CD-832, A NEW DIHYDROPYRIDINE DERIVATIVE WITH BOTH NITRATE-LIKE AND CA2+ CHANNEL ANTAGONIST VASODILATOR ACTIVITIES

We investigated the effects of CD-832 ((4R)-(-)-2-(nicotinoylamino)eth yl 3-nitroxypropyl 1,4-dihydro-2,6-dimethyl-4,3-nitrophenyl, 3,5-pyrid ine dicarboxylate), a new dihydropyridine derivative with nitrate este r, on contraction and relaxation responses induced by various vasoacti ve agents in rabbit aorta. CD-832 potently inhibited the specific bind ing of [H-3](+)-PN200-110 to rat brain membranes. The IC50 values for [(3)](+)-PN200-110 binding were 2.8 nM and 4.9 nM in CD-832 and nifedi pine, respectively. CD-832 (10(S)(-8) to 10(-5) M), diltiazem (10(-8) to 10(-5) M) and benidipine (10(-8) to 10(-5) M) inhibited the 64 mM K Cl-induced contraction of the aortic strips in a concentration-depende nt manner. Neither nitroglycerin (10(-8) to 10(-5) M) nor nicorandil ( 10(-8) to 10(-5) M) affected the 64 mM KCl-induced contraction in rabb it aorta. CD-832 (10(-8) to 10(-5) M), nitroglycerin (10(-8) to 10(-5) M) and nicorandil (10(-5) M) inhibited the 10(-6) M norepinephrine-in duced contraction of the aortic strips. However, diltiazem (10(-5) M) and benidipine (10(-5) M) had no effect on norepinephrine-induced cont raction in rabbit aorta. Nitroglycerin (10(-5) M), atrial natriuretic peptide (10(-8) M), nicorandil (10(-5) M) and CD-832 (10(-7) to 10(-5) M) augmented the isoproterenol-induced relaxation responses of rabbit aorta precontracted with endothelin-1 (1 x 10(-7) to 2 x 10(-7) M). T he effects of nitroglycerin (10(-5) M), nicorandil (10(-5) M) and CD-8 32 (10(-5) M) on isoproterenol-induced relaxation responses were antag onized by treatment with methylene blue (10(-5) M) and oxyhemoglobin ( 10(-5) M). The effect of CD-832 (10(-6) M) on isoproterenol-induced re laxation was augmented by treatment with 3 X 10(-5) M zaprinast, a pho sphodiesterase V inhibitor. Neither diltiazem nor benidipine affected isoproterenol-induced relaxation responses in rabbit aorta. CD-832 (10 (-7) to 10(-5) M) increased the levels of cyclic GMP without affecting the levels of cyclic AMP in rabbit aorta. These results indicate that CD-832 has not only a Ca2+ channel antagonist-like action but also a nitrate-like action in vascular smooth muscle of the rabbit aorta.