Enhancement of hypoxic pulmonary vasoconstriction by almitrine in the dog

In order to test the hypothesis of enhancement of hypoxic pulmonary vasoconstriction by Almitrine, 12 anesthetized and paralyzed dogs with normal lungs were studied under controlled ventilation. They were ventilated in random sequence with air, 12% O2, and 100% O2, and almitrine (0.1 mg/kg body weight) was infused over 30 min during each O2 mixture. The multiple inert gas elimination technique was used to detect alterations in ventilation-perfusion (VA/Q) mismatching before and during the interventions and to measure cardiac output (QT). Arterial, mixed venous and expired gases, inert gas concentrations, and hemodynamic measurements were made while the dogs were breathing the different O2 mixtures before infusing the drug, near the end of 30 min of infusion and 30 min after infusion had ended. There were no significant changes in pH, PaO2, PaCO2, QT, oxygen uptake, oxygen delivery index, systemic vascular resistance, mean systemic arterial pressure, heart rate, stroke volume index, or VA/Q distribution during the experiment. Significant increases in: (a) pulmonary artery pressure (PA), (b) the pressure difference between PA and pulmonary capillary wedge pressure (PCw), and (c) pulmonary vascular resistance (PVR) occurred when the drug was infused during 12% O2 and air, but not during 100% O2. The PVR increased 59.7% with almitrine infusion during 12% O2 and 38.4% during air breathing (p less than or equal to 0.01), but there was no significant change during 100% O2. Vascular responses were not dependent on the order in which the different O2 mixtures were administered. These data strongly suggest that almitrine enhances hypoxic vasoconstriction in the lung, and this effect may explain reported improvement in PaO2 in hypoxic patients given the drug.     

Sequential treatment with low dose almitrine bismesylate in hypoxaemic chronic obstructive airways disease.

Daily dose schedules of 100-200 mg of almitrine bismesylate improve arterial blood gases in patients with hypoxaemic chronic obstructive airways disease (COPD) but dose related side effects are evident. In the present study, daily doses approximately half of those previously used were employed in a randomised double blind manner in 85 patients (age 35-79 years) with hypoxaemic COPD. After a one month period to check stability of arterial blood gases, patients were allocated to almitrine (A) or placebo (P) using an unequal code (60% A, 40% P). Tablets, 50-100 mg daily were stopped for one month after 3, 6 and 9 months to counteract drug accumulation. 50 patients in group A and 35 in group P were comparable on entry; mean age 65 (SD = 8) yrs., Pao2 7.8 (0.7) kPa (58.3 (5.0) mmHg), PaCO2 5.8 (0.8) kPa (43.2 (6.0) mmHg), forced expiratory volume in one second--FEV1 0.89 (0.25) l and 6 minute walking distance 296 (97) metres. The improvement in baseline PaO2 values was the same 0.8-1.3 kPa (6-9.8 mmHg) as with previous higher dose therapy. Approximately one third of patients did not respond, defined as PaO2 elevation > 0.67 kPa (5 mmHg). The sequential dosing scheme stabilised blood levels of almitrine within the therapeutic range of 280-300 ng.ml-1. After withdrawal of therapy arterial blood gases and spirometry reverted to pre-treatment levels, suggesting no permanent reversal of pathophysiology. Dose related side effects of breathlessness, indigestion and peripheral neuropathy were not observed. Nerve conduction studies revealed no difference in peripheral nerve dysfunction in hypoxaemic COPD between active and placebo therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Is the mode of action of almitrine bismesylate dose dependent?

In order to assess whether different doses and/or plasma levels of almitrine bismesylate (ABM) could induce preferential effects on ventilation or on lung perfusion, we performed a single-blind placebo-controlled study of ABM treatment with different dosages (0.75, 1.5 and 2.25 mg.kg-1 single oral dose) in 26 patients suffering from chronic obstructive pulmonary disease (COPD). All measurements were performed according to the same time table. At control and at three 1.5-hour intervals, we measured alveolar-arterial (A-a) differences, alveolar dead space, total ventilation and ABM plasma levels. The effect on ventilation was estimated using changes in ventilatory parameters and (A-a)O2 differences. The effect on perfusion was indirectly estimated by analysis of arterial-end-tidal (a-ET)CO2 difference and alveolar dead space. The response to treatment was significant for the 1.5- and the 2.25-mg.kg-1 ABM groups, but not for the 0.75 mg.kg-1 ABM and the placebo group. A ventilatory response was often present in both 1.5- and 2.25-mg.kg-1 ABM groups, but a nonventilatory effect was present only at the highest dose according to the Severinghaus and Stupfel concept. Only the parameters reflecting an effect of the distribution of perfusion (a-ET)CO2 difference and alveolar dead space were significantly correlated with ABM plasma levels. The results suggest that a dose-dependent effect of ABM on lung perfusion may explain the controversial data in the literature about the mode of action of ABM.     

