Mechanisms of Vasodilation Induced by NKH477, a Water‐Soluble Forskolin Derivative, in Smooth Muscle of the Porcine Coronary Artery
作者:
Jonaid Shafiq,
Satoshi Suzuki,
Takeo Itoh,
Hirosi Kuriyama,
期刊:
Circulation Research
(OVID Available online 1992)
卷期:
Volume 71,
issue 1
页码: 70-81
ISSN:0009-7330
年代: 1992
出版商: OVID
关键词: cAMP;forskolin derivative;vascular smooth muscle;cellular Ca2+concentration;contractile proteins
数据来源: OVID
摘要:
To study the mechanism of vasodilation induced by 6-(3-dimethylaminopropionyl) forskolin (NKH477), a water-soluble forskolin derivative, its effects on the acetylcholine (ACh)-induced contraction of muscle strips of porcine coronary artery were examined. [Ca2+]i, isometric force, and cellular concentrations of cAMP and inositol 1,4,5-trisphosphate were measured. NKH477 (0.1–1.0 μM), isoproterenol (0.01–0.1 μM), or forskolin (0.1–1.0 μM) increased cAMP and attenuated the contraction induced by 128 mM K+or 10 μM ACh in a concentration-dependent manner. These agents, at concentrations up to 0.3 μM, did not change the amount of cGMP. NKH477 (0.1 μM) attenuated the contraction induced by 128 mM K+without corresponding changes in the evoked [Ca2+]iresponses. ACh (10 μM) produced a large phasic increase followed by a small tonic increase in [Ca2+]iand produced a sustained contraction. The ACh-induced phasic increase in [Ca2+]i, but not the tonic increase, disappeared after application of 0.1 μM ionomycin. NKH477 (0.1 μM) attenuated both the increase in [Ca2+]iand the force induced by 10 μM ACh in muscle strips that were not treated with ionomycin and inhibited the ACh-induced contraction without corresponding changes in [Ca2+]iin ionomycin-treated muscle strips. These results suggest that NKH477 inhibits ACh-induced Ca2+mobilization through its action on ionomycin-sensitive storage sites. In ionomycin-treated and 128 mM K+-treated muscle strips, 0.1 μM NKH477 shifted the [Ca2+]i-force relation to the right in the presence or absence of 10 μM ACh. In β-escin-skinned smooth muscle strips, 0.1 μM NKH477 shifted the pCa-force relation to the right but had no effects on Ca2+-independent contraction. We conclude that in smooth muscle of porcine coronary artery, NKH477 inhibits ACh-induced contraction by both attenuating ACh-induced Ca2+mobilization and reducing the sensitivity of the contractile machinery to Ca2+, possibly by activating cAMP-dependent mechanisms.
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