IMedical Hypotheses
Atrial Natriuretic Peptide in Bronchial Asthma J. J. ALMIRALL* and G. HEDENSTIERNA Department of Clinical Physiology, University Hospital, S-751 85 llplpsala Sweden, and *‘Hermanos Ameijeiras’ Hospitd, Havana, Cuba (Reprint requests to GH)
Abstract - Regulation of ion transport across the airway mucosa may be involved in the mechanisms producing hyperreactivity and asthma. Atrial Natriuretic Peptide (ANP) has been proposed to participate in the pathogenesis of asthma, and it has been found to have a bronchodilatory effect on asthmatic patients. Experimental evidences suggest that ANP also has some effect on fluid accumulation in the lungs. We hypothesise that ANP may also play a role in the pathogenesis of asthma through changes in the transport of water and ions across the airway epithelium.
Introduction
Atria1 natriuretic peptide and asthma
Some experimental data have led to the hypothesis that asthma may be an epithelial disease in which a basic defect in the airway epithelium could be related to an inability to control the osmolarity and ion concentration of the fluid lining the airways (1). Subsequent studies reporting that increased intake of dietary salt in patients with asthma increases their bronchial reactivity to histamine (2, 3) and that non-specific airway responsiveness to methacholine can increase after inhalation of nebulized hypertonic saline in bronchial asthma (4) seem to support the hypothesis that ion transport is affected. Further support is provided by the finding that pm-treatment with inhaled furosemide prevents the immediate bronchoconstriction induced in patients with asthma by exercise (5), ultrasonically nebulixed distilled water (6), inhaled metabisulphite (7). and an inhaled allergen (8,9), as well as the late asthmatic reaction induced by a specific allergen challenge (9). Date received 30 May 1990 Date accepted 15 August 1990
Atrial natriuretic peptide (ANP), which is known by its potent natriuretic properties, has been found to be increased during asthma attacks as compared to the period of remission (10). The mechanism of the increased release could be due to the more negative intrathoracic pressure during the asthma attack (11). ANP has also been reported to have a bronchodilatory effect in asthma (12), probably because of a relaxant effect on airway smooth muscle, similar to the one found on guinea-pig trachea (13, 14). These reports have supported the hypothesis that the lungs may be a target organ for ANP and this peptide may be important in the pathogenesis of asthma (10, 11). On the other hand, a protective effect of ANP on the production of pulmonary edema, not secondary to its
73
74
MEDICAL HypoTHEsEs
natriuretic and/or hypotensive action, has been found in an isolated guinea-pig lung preparation (15). This finding suggests that ANP may also have a local protective mechanism to prevent fluid accumulation in the lungs.
5.
6.
Hypothetical consideration.
According to the above findings, we then hypothesise that the beneficialeffect that ANP may have in asthmatic patients is partly due to the relaxing effect of A.bP on bronchial smooth muscle and partly to effects on the local ionic and water control, probably reducing airway mucosal thickening. Conclusions There is growing evidence suggesting that airways of asthmatics are unable to adapt properly to a stress in which ionic changes are involved. Ion exchange across the bronchial mucosa may at least be contributory in the pathogenesis of bronchial asthma. We hypothesise that ANP, which has been found to act as a bronchodiiator in bronchial asthma, may also act through changes in the transport of water and ions in the airway epithelium. References HoggJC. Eggleston
PA. Is asthma an epithelial disease? American Review of Respiratory Disease. 129: 207, 1984. Javaid A. Cushlev MJ, Bone ME Effect of dietary salt on bronchial- reactiviiy to histamine in asthma. British Medical Journal. 297: 454,1988. Bumey PGJ. Neild JE. Twort CHC. Chirm S. Jones TD. Mitchell WD. Bateman C, Cameron IR. Effect of changing dietary sodium on the airway- response to histamine. Thorax. _ 44: 36. 1989. O’Hickey SP. Amr JP, Rees PJ, Lee TH. Airway responsiveness to methacholine after inhalation of nebuked hypertonic
7.
8.
9.
IO.
Il.
12.
13.
14.
