Differential Inhibitory Effects of Nicorandil, a New Antiangina Agent, on the Contractile Responses to Alpha-1- and Alpha-2-Adrenoceptor Agonists in Isolated Rabbit Renal and Femoral Arteries

Abstract

In the renal and femoral artery, nicorandil (10^–6–10^–4 mol/l) had a much greater inhibitory effect on the responses to clonidine (CL) and BHT-920 than on the response to methoxamine (MO) but the inhibitory action of nifedipine on the responses was not different. In the presence of nifedipine, nicorandil further inhibited the responses to all agonists. In the tissue pretreated with phenoxybenzamine, nicorandil inhibited the residual maximum response to MO in the femoral artery but not in the renal artery. Nicorandil had no effect on the residual response to high concentrations of MO in the renal artery pretreated with phenoxybenzamine and nifedipine. Relationship between maximum contraction and percent-receptor occupancy was found to be nonlinear for MO but was close to linear for CL. The inhibitory effect (PA2) of prazosin on MO and CL was much greater than that of yohimbine. In both preparations, nicorandil had only a slight inhibitory effect on the responses to potassium and Ca²⁺. It is concluded that the responses induced by MO, CL and BHT are due to activation of α₁-adrenoceptors and that the differential effect of nicorandil on the responses to α₁ and α₂-agonists may be the result of differences in the amount of receptor reserves and/or efficacy of receptor-contraction coupling that exists for MO, CL and BHT.

Inhibitory Effects of Nitroglycerin on Contractile Responses to Methoxamine and Clonidine in Isolated Rabbit Renal and Femoral Arteries

“…In the present experiment, NG had only a slight inhibitory effect on contractile re sponses to potassium or Ca2+ in the renal and femoral preparations, whereas nifedi pine nearly abolished these responses [Shibata and Satake, 1987], These results, there fore, suggest that a potent inhibitory effect of NG on contractile responses to CL may not primarily be due to the inhibitory action of this compound on influx of extracellular Ca2+ through voltage-dependent Ca2+-channels. The present experiments have demon strated that nifedipine, a Ca2+-entry blocker, inhibits the responses to MO and CL in rab bit renal and femoral arteries in a noncom petitive manner.…”

“…Ariens and van Rossum [1957] sug gested that noncompetitive antagonists will show a greater inhibition when there is no receptor reserve than when a large receptor reserve exists. In a previous study, rabbit renal and femoral arteries were reported to have a receptor reserve (spare receptor) for MO much more than for CL [Shibata and Satake, 1987], These results, therefore, sug gest that the differential inhibitory effect of NG on the responses to MO and CL may be attributed to differences in the amount of receptor reserve that exists for these ago nists.…”

“…In addition, NG inhibited the Ca2*-response in the presence of CL in the renal and femoral arteries. This Ca2+-response is assumed to be due to specific recep tor-activated Ca2+-entry independently of voltage-dependent Ca2+-entry, since nifedi pine and D600 have been indicated to inhibit voltage-dependent Ca2+-entry almost com pletely in rabbit renal and femoral arteries and aorta [Hester et al, 1986;Shibata and Satake, 1987;Shibata et al, 1988], This re sult, therefore, suggests that NG also inhibits responses due to translocation of extracellu lar Ca2+ through nifedipine-insensitive Ca2+-entry channels activated by CL. However, in the presence of MO, NG showed no apparent inhibitory effect on the response to added Ca2+ in the renal artery and it had only a slight inhibitory effect in the femoral artery.…”

Nitroglycerin-sensitive and -resistant contractions mediated by receptor-operated calcium channels in rabbit ear artery.

“…In rabbit renal and femoral arteries, this Ca2+ response is assumed to be almost completely due to specific receptor-activated Ca2+-entry in dependently of voltage-dependent Ca2+ entry (11). Nitroglycerin had no effect on the response of ROCs to norepinephrine, although it did inhibit their responses to serotonin and histamine.…”