Myocardial alpha 1A-adrenoceptor subtypes in rabbit: differentiation by a selective antagonist, HV723

The influence of a newly developed alpha 1-adrenoceptor antagonist, HV723 (alpha-ethyl-3,4,5-trimethoxy-alpha-(3-((2-(2-methoxy-phenoxy)ethyl)-ami no)- propyl) benzeneacetonitrile fumarate), on the positive inotropic effect and acceleration of phosphoinositide hydrolysis induced by phenylephrine via alpha 1-adrenoceptors in the presence of bupranolol (0.3 microM) was studied in the rabbit ventricular muscle: (1) HV723 at low concentrations (1-100 pM) attenuated the maximal inotropic response by 15-20% without altering the pD2 value for and [3H]inositol monophosphate accumulation induced by phenylephrine. The inhibitory action of HV723 (1-100 pM) showed a close resemblance to that of a selective alpha 1A antagonist, (+)-niguldipine. (2) HV723 (> or = 1 nM) shifted the concentration-response curve for phenylephrine to the right and downwards in association with a partial inhibition (42.5%) of [3H]inositol monophosphate accumulation. The IC50 values of HV723 for the inhibition of the inotropic response and phosphoinositide hydrolysis were approximately equal to the Kilow value determined by displacement of [3H]prazosin-specific binding. The mode of the inhibitory action of HV723 (> or = 1 nM) resembled that of another alpha 1A antagonist, WB 4101. These results indicate that HV723 shows a differential antagonistic action on the alpha 1A-mediated responses depending on the concentration: HV723 (1-100 pM) selectively inhibits the (+)-niguldipine-sensitive subclass to lead to a decrease in the maximal inotropic response with no change in phosphoinositide hydrolysis; HV723 (> or = 1 nM) may antagonize the WB 4101-sensitive subtype coupled to acceleration of phosphoinositide hydrolysis.