DIFFERENT DESENSITIZATION MECHANISMS OF 2 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. 1990 The British Pharmacological Society