Alain Lockhart

Bronchial hyperresponsiveness to methacholine in patients with impaired left ventricular function

To elucidate the pathogenesis of bronchospasm in congestive heart failure, we studied 23 patients with chronic impairment of left ventricular function due to coronary artery disease or dilated cardiomyopathy. In 21 of them we found marked bronchial hyperresponsiveness to methacholine. The mean dose (+/- SD) of methacholine that elicited a 20 percent decrease in the forced expiratory volume in one second (FEV1) was 421 +/- 298 micrograms, nearly the same as in patients with symptomatic asthma. In contrast, there was no bronchial response to methacholine in 9 of 10 patients who had coronary artery disease but normal left ventricular function. Administration of the bronchodilator albuterol led to a partial (43 percent) reversal of the methacholine-induced bronchial obstruction. In 12 patients, pretreatment with the alpha-adrenergic agonist methoxamine (10 mg by inhalation), a potent vasoconstrictor, fully prevented the methacholine-induced decrease in FEV1. The protective effect of methoxamine was blocked by the alpha-adrenergic antagonist phentolamine in all six patients who received this agent. We conclude that bronchial hyperresponsiveness to cholinergic agonists is frequent in patients with impaired left ventricular function and may contribute to the wheezy dyspnea commonly observed in such patients. The bronchoconstriction may be mediated at least in part by dilatation of the bronchial vessels.

Improvement in Exercise Performance by Inhalation of Methoxamine in Patients with Impaired Left Ventricular Function

BACKGROUND Bronchial hyperresponsiveness to cholinergic stimuli such as the inhalation of methacholine is common in patients with impaired left ventricular function. Such hyperresponsiveness is best explained by cholinergic vasodilation of blood vessels in the small airways, with extravasation of plasma due to high left ventricular filling pressure. Because this vasodilation may be prevented by the inhalation of the vasoconstrictor agent methoxamine, we studied the effect of methoxamine on exercise performance in patients with chronic left ventricular dysfunction. METHODS We studied 19 patients with a mean left ventricular ejection fraction of 22 +/- 4 percent and moderate exertional dyspnea. In the first part of the study, we performed treadmill exercise tests in 10 patients (group 1) at a constant maximal workload to assess the effects of 10 mg of inhaled methoxamine on the duration of exercise (a measure of endurance). In the second part of the study, we used a graded exercise protocol in nine additional patients (group 2) to assess the effects of inhaled methoxamine on maximal exercise capacity and oxygen consumption. Both studies were carried out after the patients inhaled methoxamine or placebo given according to a randomized, double-blind, crossover design. RESULTS In group 1, the mean (+/- SD) duration of exercise increased from 293 +/- 136 seconds after the inhalation of placebo to 612 +/- 257 seconds after the inhalation of methoxamine (P = 0.001). In group 2, exercise time (a measure of maximal exercise capacity) increased from 526 +/- 236 seconds after placebo administration to 578 +/- 255 seconds after methoxamine (P = 0.006), and peak oxygen consumption increased from 18.5 +/- 6.0 to 20.0 +/- 6.0 ml per minute per kilogram of body weight (P = 0.03). CONCLUSIONS The inhalation of methoxamine enhanced exercise performance in patients with chronic left ventricular dysfunction. However, the improvement in the duration of exercise at a constant workload (endurance) was much more than the improvement in maximal exercise capacity assessed with a progressive workload. These data suggest that exercise-induced vasodilation of airway vessels may contribute to exertional dyspnea in such patients. Whether or not inhaled methoxamine can provide long-term benefit in patients with heart failure will require further study.

Inhibition of substance P-induced microvascular leakage by inhaled methoxamine in rat airways.

1 The effect of the inhaled α‐adrenoceptor agonist, methoxamine (MTX), was studied on experimental airway oedema induced by injection of substance P (SP) in the rat. Sprague‐Dawley rats (300–350 g) were anaesthetized with sodium thiopentone, tracheotomized and artificially ventilated. 2 MTX or its vehicle was administered by inhalation. Airway resistance and blood pressure were monitored continuously. Evans Blue dye (EB, 20 mg kg−1) was injected through a jugular catheter 1 min before SP (14.8 nmol kg−1). Airways were dissected out, weighed and placed in formamide for EB extraction and determination by spectrophotometry. 3 EB extravasation induced by SP was significantly reduced in distal intraparenchymal bronchi by inhaled MTX at doses of 50 μg kg−1 (58 ± 9 vs 96 ± 9 ng EB mg−1 tissue after vehicle, P < 0.001) and 100 μg kg−1 (69 ± 11 vs 137 ± 26 ng EB mg−1 tissue after vehicle, P < 0.01). Inhaled MTX by itself (100 μg kg−1) increased blood pressure: 172 ± 6 vs 132 ± 10 mmHg baseline (P < 0.02), but neither induced extravasation nor increased airway resistance. 4 In another set of experiments without SP, MTX was administered intravenously 1 min after EB. At 100 μg kg−1, i.v. MTX increased blood pressure to a similar extent as inhaled MTX (180 vs 147 mmHg baseline, P < 0.01), increased airway resistance and caused leakage of plasma proteins in distal intraparenchymal bronchi (79 ± 7 vs 47 ± 1 ng EB mg−1 tissue, P < 0.02). 5 Similarly, after sequential i.v. injections of doubling doses of MTX (50–800 μg kg−1), a marked EB extravasation was found in the airways. This was abrogated by pretreatment with prazosin (100 μg kg−1) but not with propranolol (2 mg kg−1). 6 These results suggest that microvascular leakage and airway oedema induced by i.v. MTX may be linked to an increase in pressure in the pulmonary circulation, resulting from vasoconstriction of the pulmonary vasculature and acute cardiac dysfunction due to systemic hypertension. 7 Our results with inhaled MTX show that direct deposition of MTX at the bronchial vasculature induces a reduction in SP‐induced microvascular leakage in rat airways and that inhaled MTX does not share the untoward effect of i.v. MTX inducing airway oedema.

