Plasma Level-Dependent Hemodynamic Effects of Theophylline in Patients with Chronic Obstructive Lung Disease and Pulmonary Hypertension

Grützmacher, Jens; Schicht, R.; Schlaeger, R; Sill, V.

doi:10.1055/s-2007-1012655

Cited by 4 publications

(3 citation statements)

References 10 publications

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“…Aminophylline has been shown to decrea$e bl. ood diversion from a lung made hypoxic in inLact dogs [8), to reduce Ppa and PVR in chronically hypoxic calves [30], to decrease PVR to the same extent as supplemental oxygen in patients with COPD [27] and to increase pcrfusion to a human left lung in which ventilation had been blocked with a balloon catheter placed in the left main bronchus [3 1]. Recently BnNUMOF and ThousoAW [91 reported in well controlled experiments that hypoxiainduced blood flow diversion from an in vivo canine left lower lobe preparation is preserved after administrotion of aminophylline.…”

Section: Discussionmentioning

confidence: 99%

Effects of theophylline and S 9795 on hyperoxic and hypoxic pulmonary vascular tone in intact dogs

Lejeune¹,

Leeman²,

Mélot³

et al. 1989

Eur Respir J

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In the literature, it remains uncertain whether methylxanthines inhibit hypoxic pulmonary vasoconstriction. We examined the effects of theophylline and of S 9795, a new methylxanthine derivative, on multipoint mean pulmonary arterial pressure (Ppa)/cardiac index (Q) relationships in 31 intact dogs, ventilated alternately in hyperoxia (fraction of inspired oxygen, FIO2 0.4) and in hypoxia (FIO2 0.1). A sequence of two 5-point Ppa/Q plots at FIO2 0.4 and at FIO2 0.1, consecutively, was performed before and after i.v. administrations of theophylline 10 mg.kg-1 (n = 8) and 25 mg.kg-1 (n = 7), of S 9795 10 mg.kg-1 (n = 8) and of placebo (n = 8). The Ppa/Q plots were rectilinear in all experimental conditions. Over the entire range of Q studied, 2-5 l.min-1.m-2, hypoxia increased Ppa in all animals. Placebo had no effect on these Ppa/Q plots. Theophylline at the lowest dose (plasma levels from 8.4-13.6 micrograms.ml-1) and S 9795 (plasma levels from 3.0-11.2 micrograms.ml-1) did not affect Ppa/Q in hyperoxia or in hypoxia. Theophylline at the highest dose (plasma levels from 17.8-40.4 micrograms.ml-1) reduced hypoxic Ppa at all levels of Q and hyperoxic Ppa at the highest Q, from 3-5 l.min-1.m-2, and inhibited hypoxia-induced increases in Ppa. We conclude that pulmonary vasoconstriction may be preserved after the lowest doses of methylxanthines recommended for the treatment of increased bronchial tone.

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Section: Discussionmentioning

confidence: 99%

Effects of theophylline and S 9795 on hyperoxic and hypoxic pulmonary vascular tone in intact dogs

Lejeune¹,

Leeman²,

Mélot³

et al. 1989

Eur Respir J

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“…The ability of milrinone, a selective inhibitor of PDE III, to reduce mean pulmonary artery pressure and pulmonary vascular resistance [30] may reflect the relaxation of pulmonary arteries in vivo, in addition to its well-characterized positive inotropic action, since theophylline (which, while less potent than milrinone in inhibiting PDE III, also inhibits PDE V and might thus be expected to relax pulmonary arteries quite effectively) has been demonstrated to alleviate pulmonary hypertension in the absence of any effect upon pulmonary capillary wedge pressure, suggesting pulmonary vascular actions [27].…”

