MYOCARDIAL ALPHA(1A)-ADRENOCEPTOR SUBTYPES IN RABBIT - DIFFERENTIATION BY A SELECTIVE ANTAGONIST, HV723

The influence of a newly developed alpha1-adrenoceptor antagonist, HV7 23 pha-(3-((2-(2-methoxyphenoxy)ethyl)-amino)-propyl) benzeneacetonitr ile fumarate), on the positive inotropic effect and acceleration of ph osphoinositide hydrolysis induced by phenylephrine via alpha1-adrenoce ptors in the presence of bupranolol (0.3 muM) was studied in the rabbi t ventricular muscle: (1) HV723 at low concentrations (1-100 pM) atten uated the maximal inotropic response by 15-20% without altering the pD 2 value for and [H-3]inositol monophosphate accumulation induced by ph enylephrine. The inhibitory action of HV723 (1-100 pM) showed a close resemblance to that of a selective alpha1A antagonist. (+)-niguldipine . (2) HV723 (greater-than-or-equal-to 1 nM) shifted the concentration- response curve for phenylephrine to the right and downwards in associa tion with a partial inhibition (42.5%) of [H-3]inositol monophosphate accumulation. The IC50 values of HV723 for the inhibition of the inotr opic response and phosphoinositide hydrolysis were approximately equal to the K(ilow) value determined by displacement of [H-3]prazosin-spec ific binding. The mode of the inhibitory action of HV723 (greater-than -or-equal-to 1 nM) resembled that of another alpha1A antagonist, WB 41 01. These results indicate that HV723 shows a differential antagonisti c action on the alpha1A-mediated responses depending on the concentrat ion: HV723 (1-100 pM) selectively inhibits the (+)-niguldipine-sensiti ve subclass to lead to a decrease in the maximal inotropic response wi th no change in phosphoinositide hydrolysis; HV723 (greater-than-or-eq ual-to 1 nM) may antagonize the WB 4101-sensitive subtype coupled to a cceleration of phosphoinositide hydrolysis.