Effects of a water‐soluble forskolin derivative (NKH477) and a membrane‐permeable cyclic AMP analogue on noradrenaline‐induced Ca2+ mobilization in smooth muscle of rabbit mesenteric artery

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Effects were studied of 6‐(3‐dimethylaminopropionyl) forskolin (NKH477), a water‐soluble forskolin derivative and of dibutyryl‐cyclic AMP, a membrane‐permeable cyclic AMP analogue on noradrenaline (NA)‐induced Ca2+ mobilization in smooth muscle strips of the rabbit mesenteric artery. The intracellular concentration of Ca2+ ([Ca2+]i), isometric force and cellular concentration of inositol 1,4,5‐trisphosphate (InsP3) were measured. NA (10 μm) produced a phasic, followed by a tonic increase in both [Ca2+]i and force in a solution containing 2.6 mm Ca2+. NKH477 (0.01–0.3 μm) attenuated the phasic and the tonic increases in both [Ca2+]i and force induced by 10 μm NA, in a concentration‐dependent manner. In Ca2+‐free solution containing 2 mm EGTA with 5.9 mm K+, NA (10 μm) produced only phasic increases in [Ca2+]i and force. NKH477 (0.01 μm) and dibutyryl‐cyclic AMP (0.1 mm) each greatly inhibited these increases. NA (10 μm) led to the production of InsP3 in intact smooth muscle strips and InsP3 (10 μm) increased Ca2+ in Ca2+‐free solution after a brief application of Ca2+ in β‐escin‐skinned smooth muscle strips. NKH477 (0.01 μm) or dibutyryl‐cyclic AMP (0.1 mm) modified neither the NA‐induced synthesis of InsP3 in intact muscle strips nor the InsP3‐induced Ca2+ release in skinned strips. In Ca2+‐free solution, high K+ (40 and 128 mm) itself failed to increase [Ca2+]i but concentration‐dependently enhanced the amplitude of the increase in [Ca2+]i induced by 10 μm NA with a parallel enhancement of the maximum rate of rise. The extent of the inhibition induced by NKH477 (0.01 μm) or dibutyryl‐cyclic AMP (0.1 mm) on the NA‐induced [Ca2+]i increase was inversely related to the maximum rate of rise of [Ca2+]i induced by NA in Ca2+‐free solution containing various concentrations of K+. These results suggest that the increase in the rate of Ca2+ release induced by NA can conceal the inhibitory action on NA‐induced Ca2+ mobilization of agents that increase cyclic AMP. Repetitive application of 10 μm NA in Ca2+‐free solution led to a disappearance of the NA‐induced increase in [Ca2+]i, but NA could again increase [Ca2+]i in Ca2+‐free solution after a brief application of Ca2+ with 40 mm K+ (‘Ca2+‐loading’). The magnitude of this NA‐induced increase in [Ca2+]i depended on the duration of the Ca2+‐loading. With application of dibutyryl‐cyclic AMP (0.1 mm) during the Ca2+‐loading period, the loading duration required for the restoration of the maximum NA‐response was shortened. Cyclopiazonic acid (10 μm, an inhibitor of Ca2+‐ATPase at intracellular storage sites) attenuated the inhibitory action of dibutyryl‐cyclic AMP on the NA‐induced increase in [Ca2+]i in Ca2+‐free solution. When NA (10 μm) was applied twice for 30 s with a 10 min interval in Ca2+‐free solution, the amplitude of response to the second application was about one third of the first response. With application of 0.1 mm dibutyryl‐cyclic AMP during the first application of NA, the increase in [Ca2+]i induced by the first application of NA was inhibited, but the response induced by the second was enhanced. These results suggest that dibutyryl‐cyclic AMP enhances Ca2+ uptake into the NA‐sensitive storage sites. We conclude that, in smooth muscle of the rabbit mesenteric artery, agents that increase cyclic AMP inhibit the NA‐induced increase in [Ca2+]i through an activation of Ca2+ uptake into the cellular storage sites. 1993 British Pharmacological Society

Original languageEnglish
Pages (from-to)1117-1125
Number of pages9
JournalBritish Journal of Pharmacology
Volume110
Issue number3
DOIs
Publication statusPublished - Jan 1 1993