15.
saline in bronchial a&ma. l&e Journal of Allergy and Clinical Immunology. 83: 472, 1989. Bianco S. Vaghi A, Robuschi M. Pasargiklim M. Prevention of exercise- induced bnmchoconstri&n by inhaled furosemide. The Lances 2: 252, 1988. Robuschi M. Vaghi A, Gambaro G, Spagnotto S. Bianco S. Inhaled fumsemide (F) is highly effective in preventing ultrasonically nebulised k&r (UNHZO) brrmchoc&stricti~ American Review of Resoiratotv Disease. 137: 412. 1988. Nichol GM, Alton EWFk. Ni; A, Geddea DM, Ckmg KF, Barnes PJ. Effect of inhaled fmsemide on me&kmlphite and methacholine induced bronchoamstriction and nasal potentials in asthmatic subjects. Thorax. 44: 85lp, 1989. Robuschi M, Pieroni M. Refini M, Bianco S. Rosscmi G. Magni F. Belti E Prevention of antigen-induced early obstmctive reaction by inhaled fumsemide in (atopic) subjects with asthma and (actively sensitized) guinea pigs. ‘Ihe Joumal of Allergy and brnicai Immunology. 85: lo.r990. Bianco S. Pieroni M. Retini RM. Rocolli L. Sestini R Protective efiect of inhaled furosemicie on allergkiiduced early and late asthmatic teactions. Tlte New England Joumal of Medicine, 321: 1069. 1989. Watanabe H. Furui H. Yamaki K. Suzuki R, Takagi K. Sasamoto M, Miwa T, Sat&e T. Plasma atrial natriuretic polypeptide in chronic respiratory disease. American Review of Respiratory Disease. 135: A145 1987. Amyot R, Michoud MC, Lcduc T. Marleau S. Gng H. DuSouich P, Larochelle P, Hamet P, Kiichel0. Release of auial natriumtic factor (ANF) induced by acute airway obstmction. Biochemical and Bicphysical Research Communicationa. 160: 808, 1989. Hulks G, Jardine A. Gxmell JMC, llmmson NC. Bnmchodilator effect of atrial natriuretic peptide in asthma. British Medical Journal. 299: 1081.1989. O’Donnell M, Garippa R, Welton AE Relaxant effect of atiopeptins in isolated guinea-pig airway and vascular smo& muscle. Peptides. 6: 597, 1985. Watanabe H, Furui H. Yamaki K. Suzuki R, Takagi T, Satake T. Atrial natriuretic polype~ide causes dose-dependent relaxant effect on guinea pig vacheal smooth muscle. American Review of Respiratory Disease. 137: 102, 1988. hnamun T, Ohnumr N, Iwasa F, Fmuya M, Hayashi Y. Inomata N, Ishihara T, Noguchi T. Protective effect of alpha-human atrial natriurrtic polypepide (alpha-hANP) on chemicalinduced puhnonaty edema. Life Sciences. 42: 403, 1988.
Atrial Natriuretic Peptide in Bronchial Asthma J. J. ALMIRALL* and G. HEDENSTIERNA Department of Clinical Physiology, University Hospital, S-751 85 llplpsala Sweden, and *‘Hermanos Ameijeiras’ Hospitd, Havana, Cuba (Reprint requests to GH)
Abstract - Regulation of ion transport across the airway mucosa may be involved in the mechanisms producing hyperreactivity and asthma. Atrial Natriuretic Peptide (ANP) has been proposed to participate in the pathogenesis of asthma, and it has been found to have a bronchodilatory effect on asthmatic patients. Experimental evidences suggest that ANP also has some effect on fluid accumulation in the lungs. We hypothesise that ANP may also play a role in the pathogenesis of asthma through changes in the transport of water and ions across the airway epithelium.
Introduction
Atria1 natriuretic peptide and asthma
Some experimental data have led to the hypothesis that asthma may be an epithelial disease in which a basic defect in the airway epithelium could be related to an inability to control the osmolarity and ion concentration of the fluid lining the airways (1). Subsequent studies reporting that increased intake of dietary salt in patients with asthma increases their bronchial reactivity to histamine (2, 3) and that non-specific airway responsiveness to methacholine can increase after inhalation of nebulized hypertonic saline in bronchial asthma (4) seem to support the hypothesis that ion transport is affected. Further support is provided by the finding that pm-treatment with inhaled furosemide prevents the immediate bronchoconstriction induced in patients with asthma by exercise (5), ultrasonically nebulixed distilled water (6), inhaled metabisulphite (7). and an inhaled allergen (8,9), as well as the late asthmatic reaction induced by a specific allergen challenge (9). Date received 30 May 1990 Date accepted 15 August 1990
Atrial natriuretic peptide (ANP), which is known by its potent natriuretic properties, has been found to be increased during asthma attacks as compared to the period of remission (10). The mechanism of the increased release could be due to the more negative intrathoracic pressure during the asthma attack (11). ANP has also been reported to have a bronchodilatory effect in asthma (12), probably because of a relaxant effect on airway smooth muscle, similar to the one found on guinea-pig trachea (13, 14). These reports have supported the hypothesis that the lungs may be a target organ for ANP and this peptide may be important in the pathogenesis of asthma (10, 11). On the other hand, a protective effect of ANP on the production of pulmonary edema, not secondary to its
73
74
MEDICAL HypoTHEsEs
natriuretic and/or hypotensive action, has been found in an isolated guinea-pig lung preparation (15). This finding suggests that ANP may also have a local protective mechanism to prevent fluid accumulation in the lungs.
