± 1.2 to 40.6 ± 9.5 mm Hg, p < 0.01) and pulmonary edema with marked increase in the pulmonary generation of thromboxane and leukotrienes C4 and/or D4. Albumin (2 g%) in the perfusate prevents any increase in lung perfusion pressure or edema formation. When lung perfusion pressure increase is blocked with the combined cyclooxygenase and lipoxygenase inhibitor enolicam sodium (CG5391B, 35 μM in perfusate), significant lung edema still occurs after amiodarone, indicating that amiodarone causes increased alveolar-capillary membrane permeability. Addition of catalase (100 U/ml) or superoxide dismutase and catalase (100 U/ml each) to perfusate fails to protect from amiodarone lung injury. Immediate infusion of amiodarone (10 mg) into lungs ventilated with room air (ADR + RA) causes an increase in lung weight gain from baseline (ΔW) of 5.7 ± 1.5 g/min. Compared with ADR + RA, ventilation of lungs with 4% O2 (AW = 0.7 ± 0.3 g/min, p < 0.05). pretreatment of rabbits for 3 days with butylated hydroxyanisole (BHA, 100 mg/kg/day i.p., ΔW = 0.05 ± 0.02 g/min, p < 0.01), pretreatment of rabbits for 3 days with vitamin E (Vit E, 300 U/day orally, ΔW = 0.6 ± 0.2 g/min, p < 0.05), or addition of N-acetylcysteine to the lung perfusate (NAC, 5 mM, ΔW = 0.1 ± 0.08 g/min, p < 0.01) all protect from lung edema formation after amiodarone. Amiodarone (100 mg) also caused a marked increase in luminol-enhanced lung chemiluminescence, lung production of superoxide anion (O2−), and tissue levels of lung glutathione disulfide. These results suggest that amiodarone causes lung injury by an oxidant mechanism.

Comparison of the effects of dobutamine, dopamine, and isoproterenol on hypoxic pulmonary vasoconstriction in the pig.

The relative vasodilating properties of isoproterenol, dopamine, and dobutomine on hypoxic pulmonary vasoconstriction were examined in isolated pig lungs, ventilated and perfused in situ. The flow-resistant properties of the pulmonary circulation were assessed by measuring the relationship between pulmonary arterial pressure (PAP) and flow (Q). Hypoxia ( a decrease in inspired O2 tension form 200 torr to 50 torr) caused a rightward shift and decreased in the slope of this relationship. This increase PAP an average of 18.8 torr when measured at a blood flow of 1 L/min. Isoproterenol and dobutamine inhibited hypoxic pulmonary vasoconstriction, whereas dopamine had no effect. Because of its relative freedom from adverse side-effects in clinical trials, dobutamine should be considered in patients with hypoxic pulmonary vasoconstriction and right heart failure.

Calcium channel blockers in hypoxic pulmonary hypertension

Hypoxia is the major cause of pulmonary hypertension and right ventricular hypertrophy in chronic obstructive pulmonary disease, cystic fibrosis, kyphoscoliosis, chronic mountain sickness, and the obesity-hypoventilation and sleep apnea syndromes. Pulmonary hypertension develops in these patients because the long-standing vasoconstriction produced by hypoxia causes muscular hypertrophy of the pulmonary arteries and arterioles. These pathologic changes may regress if alveolar hypoxia is corrected and hypoxic pulmonary vasoconstriction is continuously inhibited. Intermittent inhibition of hypoxic pulmonary vasoconstriction does not reverse these pathologic changes. Since patient noncompliance with oxygen therapy makes it difficult to achieve continual relief of alveolar hypoxia, a drug that inhibits hypoxic vasoconstriction may be useful. Experimental findings indicate that hypoxic pulmonary vasoconstriction requires calcium influx and can be inhibited by certain slow-channel calcium blockers. Studies also demonstrate that slow-channel calcium antagonists can attenuate the pulmonary hypertension and right ventricular hypertrophy produced in rats by chronic hypoxia. Recently, two studies have shown that nifedipine inhibits hypoxic pulmonary vasoconstriction in patients with chronic obstructive pulmonary disease. If further studies demonstrate that these short-term effects are sustained, certain slow-channel calcium blockers may become a useful adjuvant to low-flow oxygen therapy in the treatment of hypoxic pulmonary hypertension.

Amiodarone-induced lymphocyte toxicity and mitochondrial function.

Amiodarone is one of the most effective antiarrhythmic drugs available. However, its use is often limited by potentially life-threatening toxicities, including hepatotoxicity and pulmonary toxicity. We have used human lymphocytes as a system in which to study amiodarone-induced cytotoxicity. Using a tetrazolium dye reduction assay, we observed amiodarone-induced cytotoxicity with a lethal dose (LD)50 of 10.0 +/- 31.1 microM (mean +/- SD, n = 5) with a cellular concentration of 2.2 +/- 0.2 million/ml and of 55.5 and 39.2 microM with cellular concentrations of 8.9 and 7.2 million/ml, respectively, after only 2.75 h of drug exposure. Damage to mitochondria, but not other organelles, was observed with electron microscopy at an amiodarone concentration of 7.3 microM. Alterations in ATP synthesis and lactate dehydrogenase (LDH) release from cells had concentration-response curves similar to those for cytotoxicity. However, we did not observe extracellular accumulation of adenine nucleotides. These results suggest that amiodarone may have a direct toxic effect on mitochondria, beginning at < 10 microM, with membrane-damaging effects at higher drug concentrations.

Hydroxyl radical generating activity of hydrous but not calcined kaolin is prevented by surface modification with dipalmitoyl lecithin

The catalytic activity of kaolin, an aluminum silicate, for generating hydroxyl radicals (.OH) from hydrogen peroxide (H2O2) was studied in a chemical system that measured .OH as evolution of methane (CH4) from dimethyl sulfoxide. In the presence of a reducing agent and 10 mM H2O2, hydrous and calcined kaolin generated mean +/- SE CH4 concentrations of 1634 +/- 328 and 1395 +/- 29 ppm, respectively. Surface modification with dipalmitoyl lecithin, the lipid of pulmonary surfactant, blocked generation of .OH in hydrous kaolin (38 +/- 38 ppm CH4) but not in calcined kaolin (875 +/- 262 ppm CH4). The catalytic activity of kaolin for producing .OH from H2O2 may be important in the pathogenesis of kaolin toxicity, and calcined kaolin may be more toxic than hydrous kaolin because the calcined form is resistant to surface modification by lipids of pulmonary surfactant.

Differences in lung function and prevalence of pneumoconiosis between two kaolin plants.

To investigate the origin of differences in previously published pulmonary function studies of workers in kaolin plants in Georgia, spirometric and radiographic data collected in a cross sectional survey of two large plants were analysed. As compared with workers in plant 2, workers in plant 1 had a 2.7-fold greater prevalence of pneumoconiosis and a mean 0.361 decrement in adjusted forced vital capacity. Our previous finding that exposure to kaolin was not associated with a decrement in lung function may have resulted from failure to consider differences between the plants.

The Effect of Treatment with Nitrendipine and Other Calcium Channel Blockers on the Physiologic and Pathologic Changes Caused by Hypoxia in Rats

Nitrendipine and other calcium channel blokers acutely inhibit hypoxic pulmonary vasoconstriction and show promise in the prevention of the pulmonary vascular and cardiac changes produced by chronic alveolar hypoxia. This paper reviews the current information available from animal and clinical studies.