Fingerprint

Mesenteric Arteries
Colforsin
Cyclic AMP
Smooth Muscle
Norepinephrine
Rabbits
Adenosine Monophosphate
Calcium-Transporting ATPases
Egtazic Acid
Inositol

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

@article{3cb1a57e02b2428e9745609e71378294,
title = "Effects of a water‐soluble forskolin derivative (NKH477) and a membrane‐permeable cyclic AMP analogue on noradrenaline‐induced Ca2+ mobilization in smooth muscle of rabbit mesenteric artery",
abstract = "Effects were studied of 6‐(3‐dimethylaminopropionyl) forskolin (NKH477), a water‐soluble forskolin derivative and of dibutyryl‐cyclic AMP, a membrane‐permeable cyclic AMP analogue on noradrenaline (NA)‐induced Ca2+ mobilization in smooth muscle strips of the rabbit mesenteric artery. The intracellular concentration of Ca2+ ([Ca2+]i), isometric force and cellular concentration of inositol 1,4,5‐trisphosphate (InsP3) were measured. NA (10 μm) produced a phasic, followed by a tonic increase in both [Ca2+]i and force in a solution containing 2.6 mm Ca2+. NKH477 (0.01–0.3 μm) attenuated the phasic and the tonic increases in both [Ca2+]i and force induced by 10 μm NA, in a concentration‐dependent manner. In Ca2+‐free solution containing 2 mm EGTA with 5.9 mm K+, NA (10 μm) produced only phasic increases in [Ca2+]i and force. NKH477 (0.01 μm) and dibutyryl‐cyclic AMP (0.1 mm) each greatly inhibited these increases. NA (10 μm) led to the production of InsP3 in intact smooth muscle strips and InsP3 (10 μm) increased Ca2+ in Ca2+‐free solution after a brief application of Ca2+ in β‐escin‐skinned smooth muscle strips. NKH477 (0.01 μm) or dibutyryl‐cyclic AMP (0.1 mm) modified neither the NA‐induced synthesis of InsP3 in intact muscle strips nor the InsP3‐induced Ca2+ release in skinned strips. In Ca2+‐free solution, high K+ (40 and 128 mm) itself failed to increase [Ca2+]i but concentration‐dependently enhanced the amplitude of the increase in [Ca2+]i induced by 10 μm NA with a parallel enhancement of the maximum rate of rise. The extent of the inhibition induced by NKH477 (0.01 μm) or dibutyryl‐cyclic AMP (0.1 mm) on the NA‐induced [Ca2+]i increase was inversely related to the maximum rate of rise of [Ca2+]i induced by NA in Ca2+‐free solution containing various concentrations of K+. These results suggest that the increase in the rate of Ca2+ release induced by NA can conceal the inhibitory action on NA‐induced Ca2+ mobilization of agents that increase cyclic AMP. Repetitive application of 10 μm NA in Ca2+‐free solution led to a disappearance of the NA‐induced increase in [Ca2+]i, but NA could again increase [Ca2+]i in Ca2+‐free solution after a brief application of Ca2+ with 40 mm K+ (‘Ca2+‐loading’). The magnitude of this NA‐induced increase in [Ca2+]i depended on the duration of the Ca2+‐loading. With application of dibutyryl‐cyclic AMP (0.1 mm) during the Ca2+‐loading period, the loading duration required for the restoration of the maximum NA‐response was shortened. Cyclopiazonic acid (10 μm, an inhibitor of Ca2+‐ATPase at intracellular storage sites) attenuated the inhibitory action of dibutyryl‐cyclic AMP on the NA‐induced increase in [Ca2+]i in Ca2+‐free solution. When NA (10 μm) was applied twice for 30 s with a 10 min interval in Ca2+‐free solution, the amplitude of response to the second application was about one third of the first response. With application of 0.1 mm dibutyryl‐cyclic AMP during the first application of NA, the increase in [Ca2+]i induced by the first application of NA was inhibited, but the response induced by the second was enhanced. These results suggest that dibutyryl‐cyclic AMP enhances Ca2+ uptake into the NA‐sensitive storage sites. We conclude that, in smooth muscle of the rabbit mesenteric artery, agents that increase cyclic AMP inhibit the NA‐induced increase in [Ca2+]i through an activation of Ca2+ uptake into the cellular storage sites. 1993 British Pharmacological Society",
author = "Shinichi Ito and Satoshi Suzuki and Takeo Itoh",
year = "1993",
month = "1",
day = "1",
doi = "10.1111/j.1476-5381.1993.tb13930.x",
language = "English",
volume = "110",
pages = "1117--1125",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - Effects of a water‐soluble forskolin derivative (NKH477) and a membrane‐permeable cyclic AMP analogue on noradrenaline‐induced Ca2+ mobilization in smooth muscle of rabbit mesenteric artery