5.
6.
Hypothetical consideration.
According to the above findings, we then hypothesise that the beneficialeffect that ANP may have in asthmatic patients is partly due to the relaxing effect of A.bP on bronchial smooth muscle and partly to effects on the local ionic and water control, probably reducing airway mucosal thickening. Conclusions There is growing evidence suggesting that airways of asthmatics are unable to adapt properly to a stress in which ionic changes are involved. Ion exchange across the bronchial mucosa may at least be contributory in the pathogenesis of bronchial asthma. We hypothesise that ANP, which has been found to act as a bronchodiiator in bronchial asthma, may also act through changes in the transport of water and ions in the airway epithelium. References HoggJC. Eggleston
PA. Is asthma an epithelial disease? American Review of Respiratory Disease. 129: 207, 1984. Javaid A. Cushlev MJ, Bone ME Effect of dietary salt on bronchial- reactiviiy to histamine in asthma. British Medical Journal. 297: 454,1988. Bumey PGJ. Neild JE. Twort CHC. Chirm S. Jones TD. Mitchell WD. Bateman C, Cameron IR. Effect of changing dietary sodium on the airway- response to histamine. Thorax. _ 44: 36. 1989. O’Hickey SP. Amr JP, Rees PJ, Lee TH. Airway responsiveness to methacholine after inhalation of nebuked hypertonic
7.
8.
9.
IO.
Il.
12.
13.
14.
15.
saline in bronchial a&ma. l&e Journal of Allergy and Clinical Immunology. 83: 472, 1989. Bianco S. Vaghi A, Robuschi M. Pasargiklim M. Prevention of exercise- induced bnmchoconstri&n by inhaled furosemide. The Lances 2: 252, 1988. Robuschi M. Vaghi A, Gambaro G, Spagnotto S. Bianco S. Inhaled fumsemide (F) is highly effective in preventing ultrasonically nebulised k&r (UNHZO) brrmchoc&stricti~ American Review of Resoiratotv Disease. 137: 412. 1988. Nichol GM, Alton EWFk. Ni; A, Geddea DM, Ckmg KF, Barnes PJ. Effect of inhaled fmsemide on me&kmlphite and methacholine induced bronchoamstriction and nasal potentials in asthmatic subjects. Thorax. 44: 85lp, 1989. Robuschi M, Pieroni M. Refini M, Bianco S. Rosscmi G. Magni F. Belti E Prevention of antigen-induced early obstmctive reaction by inhaled fumsemide in (atopic) subjects with asthma and (actively sensitized) guinea pigs. ‘Ihe Joumal of Allergy and brnicai Immunology. 85: lo.r990. Bianco S. Pieroni M. Retini RM. Rocolli L. Sestini R Protective efiect of inhaled furosemicie on allergkiiduced early and late asthmatic teactions. Tlte New England Joumal of Medicine, 321: 1069. 1989. Watanabe H. Furui H. Yamaki K. Suzuki R, Takagi K. Sasamoto M, Miwa T, Sat&e T. Plasma atrial natriuretic polypeptide in chronic respiratory disease. American Review of Respiratory Disease. 135: A145 1987. Amyot R, Michoud MC, Lcduc T. Marleau S. Gng H. DuSouich P, Larochelle P, Hamet P, Kiichel0. Release of auial natriumtic factor (ANF) induced by acute airway obstmction. Biochemical and Bicphysical Research Communicationa. 160: 808, 1989. Hulks G, Jardine A. Gxmell JMC, llmmson NC. Bnmchodilator effect of atrial natriuretic peptide in asthma. British Medical Journal. 299: 1081.1989. O’Donnell M, Garippa R, Welton AE Relaxant effect of atiopeptins in isolated guinea-pig airway and vascular smo& muscle. Peptides. 6: 597, 1985. Watanabe H, Furui H. Yamaki K. Suzuki R, Takagi T, Satake T. Atrial natriuretic polype~ide causes dose-dependent relaxant effect on guinea pig vacheal smooth muscle. American Review of Respiratory Disease. 137: 102, 1988. hnamun T, Ohnumr N, Iwasa F, Fmuya M, Hayashi Y. Inomata N, Ishihara T, Noguchi T. Protective effect of alpha-human atrial natriurrtic polypepide (alpha-hANP) on chemicalinduced puhnonaty edema. Life Sciences. 42: 403, 1988.
