Am. J. Respir. Crit. Care Med., Vol 153, No. 5, May 1996, 1489-1495.
Functional and binding characteristics of long-acting beta 2-agonists in lung and heart
FJ Roux, B Grandordy and JS Douglas
John B. Pierce Laboratory, Yale University School of Medicine, New Haven, Connecticut 06519, USA.
Salmeterol and formoterol, two new long-acting beta 2-agonists were
equipotent (values of negative log molar concentration eliciting half-
maximal effect [pD2] 9.2 +/- 0.03 and 8.9 +/- 0.03, respectively) in
relaxing maximally contracted guinea pig tracheal spirals (histamine, 100
microM). Both agonists were 10 times more potent than L- isoproterenol and
fenoterol and 100 times more potent than albuterol. L- Isoproterenol and
fenoterol induced > 90% relaxation (percentage of maximal aminophylline
relaxation). Formoterol and albuterol were equally efficacious. Formoterol
was more efficacious (86 +/- 5%) than salmeterol (62 +/- 3%) or soterenol
(59 +/- 3%). In minimally contracted tissues (10 microM histamine), agonist
potencies increased 10-fold and relaxation was complete. In
[125I]iodocyanopindolol-labeled bronchial membranes, formoterol and
salmeterol induced high-affinity states of the beta 2-receptor (pKh 9.6 +/-
0.4 and 10.4 +/- 0.7, respectively), the former inducing a higher
percentage (57 +/- 6 versus 28 +/- 4, p < 0.05). Only low-affinity
binding (pKI) was observed when guanine nucleotide was present. pD2 values
were similar to pKh values and relative efficacies significantly correlated
with percentage of pKI sites. Formoterol and salmeterol were highly
selective for the beta 2 versus beta 1-subtype (pKI values were 8.2 +/-
0.09 and 6.25 +/- 0.06 and 8.3 +/- 0.04 and 5.7 +/- 0.04, respectively).
Albuterol (5.83 +/- 0.06 and 4.71 +/- 0.16) and fenoterol (6.33 +/- 0.07
and 5.67 +/- 0.05) were less selective. These results can explain the
potencies and efficacies of salmeterol and formoterol in humans.