AU - Ito, Shinichi

AU - Suzuki, Satoshi

AU - Itoh, Takeo

PY - 1993/1/1

Y1 - 1993/1/1

N2 - Effects were studied of 6‐(3‐dimethylaminopropionyl) forskolin (NKH477), a water‐soluble forskolin derivative and of dibutyryl‐cyclic AMP, a membrane‐permeable cyclic AMP analogue on noradrenaline (NA)‐induced Ca2+ mobilization in smooth muscle strips of the rabbit mesenteric artery. The intracellular concentration of Ca2+ ([Ca2+]i), isometric force and cellular concentration of inositol 1,4,5‐trisphosphate (InsP3) were measured. NA (10 μm) produced a phasic, followed by a tonic increase in both [Ca2+]i and force in a solution containing 2.6 mm Ca2+. NKH477 (0.01–0.3 μm) attenuated the phasic and the tonic increases in both [Ca2+]i and force induced by 10 μm NA, in a concentration‐dependent manner. In Ca2+‐free solution containing 2 mm EGTA with 5.9 mm K+, NA (10 μm) produced only phasic increases in [Ca2+]i and force. NKH477 (0.01 μm) and dibutyryl‐cyclic AMP (0.1 mm) each greatly inhibited these increases. NA (10 μm) led to the production of InsP3 in intact smooth muscle strips and InsP3 (10 μm) increased Ca2+ in Ca2+‐free solution after a brief application of Ca2+ in β‐escin‐skinned smooth muscle strips. NKH477 (0.01 μm) or dibutyryl‐cyclic AMP (0.1 mm) modified neither the NA‐induced synthesis of InsP3 in intact muscle strips nor the InsP3‐induced Ca2+ release in skinned strips. In Ca2+‐free solution, high K+ (40 and 128 mm) itself failed to increase [Ca2+]i but concentration‐dependently enhanced the amplitude of the increase in [Ca2+]i induced by 10 μm NA with a parallel enhancement of the maximum rate of rise. The extent of the inhibition induced by NKH477 (0.01 μm) or dibutyryl‐cyclic AMP (0.1 mm) on the NA‐induced [Ca2+]i increase was inversely related to the maximum rate of rise of [Ca2+]i induced by NA in Ca2+‐free solution containing various concentrations of K+. These results suggest that the increase in the rate of Ca2+ release induced by NA can conceal the inhibitory action on NA‐induced Ca2+ mobilization of agents that increase cyclic AMP. Repetitive application of 10 μm NA in Ca2+‐free solution led to a disappearance of the NA‐induced increase in [Ca2+]i, but NA could again increase [Ca2+]i in Ca2+‐free solution after a brief application of Ca2+ with 40 mm K+ (‘Ca2+‐loading’). The magnitude of this NA‐induced increase in [Ca2+]i depended on the duration of the Ca2+‐loading. With application of dibutyryl‐cyclic AMP (0.1 mm) during the Ca2+‐loading period, the loading duration required for the restoration of the maximum NA‐response was shortened. Cyclopiazonic acid (10 μm, an inhibitor of Ca2+‐ATPase at intracellular storage sites) attenuated the inhibitory action of dibutyryl‐cyclic AMP on the NA‐induced increase in [Ca2+]i in Ca2+‐free solution. When NA (10 μm) was applied twice for 30 s with a 10 min interval in Ca2+‐free solution, the amplitude of response to the second application was about one third of the first response. With application of 0.1 mm dibutyryl‐cyclic AMP during the first application of NA, the increase in [Ca2+]i induced by the first application of NA was inhibited, but the response induced by the second was enhanced. These results suggest that dibutyryl‐cyclic AMP enhances Ca2+ uptake into the NA‐sensitive storage sites. We conclude that, in smooth muscle of the rabbit mesenteric artery, agents that increase cyclic AMP inhibit the NA‐induced increase in [Ca2+]i through an activation of Ca2+ uptake into the cellular storage sites. 1993 British Pharmacological Society