Section: Pulmonary Vasculaturementioning

confidence: 99%

Cyclic nucleotide phosphodiesterases in the human lung

Dent

Magnussen

Rabe

1994

Lung

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Although theophylline has been used in the treatment of lung diseases, particularly bronchial asthma, since the nineteenth century, the mechanisms underlying its effectiveness remained poorly understood until quite recently. The identification of cyclic nucleotide phosphodiesterase (PDE)--the enzyme responsible for breaking down cyclic AMP and cyclic GMP within cells--as a target for methylxanthines such as theophylline led to a research effort that has resulted in the characterization of multiple forms of the PDE enzyme and the development of selective inhibitors for some of these forms. Using these drugs, it has been possible to identify the PDE "isoenzymes" in a number of tissues and cells and to demonstrate the functional effects of the inhibition of different PDEs upon these tissues. Studies on the smooth muscle of human airways and pulmonary arteries have identified isoenzyme-selective PDE inhibitors that are effective broncho- and vasorelaxants in vitro, and it is hoped that these agents may be effective in relieving airway obstruction and pulmonary hypertension in patients. In addition, selective inhibitors of certain PDE isoenzymes suppress the proinflammatory functions of a range of immune cells, including the lung mast cell and the alveolar macrophage. Selective inhibitors of PDE isoenzymes are beginning to undergo clinical trials for the treatment of asthma. The advancing understanding of the PDE distribution in the lung and the ever more precise characterization of distinct enzyme proteins should allow the development of site-selective drugs for the treatment of lung diseases, while minimizing the systemic side effects associated with nonselective PDE inhibitors such as theophylline.

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“…The actions of theophylline in asthmatics are clearly dose-related [12,14], and, interestingly, the protective effect is more pronounced against histamine-induced than methacholine-induced bronchoconstriction [14]. Theophylline also decreases mean pulmonary arterial pressure [16][17][18], implying a relaxation both of airway and vascular smooth muscle. Various mechanisms have been proposed for this action, of which inhibition of cyclic nucleotide phosphodiesterase (PDE) is the most widely accepted.…”

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confidence: 99%

Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants

Rabe¹,

Magnussen²,

Dent³

1995

Eur Respir J

134

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In addition to its emerging immunodulatory properties, theophylline is a bronchodilator and also decreases mean pulmonary arterial pressure in vivo. The mechanism of action of this drug remains controversial; adenosine antagonism, phosphodiesterase (PDE) inhibition and other actions have been advanced to explain its effectiveness in asthma. Cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP) are involved in the regulation of smooth muscle tone, and the breakdown of these nucleotides is catalysed by multiple PDE isoenzymes. The PDE isoenzymes present in human bronchus and pulmonary artery have been identified, and the pharmacological actions of inhibitors of these enzymes have been investigated. Human bronchus and pulmonary arteries are relaxed by theophylline and by selective inhibitors of PDE III, while PDE IV inhibitors also relax precontracted bronchus and PDE V/I inhibitors relax pulmonary artery. There appears to be some synergy between inhibitors of PDE III and PDE IV in relaxing bronchus, and a pronounced synergy between PDE III and PDE V inhibitors in relaxing pulmonary artery. In neither tissue does 8-phenyltheophylline, a xanthine exhibiting adenosine antagonism but not PDE inhibition, cause any significant relaxation, implying that theophylline does not exert its actions through adenosine antagonism. The close correspondence of theophylline concentrations inhibiting bronchus or pulmonary artery PDE and those causing relaxation points towards PDE inhibition as the major mechanism of action of theophylline in smooth muscle relaxation.

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Plasma Level-Dependent Hemodynamic Effects of Theophylline in Patients with Chronic Obstructive Lung Disease and Pulmonary Hypertension

Cited by 4 publications

References 10 publications

Effects of theophylline and S 9795 on hyperoxic and hypoxic pulmonary vascular tone in intact dogs

Effects of theophylline and S 9795 on hyperoxic and hypoxic pulmonary vascular tone in intact dogs

Cyclic nucleotide phosphodiesterases in the human lung

Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants

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