The effect of almitrine bismesylate on hypoxemia in chronic obstructive pulmonary disease

Almitrine bismesylate was studied for its effects on hypoxemia in 67 patients with chronic obstructive lung disease in a placebo-controlled, double-blind study. Arterial Po2 rose by 11.2 mm Hg (p less than 0.05) in 21 patients receiving 100 mg twice daily and by 6.0 mm Hg (p less than 0.05) in 22 patients receiving 50 mg twice daily. Arterial Pco2 decreased by 3.8 mm Hg (p less than 0.05) in the group receiving 100 mg twice daily but was unchanged in patients receiving 50 mg twice daily. Lung function was unaltered except for a slight increase in forced mid-expiratory flow in both dosage groups (p less than 0.05). The major side effect was the unexplained worsening of dyspnea, which occurred in 4 patients (19%) receiving 100 mg twice daily, 2 (9%) receiving 50 mg twice daily group, and 1 (4%) receiving placebo. Almitrine bismesylate improves arterial blood gas values in patients with chronic obstructive lung disease, apparently by reducing intrapulmonary ventilation-perfusion mismatching, and appears to be useful in the long-term management of these patients.     

Two years treatment with almitrine bismesylate in patients with hypoxic chronic obstructive airways disease

Eighty nine patients with hypoxic chronic obstructive airways disease (COAD) were enrolled into the 1 year Vectarion International Multicentre Study-VIMS in 4 centres, Sheffield (UK), and Antwerp, Liege and Namur (Belgium). At the end of the year the remainder were invited to continue taking placebo or almitrine bismesylate (100-200 mg daily) in the same double blind manner for a further 12 months. In the almitrine treated patients mean arterial oxygen tension (Pao2) at the end of the treatment period improved from 7.5 (0.5) kPa to 8.2 (1.3) kPa (p less than 0.01) and arterial carbon dioxide tension (Paco2) fell from 6.1 (0.8) kPa to 5.8 (0.9) kPa (p less than 0.01). Forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and measurements of breathlessness were unchanged. In the placebo treated group changes in the above variables were not significant. Twenty nine patients withdrew from the almitrine group with seven deaths and six cases of peripheral neuropathy, and 22 patients withdrew from the placebo group with six deaths and two cases of peripheral neuropathy. Death rates between the groups were not significantly different. In conclusion, 2 yrs of almitrine treatment (100-200 mg daily) leads to a persistent slight improvement in PaO2 and PaCO2 but no benefit in survival was demonstrated. Patients in this study had a high incidence of drug related side-effects. Lower dose schedules should be investigated.     

Effects of vasodilators on hypoxic pulmonary vasoconstriction in normal man

A reduction of arterial PO2 is generally observed when vasodilators are given to patients with cardiac or pulmonary disease. This has been attributed to a release of preexisting hypoxic pulmonary vasoconstriction (HPV). We investigated the effects of hemodynamics and blood gases of IV nitroglycerin, IV nitroprusside and sublingual nifedipine, at dosages currently used in clinical practice, in 23 healthy volunteers at normoxic conditions (fraction of inspired O2, FIO2 0.21) and at acute inspiratory hypoxia (FIO2 0.125 during 10 min). Breathing FIO2 0.125 elicited pulmonary vasoconstriction in all the subjects. At FIO2 0.21, nitroglycerin reduced preload, nifedipine reduced afterload, nitroprusside had balanced effects, but none of the drugs induced pulmonary vasodilation and only nitroglycerin deteriorated arterial oxygenation. At FIO2 0.125, nitroglycerin did not at all affect the pulmonary pressor response, while both nitroprusside and nifedipine decreased it. An inhibition of HPV was obtained with certainty in only one subject who received nitroprusside. In all the subjects in whom HPV was partially inhibited by vasodilator administration, the alveolar-arterial PO2 gradients remained significantly lowered, suggesting that the pulmonary vascular tone adaptation to alveolar hypoxia still was effective in improving ventilation/perfusion relationships. The role of impaired HPV in the reduction of arterial PO2 in patients under vasodilator therapy may have to be reevaluated.     