AB - Effects were studied of 6‐(3‐dimethylaminopropionyl) forskolin (NKH477), a water‐soluble forskolin derivative and of dibutyryl‐cyclic AMP, a membrane‐permeable cyclic AMP analogue on noradrenaline (NA)‐induced Ca2+ mobilization in smooth muscle strips of the rabbit mesenteric artery. The intracellular concentration of Ca2+ ([Ca2+]i), isometric force and cellular concentration of inositol 1,4,5‐trisphosphate (InsP3) were measured. NA (10 μm) produced a phasic, followed by a tonic increase in both [Ca2+]i and force in a solution containing 2.6 mm Ca2+. NKH477 (0.01–0.3 μm) attenuated the phasic and the tonic increases in both [Ca2+]i and force induced by 10 μm NA, in a concentration‐dependent manner. In Ca2+‐free solution containing 2 mm EGTA with 5.9 mm K+, NA (10 μm) produced only phasic increases in [Ca2+]i and force. NKH477 (0.01 μm) and dibutyryl‐cyclic AMP (0.1 mm) each greatly inhibited these increases. NA (10 μm) led to the production of InsP3 in intact smooth muscle strips and InsP3 (10 μm) increased Ca2+ in Ca2+‐free solution after a brief application of Ca2+ in β‐escin‐skinned smooth muscle strips. NKH477 (0.01 μm) or dibutyryl‐cyclic AMP (0.1 mm) modified neither the NA‐induced synthesis of InsP3 in intact muscle strips nor the InsP3‐induced Ca2+ release in skinned strips. In Ca2+‐free solution, high K+ (40 and 128 mm) itself failed to increase [Ca2+]i but concentration‐dependently enhanced the amplitude of the increase in [Ca2+]i induced by 10 μm NA with a parallel enhancement of the maximum rate of rise. The extent of the inhibition induced by NKH477 (0.01 μm) or dibutyryl‐cyclic AMP (0.1 mm) on the NA‐induced [Ca2+]i increase was inversely related to the maximum rate of rise of [Ca2+]i induced by NA in Ca2+‐free solution containing various concentrations of K+. These results suggest that the increase in the rate of Ca2+ release induced by NA can conceal the inhibitory action on NA‐induced Ca2+ mobilization of agents that increase cyclic AMP. Repetitive application of 10 μm NA in Ca2+‐free solution led to a disappearance of the NA‐induced increase in [Ca2+]i, but NA could again increase [Ca2+]i in Ca2+‐free solution after a brief application of Ca2+ with 40 mm K+ (‘Ca2+‐loading’). The magnitude of this NA‐induced increase in [Ca2+]i depended on the duration of the Ca2+‐loading. With application of dibutyryl‐cyclic AMP (0.1 mm) during the Ca2+‐loading period, the loading duration required for the restoration of the maximum NA‐response was shortened. Cyclopiazonic acid (10 μm, an inhibitor of Ca2+‐ATPase at intracellular storage sites) attenuated the inhibitory action of dibutyryl‐cyclic AMP on the NA‐induced increase in [Ca2+]i in Ca2+‐free solution. When NA (10 μm) was applied twice for 30 s with a 10 min interval in Ca2+‐free solution, the amplitude of response to the second application was about one third of the first response. With application of 0.1 mm dibutyryl‐cyclic AMP during the first application of NA, the increase in [Ca2+]i induced by the first application of NA was inhibited, but the response induced by the second was enhanced. These results suggest that dibutyryl‐cyclic AMP enhances Ca2+ uptake into the NA‐sensitive storage sites. We conclude that, in smooth muscle of the rabbit mesenteric artery, agents that increase cyclic AMP inhibit the NA‐induced increase in [Ca2+]i through an activation of Ca2+ uptake into the cellular storage sites. 1993 British Pharmacological Society

UR - http://www.scopus.com/inward/record.url?scp=0027138851&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027138851&partnerID=8YFLogxK

U2 - 10.1111/j.1476-5381.1993.tb13930.x

DO - 10.1111/j.1476-5381.1993.tb13930.x

M3 - Article

VL - 110

SP - 1117

EP - 1125

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 3

ER -