The interaction of α‐human atrial natriuretic peptide (ANP) with salbutamol, sodium nitroprusside and isosorbide dinitrate in human bronchial smooth muscle

Abstract

1 Contractions in human bronchial rings evoked by methacholine (10-6M) were reversed by single contractions of a-human atrial natriuretic peptide (10-6 M), salbutamol (10-6 M), sodium nitroprusside (10-6 M) or isosorbide dinitrate (4.2 x 10-M) and the extent of the relaxations compared. The activity of combinations of ANP with salbutamol, sodium nitroprusside and isosorbide dinitrate were compared with those for each agonist alone. 2 ANP and salbutamol were equipotent in reversing methacholine-evoked contraction and, in combination these agonists evoked an additive response. ANP and sodium nitroprusside also evoked similar degrees of relaxation and were additive, as were ANP and isosorbide dinitrate; however, with isosorbide dinitrate a higher concentration was required to evoke the same degree of relaxation as ANP, sodium nitroprusside or salbutamol. 3 Cumulative concentration-response curves to methacholine (10-9-3 x 10-4 M) were examined in the presence and absence of the above bronchodilator substances, alone and in combination allowing their abilities to protect against contraction to be compared. ANP (10-6M) and salbutamol (10-6M) each attenuated subsequent contractions evoked by methacholine, an ability not shared with sodium nitroprusside (10-6M) or isosorbide dinitrate (4.2 x 10-' M). Indeed at lower concentrations of methacholine (<3 x 10-7M), sodium nitroprusside evoked a paradoxical enhancement of methacholine-evoked contractions. 4 In combination, ANP and salbutamol attenuated contractions evoked by methacholine to a significantly greater degree than that seen with either agonist alone, whilst a combination of ANP and sodium nitroprusside evoked no greater effect than that seen with ANP alone. By contrast, isosorbide dinitrate and ANP together evoked a greater inhibition than ANP alone. 5 These results suggest that a combination of agents such as ANP and salbutamol evokes a greater effect than either alone, both in reversing and protecting against methacholine-evoked contractions. Such combinations may be of benefit in the treatment of patients, allowing lower doses of drug to be used. Combinations of ANP and isosorbide dinitrate may likewise be of interest; however, the mechanism underlying the enhancement of ANP responses by isosorbide dinitrate requires further study.

Salbutamol Up-regulates PDE4 Activity and Induces a Heterologous Desensitization of U937 Cells to Prostaglandin E2

“…In a previous study (Torphy et al, 1992), we demonstrated that PDE4 activity is up-regulated by salbutamol, used alone or in combination with rolipram, over a concentration range of 10 nM to 10 M. This range is identical to that required to relax human airway smooth muscle in vitro (Goldie et al 1986;Nally et al, 1994). While it is virtually impossible to determine the local concentrations of inhaled salbutamol within the airway, this information strongly suggests that salbutamol up-regulates PDE4 activity at clinically relevant concentrations.…”

Guanylyl cyclases, nitric oxide, natriuretic peptides, and airway smooth muscle function

“…ANP also relaxes human airways in vitro. ANP was reported to reverse and protect against methacholineinduced contraction of human bronchi (6,20,84). ANP was more potent than SNP and salbutamol (20).…”

“…Further studies addressing possible interactions in vitro may be of great interest. The demonstration of an additive effect of NO and NO donors on ␤ 2 -agonist-induced bronchodilation in asthmatic subjects (50,104) and that a combination of ANP and salbutamol evokes a greater effect than either alone in reversing and protecting against methacholine-evoked contraction in isolated human bronchi (84) suggest that such combinations could be of benefit in the treatment of asthma, allowing lower doses of each individual drug to be used.…”

Bronchodilator Effect of Infused B-Type Natriuretic Peptide in Asthma

“…ASTHMA there is a theoretical advantage in the concomitant use of BNP together with ␤-agonist inhalation. 12 BNP increases cellular concentration of cyclic guanosine monophosphate (cGMP) secondary to a rise in intracellular Ca ϩϩ concentration. 13,14 This is in contrast to cyclic adenosine monophosphatedependent stimulation of the receptor on bronchial smooth-muscle cells receptors by ␤-agonists.…”