Mechanisms of vasodilation induced by NKH477, a water-soluble forskolin derivative, in smooth muscle of the porcine coronary artery

Jonaid Shafiq, Satoshi Suzuki, Takeo Itoh, Hirosi Kuriyama

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Abstract

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+]i responses. ACh (10 μM) produced a large phasic increase followed by a small tonic increase in [Ca2+]i and 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+]i and 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+]i in 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.

Original languageEnglish
Pages (from-to)70-81
Number of pages12
JournalCirculation research
Volume71
Issue number1
DOIs
Publication statusPublished - Jan 1 1992

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Colforsin
Vasodilation
Smooth Muscle
Coronary Vessels
Acetylcholine
Swine
Water
Ionomycin
Muscles
Escin
Inositol 1,4,5-Trisphosphate
Muscle Contraction
Isoproterenol

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Mechanisms of vasodilation induced by NKH477, a water-soluble forskolin derivative, in smooth muscle of the porcine coronary artery. / Shafiq, Jonaid; Suzuki, Satoshi; Itoh, Takeo; Kuriyama, Hirosi.

In: Circulation research, Vol. 71, No. 1, 01.01.1992, p. 70-81.

Research output: Contribution to journalArticle

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N2 - 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+]i responses. ACh (10 μM) produced a large phasic increase followed by a small tonic increase in [Ca2+]i and 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+]i and 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+]i in 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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