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 animal's 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 μg/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.     

Long-term effect of almitrine bismesylate in patients with hypoxemic chronic obstructive pulmonary disease

A long-term evaluation of the therapeutic efficacy and safety of oral almitrine bismesylate (AB) (50 mg twice daily) was made on 25 patients with COPD and moderate hypoxemia residing at an altitude of 1,500 m in a double-blind placebo-controlled study. Thirteen patients receiving AB (baseline PaO2, 54.3 +/- 4.9 mm Hg; mean +/- SD) and 12 patients receiving placebo (baseline PaO2, 53.0 +/- 4.1 mmHg) were periodically followed by arterial blood gas and other pulmonary function studies and plasma levels of AB. Eight patients receiving AB and nine patients receiving placebo were followed for 1 yr; all patients were followed for at least 90 days. AB administration resulted in an increase in PaO2 to 62.2 +/- 9.3 mm Hg (p less than 0.01) on Day 28. The increase was maintained until Day 360 (63.8 +/- 4.6 mm Hg; p less than 0.01). The mean plasma concentration of AB on Day 28 was approximately one-half that on Day 90 when the plasma level reached a near maximum. AB was associated with weight loss (five of 13 patients receiving AB lost more than 10% of their baseline body weight) and peripheral paresthesias of the lower extremities (three patients), both occurring at the peak plasma levels of the drug. We conclude that AB causes a long-term improvement in arterial oxygenation in hypoxemic patients with COPD residing at an altitude of 1,500 m. Our data suggest that lower doses of AB might produce the same effect on PaO2 with less adverse associated effects, and this should be tested in future studies.     

Mechanisms of hypoxic pulmonary vasoconstriction

During the last 4 decades hypoxic vasoconstriction has been acknowledged as an important pulmonary control mechanism that via matching ventilation and perfusion regulates one of the important physiologic parameters--PaO2. Whether the hypoxic vasoconstriction occurs directly in a localized vascular site with distinct biochemistry or whether it is mediated by a local hormone has not been resolved. Progress has been made because of the introduction of micropuncture techniques that allow direct pressure measurements in small segments of the lung vascular tree. Measurements of the force of contraction and membrane potential (118) and manipulation of the environment of pulmonary microvessels are the most recent progress in the elucidation of the mechanism of hypoxic vasoconstriction. Elements of energy, oxygen, and lipid metabolism appear to contribute to the biochemistry of this elusive response.     

Oxygen sensors in hypoxic pulmonary vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism adapting lung perfusion to regional ventilation. Perturbations to HPV, such as those occurring in pneumonia, acute respiratory distress syndrome and liver failure, can result in arterial hypoxemia. Under conditions of general hypoxia, HPV increases pulmonary vascular resistance and thus causes acute pulmonary hypertension. Despite intensive research, the underlying mechanisms of HPV have not been fully elucidated. Deciphering signalling pathways that result in HPV could suggest novel approaches to address a failure of HPV, as well as for the treatment of pulmonary hypertension associated with HPV. Within this context, this review focuses on current concepts in the oxygen sensing mechanisms that underlie HPV.     

Enhanced hypoxic pulmonary vasoconstriction in hypertension

In this study, we tested the hypothesis that hypoxic pulmonary vasoconstriction may be enhanced in systemic hypertension. The hypothesis took origin from the following two considerations: alveolar hypoxia constricts the pulmonary vessels by enhancing the Ca2+ penetration across sarcolemma of the smooth muscle cells and systemic high blood pressure is associated with an elevation of tone and reactivity of the lung vessels, which seems to depend on an excessive cytosol free Ca2+ concentration due to alterations in sodium handling and in the Na+-Ca2+ exchange system. These considerations suggest the possibility that the disorders in the biochemistry of smooth muscle contraction in hypertension facilitate the rise of cytosol Ca2+ concentration during alveolar hypoxia, thus resulting in a potentiation of the vasoconstrictor properties of this stimulus. In 43 hypertensive and 17 normotensive men, pulmonary arteriolar resistance has been evaluated during air respiration and after 15 minutes of breathing 17%, 15%, and 12% oxygen in nitrogen. Curves relating changes in pulmonary arteriolar resistance to oxygen breathing contents had similar configuration in the two populations but in hypertension were steeper and significantly shifted to the left, reflecting a lower threshold and an enhanced reactivity. This pattern was not related to differences in severity of the hypoxic stimulus, plasma catecholamine concentration, or hypocapnia and respiratory alkalosis induced by hypoxia and probably was not mediated through alpha-receptor activation. Calcium channel blockade with nifedipine was able to almost abolish both the normotensive and the hypertensive pulmonary vasoconstriction reaction. These findings support the hypothesis that hypoxic pulmonary vasoconstriction may be enhanced in systemic hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction

