THE SPECIFIC CONTRIBUTION OF THE NOVEL ALPHA-1D ADRENOCEPTOR TO THE CONTRACTION OF VASCULAR SMOOTH-MUSCLE

With a selective antagonist, the specific contribution of the alpha-1D adrenoceptor (AR) to vascular smooth muscle contraction has been asse ssed. BMY 7378 bound to membranes expressing the cloned rat alpha-1D A R with a > 100-fold higher affinity (K-1 = 2 nM) than binding to eithe r the cloned rat alpha-1A AR (K-i = 800 nM) or the hamster alpha-1B AR (K-i = 600 nM). BMY 7378 exhibited differential potency in inhibiting vascular smooth muscle contraction. In the rat aorta and iliac artery , BMY 7378 was a high-affinity antagonist, producing parallel shifts i n the phenylephrine concentration-response curve. The dissociation con stants for this compound by Schild analysis were 0.95 and 4 nM for the aorta and iliac artery, respectively. The slopes of these Schild plot s were not significantly different from unity. BMY 7378 was a weak ant agonist in the rat caudal, mesenteric resistance and renal arteries, w ith Schild slopes significantly < 1. With ribonuclease protection assa ys, alpha-1D mRNA was found in all blood vessels examined, These data suggest that (1) BMY 7378 is a selective alpha-1D AR antagonist that c an be used in functional systems to assess the contribution of this re ceptor in vascular smooth muscle contraction; (2) the alpha-to AR appe ars to play a major role in the contraction of the aorta and iliac art ery; (3) despite the fact that the mRNA for the alpha-1D AR can be det ected in the caudal, mesenteric resistance (4) and renal arteries, it does not appear to play a role in mediating contraction of these blood vessels; and (4) expression of alpha-1D mRNA in a particular artery d oes not ensure that this receptor is involved in regulating the contra ction of that artery.