RS-7897, a novel organic nitrate, structurally contains aminoethylnitrate (AEN) and L-2-oxothiazolidine-4-carboxylic acid (L-OTCA), which are linked together via an amide bond. Vasodilating activity of RS-7897 was 130 times weaker than that of AEN in vitro, while in vivo it was comparable to but longer lasting than those of AEN and nitroglycerin in anesthetized dogs. Intravenous administration of RS-7897 to dogs resulted in the appearance in plasma of AEN, which decreased with about 2.5 times longer t(1/2) (0.49 h) than that after administration of AEN itself. The T(max) value of AEN (0.25 h) after RS-7897 dosing agreed with the time showing the maximum vasodilating effect, indicating that RS-7897 serves as a prodrug releasing AEN slowly in vivo. The activity to hydrolyze RS-7897 to AEN and L-OTCA was localized in the cytosolic fractions of dog tissues, inhibited by thiol-blocking agents and was strongly inhibited by thyrotropin-releasing hormone, a substrate of pyroglutamyl aminopeptidase I (PAP-I). Furthermore, the RS-7897-hydrolyzing activity in dog liver cytosol was completely inhibited by an antibody against rat PAP-I. Therefore, it was found that PAP-I is involved in bioactivation of RS-7897 by amide bond hydrolysis, recognizing the sulfur-substituted L-pyroglutamyl moiety (L-OTCA) of this xenobiotic substrate.

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We examined antianginal effects of azelnidipine and amlodipine in an arginine vasopressin-induced rat anginal model. Oral administration of azelnidipine or amlodipine produced long lasting inhibition of arginine vasopressin-induced ST-segment depression in electrocardiogram. The degrees of inhibition with azelnidipine at doses of 1 and 3 mg/kg were comparable to those with amlodipine at 3 and 10 mg/kg. Both drugs lowered mean blood pressure in a dose-related manner, whereas only azelnidipine decreased heart rate. Azelnidipine at 3 mg/kg and amlodipine at 10 mg/kg produced a similar decrease in the rate pressure product, an index for cardiac oxygen consumption. Their inhibitory effects on calcium-induced vascular contraction were compared in isolated porcine coronary arteries. Both drugs produced a slow-developing inhibition of calcium-induced contraction. Although their inhibitory effects were similar, the way the both drugs inhibited calcium-induced contraction differed with each other. After removing the drug from bathing solution, the inhibitory effects of azelnidipine were not blunted but were sustained for a long time, which indicates that azelnidipine has high vascular affinity. On the other hand, those of amlodipine were rapidly blunted. These results suggest that the mechanisms underlying antianginal effects of azelnidipine differ from those of amlodipine. The antianginal effect with azelnidipine may be accounted for by its high affinity to the coronary blood vessels and the heart rate slowing effect, both of which are not shared with amlodipine.