Endocannabinoids are important regulators of organ homeostasis. Although their role in systemic vasculature has been extensively studied, their impact on pulmonary vessels remains less clear. Herein, we show that the endocannabinoid anandamide (AEA) is a key mediator of hypoxic pulmonary vasoconstriction (HPV) via fatty acid amide hydrolase (FAAH)-dependent metabolites. This is underscored by the prominent vasoconstrictive effect of AEA on pulmonary arteries and strongly reduced HPV in FAAH^−/− mice and wild-type mice upon pharmacological treatment with FAAH inhibitor URB597. In addition, mass spectrometry measurements revealed a clear increase of AEA and the FAAH-dependent metabolite arachidonic acid in hypoxic lungs of wild-type mice. We have identified pulmonary vascular smooth muscle cells as the source responsible for hypoxia-induced AEA generation. Moreover, either FAAH^−/− mice or wild-type mice treated with FAAH inhibitor URB597 are protected against hypoxia-induced pulmonary hypertension and the concomitant vascular remodeling in the lung. Thus, the AEA/FAAH pathway is an important mediator of HPV and is involved in the generation of pulmonary hypertension.Endocannabinoids have been shown to induce vasorelaxation in systemic vessels which is primarily mediated by the specific cannabinoid 1 and 2 (CB1/CB2) and also other G protein-coupled receptors (e.g., non-CB1/CB2 receptors) (1, 2). Based on these results, especially CB1 receptors have been proposed as promising therapeutic targets for the treatment of arterial hypertension (2). Endocannabinoids are also known to potentially act via their intracellular enzymatic metabolization by the fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) to (vaso)active intermediates (3, 4), but these pathways are considered less important for the regulation of vascular tone in systemic vessels.Pulmonary arteries are unique because of their prominent vasoconstriction in response to hypoxia. Hypoxic vasoconstriction is responsible for adapting perfusion to ventilation in the lungs and therefore also plays an important role in pathophysiological situations characterized by a high ventilation/perfusion mismatch such as acute lung injury or liver cirrhosis (5, 6). In addition, this mechanism potentially contributes to the onset of pulmonary hypertension in response to hypoxia occurring in high altitude or in various respiratory diseases such as chronic obstructive pulmonary disease or fibrosis (7–9). Pulmonary arterial smooth muscle cells are suggested to play a major role in hypoxic vasoconstriction (10), but the precise mechanisms and the underlying signals are still not well understood. Earlier experimental evidence suggested that the endocannabinoid anandamide (AEA) can either enhance (11) or reduce (12) pulmonary arterial tone, and this prompted us to reexplore the role of endocannabinoids in basic physiological and pathophysiological responses of pulmonary arteries using experimental in vitro, ex vivo, and in vivo approaches.     

Restored hypoxic pulmonary vasoconstriction by peripheral chemoreceptor agonists in dogs

Hypoxic stimulation of the peripheral chemoreceptors inhibits hypoxic pulmonary vasoconstriction (HPV). On the other hand, almitrine, a peripheral chemoreceptor agonist, has been reported in some studies to enhance HPV. To further explore this apparent contradiction, we investigated the effects of two different low intravenous doses of almitrine on pulmonary arterial pressure (Ppa) versus cardiac index (Q) plots in 32 pentobarbital-anesthetized dogs ventilated alternatively in hyperoxia (FIO2, 0.4) and in hypoxia (FIO2 0.1). HPV, defined as a hypoxia-induced increase in Ppa over the entire range of Q studied, from 2 to 5 L/min/m2, was elicited in 16 dogs. In the first eight of these "responders," almitrine 2 micrograms/kg/min had no vascular effect, and in the other eight, almitrine 4 micrograms/kg/min inhibited HPV. In 16 other dogs, hypoxia did not affect Ppa over the entire range of Q. In these "nonresponders," almitrine 2 micrograms/kg/min (n = 8) as well as 4 micrograms/kg/min (n = 8) restored HPV. To answer the question whether the ability to restore HPV would be specific to almitrine, we administered intravenously the structurally unrelated chemoreceptor agonist doxapram at the dose of 20 micrograms/kg/min to an additional group of eight "nonresponders," and this treatment also restored HPV. Intravenous infusion of the malic acid solution solvent of almitrine had no effect on Ppa/Q plots in a final group of eight "nonresponders". We conclude that low dose almitrine and doxapram restore HPV in dogs with a naturally absent hypoxic pulmonary pressor response, probably by a direct effect at the pulmonary vessels.     

