FUNCTIONAL EVIDENCE OF INVERSE AGONISM IN VASCULAR SMOOTH-MUSCLE

1 In the present study, depletion of internal Ca2+ stores sensitive to noradrenaline (1 mu M) in rat aorta, is the signal for the entry of e xtracellular Ca2+, not only to refill the stores but also, in our expe rimental conditions, to activate the contractile proteins. This induce s an increase in the resting tone that constitutes, the first function al evidence of this Ca2+ entry. 2 The fact that methoxamine (100 mu M) reproduces the same processes as noradrenaline but clonidine (1 mu M) does not, indicates that alpha(1)-adrenoceptor activation is related to the increase in the resting tone observed after depletion of adreno ceptor-sensitive internal Ca2+-stores. 3 Benoxathian and WB 4101 (alph a(1A)- and alpha(1D)-adrenoceptor antagonists) selectively inhibit, in a concentration-dependent manner, this mechanical response observed i n absence of the agonist, which suggests that these agents can act as inverse agonists and provide a functional model for studying this phen omenon. Since chloroethylclonidine (100 mu M) has no effect on this re sponse, the participation of alpha(1B)-adrenoceptors can be ruled out. 4 Contractile responses to noradrenaline (1 mu M) in Ca2+-free medium were selectively blocked by chloroethylclonidine. This suggests that the response to noradrenaline in Ca2+-free medium mainly depends on th e activation of the alpha(1B)-adrenoceptor subtype.