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 language | English |
|---|---|
| Pages (from-to) | 70-81 |
| Number of pages | 12 |
| Journal | Circulation research |
| Volume | 71 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 1 1992 |
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All Science Journal Classification (ASJC) codes
- Physiology
- Cardiology and Cardiovascular Medicine
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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 journal › Article
}
TY - JOUR
T1 - Mechanisms of vasodilation induced by NKH477, a water-soluble forskolin derivative, in smooth muscle of the porcine coronary artery
AU - Shafiq, Jonaid
AU - Suzuki, Satoshi
AU - Itoh, Takeo
AU - Kuriyama, Hirosi
PY - 1992/1/1
Y1 - 1992/1/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0026716538&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0026716538&partnerID=8YFLogxK
U2 - 10.1161/01.RES.71.1.70
DO - 10.1161/01.RES.71.1.70
M3 - Article
C2 - 1318797
AN - SCOPUS:0026716538
VL - 71
SP - 70
EP - 81
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 1
ER -