Ventilatory effects of almitrine bismesylate in congenital central hypoventilation syndrome

Patients with congenital central hypoventilation syndrome (CCHS) lack hypercapnic and hypoxic stimulation of ventilation but have demonstrated carotid body function in response to hyperoxia and to pharmacological stimulation with doxapram. This study investigated the ventilatory effects of almitrine bismesylate, a carotid body stimulant, in 12 patients with CCHS. Measurements of minute ventilation, tidal volume (VT), respiratory rate (RR) and transcutaneous PO2 (TCPO2) were taken before and after administration of 4.5 mg/kg and 6 mg/kg of almitrine. Twenty-four hour pharmacokinetic studies were performed in 7 patients who received 4.5 mg/kg and in 6 patients who received 6 mg/kg almitrine. There was no significant improvement in ventilatory and gas exchange parameters at either dose of almitrine despite appropriate peak serum concentration of the drug at the time of the studies. These results suggest that almitrine is not a useful ventilatory stimulant in children with CCHS.     

Atrial natriuretic peptides in canine hypoxic pulmonary vasoconstriction

STUDY OBJECTIVE--The aim of the study was to investigate whether atrial natriuretic peptides have a physiological role in regulation of the pulmonary circulation. DESIGN--Plasma concentrations of immunoreactive atrial natriuretic peptide and guanosine-3',5'-cyclic monophosphate (cGMP) were measured during evaluation of pulmonary vascular tone by multipoint pulmonary arterial pressure-cardiac index (Ppa/Q) relationships. SUBJECTS--Experimental animals were 17 mongrel dogs of either sex, 21-35 kg weight, anaesthetised with pentobarbitone. MEASUREMENTS and MAIN RESULTS--Measurements of Ppa/Q relationships and atrial natriuretic peptide/cGMP were made during hyperoxia (Fio2 0.4) and hypoxia (Fio2 0.1). Hypoxic pulmonary vasoconstriction, defined as hypoxia induced increase in pulmonary artery pressure over the entire range of Q studied from 2-5 litre.min-1.m-2, was elicited in nine dogs ("responders"). In the other eight dogs, hypoxia did not change pulmonary artery pressure over the entire range of Q studied ("non-responders"). At neither the highest nor the lowest Q in hyperoxia did atrial natriuretic peptide and cGMP concentrations differ between these two groups, nor did acute reduction in Q affect the concentrations in either group. At the highest Q, plasma atrial natriuretic peptide increased in hypoxia from 11(SEM 2) to 15(3) pmol.litre-1 in the responders (p less than 0.05), and from 15(2) to 20(2) pmol.litre-1 in the non-responders (p less than 0.05). However at the lowest Q, atrial natriuretic peptide was increased in non-responders only, from 17(3) to 23(4) pmol.litre-1 (p less than 0.05). CGMP did not vary significantly in any experimental condition. CONCLUSIONS--Hypoxia slightly increased plasma atrial natriuretic peptides without any relationship with associated pulmonary haemodynamic changes. These data do not support the hypothesis that atrial natriuretic peptides play a physiological role in the regulation of the pulmonary circulation in dogs.     

Naloxone: effects on hypoxic pulmonary vasoconstriction

To determine the effect of naloxone on the hypoxic pulmonary vasoconstrictive response, six mongrel dogs were rendered hypoxic with 10% oxygen and were given either saline or naloxone. Following hypoxia all dogs had significant increases in mean pulmonary artery pressure (PAP) and pulmonary arterial resistance index (PARI) without changes in cardiac output or systemic blood pressure. Beta endorphins did not change at any time following hypoxia. Dogs receiving naloxone had significant lowering of PAP and PARI without changes in plasma beta endorphin levels. We conclude that naloxone attenuates hypoxic pulmonary vasoconstriction without measurable alterations of plasma beta endorphin levels.