Premium
Functional evidence of inverse agonism in vascular smooth muscle
Author(s) -
Noguera M. Antonia,
Ivorra M. Dolores,
D'Ocon Pilar
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15689.x
Subject(s) - methoxamine , medicine , extracellular , agonist , chemistry , endocrinology , vascular smooth muscle , biophysics , receptor , biology , smooth muscle , biochemistry
1 In the present study, depletion of internal Ca 2+ stores sensitive to noradrenaline (1 μ m ) in rat aorta, is the signal for the entry of extracellular Ca 2+ , not only to refill the stores but also, in our experimental conditions, to activate the contractile proteins. This induces an increase in the resting tone that constitutes, the first functional evidence of this Ca 2+ entry. 2 The fact that methoxamine (100 μ m ) reproduces the same processes as noradrenaline but clonidine (1 μ m ) does not, indicates that α 1 ‐adrenoceptor activation is related to the increase in the resting tone observed after depletion of adrenoceptor‐sensitive internal Ca 2+ ‐stores. 3 Benoxathian and WB 4101 (α 1A ‐ and α 1D ‐adrenoceptor antagonists) selectively inhibit, in a concentration‐dependent manner, this mechanical response observed in absence of the agonist, which suggests that these agents can act as inverse agonists and provide a functional model for studying this phenomenon. Since chloroethylclonidine (100 μ m ) has no effect on this response, the participation of α 1B ‐adrenoceptors can be ruled out. 4 Contractile responses to noradrenaline (1 μ m ) in Ca 2+ ‐free medium were selectively blocked by chloroethylclonidine. This suggests that the response to noradrenaline in Ca 2+ ‐free medium mainly depends on the activation of the α 1B ‐adrenoceptor subtype.