Effect of inhaled morphine on the bronchial response to isocapnic hyperventilation in patients with allergic asthma

The cholinergic and non-cholinergic excitatory systems have a bronchoconstrictor effect in asthma through local release of acetylcholine and neuropeptides, respectively [1]. Whether release of such neuromediators is involved in isocapnic hyperventi lat ion (IH)-induced asthma is not firmly established. Since opiates are capable of inhibiting the release of neuromediators in guinea-pig airways, prevention by opiates of such a bronchial response would favour the importance of the release of neuromediators in mediating IH-induced asthma [2-4]. Nine atopic asthmatic subjects underwent a multistep I H challenge whilst breathing dry air at room temperature. They were pre t rea ted with inhaled saline or morphine hydrochloride 10 mg on two different days, in a double blind randomized cross-over design. Successive levels of ventilation (10, 20, 40 and 80% of maximal voluntary ventilation) were maintained for 3 min. At each step, forced expiratory volume in 1 s (FEV1) was serially measured.

Muscarinic receptors after syngeneic unilateral lung transplantation

We have characterized the muscarinic cholinergic receptor population by binding assay in left and right lung membranes from syngeneic Lewis rats one month after unilateral left lung transplantation and from controls. The density of muscarinic receptors measured by [3H](-)QNB binding was similar in left and right lung membranes one month after unilateral left lung transplantation (Bmax = 28.2 +/- 2.2 and 29.0 +/- 1.4 fmol/mg protein, respectively) and was similar between transplanted and control rats. Binding affinity also was similar on both sides (Kd = 28.5 +/- 9.5 and 32.3 +/- 2.7 pM, respectively). Binding parameters (Ki) of four selective muscarinic antagonists determined from competitive binding experiments of 0.5 nM [3H](-)QNB showed an order of potency: atropine > 4-DAMP > AF-DX 116 BS > pirenzepine both in transplanted and in control lungs. There was no significant difference in Ki values between left transplanted and right non transplanted lungs (1.8 +/- 0.1 and 1.9 +/- 0.1 nM; 4.3 +/- 0.5 and 3.5 +/- 0.5 nM; 80.9 +/- 13.8 and 78.9 +/- 18.8 nM; 480.4 +/- 40.9 and 481.7 +/- 78.2 nM, respectively for atropine, 4-DAMP, AF-DX 116 BS and pirenzepine). Values were also similar between transplanted and control lungs. These observations suggest a similar population of muscarinic receptors in the transplanted and the non transplanted lung in the Lewis rat. This result is in accordance with the similar physiological effect of exogenous acetylcholine that we previously observed in transplanted and non transplanted bronchi.

Bronchial responses to substance P after antigen challenge in the guinea-pig: in vivo and in vitro studies

The effect of antigen challenge on the airway responses to substance P and on the epithelial neutral endopeptidase (NEP) activity was investigated in aerosol sensitized guinea-pigs. In vivo, bronchial responses to aerosolized substance P were similar to the responses observed in antigen-challenged guinea-pigs and in the control groups. In contrast, when the guinea-pigs were pretreated with the NEP inhibitor, phosphoramidon, a significant increase in the airway responses to substance P was observed after antigen challenge in vivo. However, in vitro, the contractile responses of the tracheal smooth muscle to substance P were similar between groups of guinea-pigs, in respect to the presence or absence of the epithelium and/or phosphoramidon. Histological studies showed an accumulation of eosinophils in the tracheal submucosa after antigen challenge and intact epithelial cells. These results show that in vivo bronchial hyperresponsiveness to substance P after antigen challenge in the guinea-pig is not associated with increased responses of the smooth muscle to exogenous SP in vitro. In addition, the results with phosphoramidon suggest that loss of NEP activity cannot account for the in vivo bronchial hyperresponsiveness to substance P presently observed.