Role of cyclic GMP in inhibitory effects of CD-349 in isolated blood vessels

Abstract 1. We investigated the effects of CD-349, a dihydropyridine derivative with nitrate ester, on contractile responses induced by high K + , norepinephrine (NE) and Ca 2+ in isolated rabbit aorta. 2. CD-349 (10 −9 −10 −5 M) and nifedipine (10 −9 −10 −5 M) equally inhibited the 64 mM KCL-induced contraction of the aortic strips in a concentration-dependent manner. 8-Br-cyclic GMP (10 −3 M) did not inhibit the KCl-induced contraction of the aortic strips. 3. CD-349 (10 −8 −10 −5 M) and 8-Br-cyclic GMP (10 −6 −10 −3 M) inhibited the 10 −6 M NE-induced contraction of the aortic strips in a concentration-dependent manner. However, nifedipine had no effect on the NE-induced contraction in rabbit aorta. 4. The inhibitory effects of CD-349 on NE-induced contraction were antagonized by treatment with methylene blue and oxyhemoglobin, while they were augmented by treatment with zaprinast. 5. CD-349 (10 −8 −10 −5 M) and 8-Br-cyclic GMP (10 −5 −10 −4 M) inhibited the NE-induced phasic contraction and Ca 2+ -induced contraction of the aortic strips preincubated with NE in Ca 2+ -free medium. However, nifedipine (10 −5 M) had little or no effect on both NE-induced phasic contraction and Ca 2+ -induced contraction of the aortic strips preincubated with NE in Ca 2+ -free medium. 6. CD-349 (10 −7 −10 −5 M) increased the levels of cyclic GMP in rabbit aorta. 7. These results indicate that CD-349 has a hybrid property deriving from Ca 2+ -antagonist and cyclic GMP increasing agents.