Different desensitization mechanisms of two alpha 1-adrenoceptor subtypes in the contraction of rabbit aorta.

Using alpha 1-adrenoceptor selective antagonists chlorethylclonidine (CEC) and WB4101, both functional and radioligand binding studies showed that rabbit aorta contains at least two pharmacologically distinct alpha 1-adrenoceptor subtypes of approximately 10% alpha 1a and 90% alpha 1b receptors, and that each receptor subtype has a distinct role in the alpha 1-adrenoceptor-mediated vasoconstrictive response through different biochemical mechanisms for increasing intracellular Ca2+; alpha 1a receptors cause tonic response predominantly dependent on the influx of extracellular Ca2+, while alpha 1b receptors stimulate phosphoinositides (PI) hydrolysis/intracellular Ca2+ mobilization and cause phasic response mainly independent of extracellular Ca2+. Incubation of rabbit aorta with 10 microM noradrenaline (NA) for 2 h resulted in a reduction in the phasic response and PI hydrolysis to NA with no change in the tonic response. Similar to the NA incubation, the protein kinase C stimulator PMA (1 microM) selectively attenuated alpha 1b-receptor mediated PI hydrolysis and phasic contraction but had little effect on alpha 1a-receptor-mediated tonic response. The protein kinase C inhibitor H-7 (10 microM) blocked these inhibitory effects of PMA. Treatment with H-7 (10 microM) prevented the NA-induced alpha 1b receptor desensitization in inositol monophosphate (IP) formation and phasic response. The results suggest that activation of C kinase may be involved in the development of selective desensitization of alpha 1b receptors by a short-time in vitro incubation of NA.