Dilator prostanoid-induced cyclic AMP formation and release by cerebral microvascular smooth muscle cells: Inhibition by indomethacin

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Abstract

The effect of indomethacin on dilator prostanoid receptor-mediated cAMP formation was investigated using primary cultures of vascular smooth muscle cells from the newborn pig cerebral microvessels. Cerebral microvascular smooth muscle cells responded to dilator prostanoids (iloprost > PGE2) by increasing cAMP formation and release in to the media (EC50 = 2 x 10-8 M and 2 x 10-7 M for iloprost and PGE2, respectively). Indomethacin inhibited iloprost- and PGE2-evoked increases in cAMP formation (IC50 = 10-4 M) and release (IC50 = 10-6 M) by microvascular smooth muscle cells (maximal inhibition 80-90%), whereas isoproterenol-induced cAMP formation was only slightly attenuated at the highest concentration of indomethacin used (10-3 M). Aspirin was much less effective in inhibiting dilator prostanoid-induced cAMP formation and release by the cells. Direct analysis of prostacyclin receptor sites using [3H]iloprost as the ligand revealed saturable, high affinity (ED50 = 2 x 10-8 M) and reversible binding to the membranes isolated from cerebrovascular smooth muscle cells. Indomethacin dose-dependently inhibited [3H]iloprost receptor binding (ID50 = 10-4 M; maximal inhibition, 70%). The present data suggest that combination of highly effective inhibition of prostaglandin H synthase and receptor binding resulting in inhibition of dilator prostanoid-mediated cAMP formation in target cells may contribute to the increased efficacy of indomethacin compared with other prostaglandin H synthase inhibitors in blocking certain vasodilator responses associated with prostanoids.

Original languageEnglish (US)
Pages (from-to)44-52
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume272
Issue number1
StatePublished - Jan 1 1995

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Iloprost
Indomethacin
Cyclic AMP
Prostaglandins
Smooth Muscle Myocytes
Prostaglandin-Endoperoxide Synthases
Dinoprostone
Inhibitory Concentration 50
Epoprostenol Receptors
Cyclic AMP Receptors
Prostaglandin Receptors
Cyclooxygenase Inhibitors
Microvessels
Vasodilator Agents
Vascular Smooth Muscle
Isoproterenol
Aspirin
Swine
Ligands
Membranes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "Dilator prostanoid-induced cyclic AMP formation and release by cerebral microvascular smooth muscle cells: Inhibition by indomethacin",
abstract = "The effect of indomethacin on dilator prostanoid receptor-mediated cAMP formation was investigated using primary cultures of vascular smooth muscle cells from the newborn pig cerebral microvessels. Cerebral microvascular smooth muscle cells responded to dilator prostanoids (iloprost > PGE2) by increasing cAMP formation and release in to the media (EC50 = 2 x 10-8 M and 2 x 10-7 M for iloprost and PGE2, respectively). Indomethacin inhibited iloprost- and PGE2-evoked increases in cAMP formation (IC50 = 10-4 M) and release (IC50 = 10-6 M) by microvascular smooth muscle cells (maximal inhibition 80-90{\%}), whereas isoproterenol-induced cAMP formation was only slightly attenuated at the highest concentration of indomethacin used (10-3 M). Aspirin was much less effective in inhibiting dilator prostanoid-induced cAMP formation and release by the cells. Direct analysis of prostacyclin receptor sites using [3H]iloprost as the ligand revealed saturable, high affinity (ED50 = 2 x 10-8 M) and reversible binding to the membranes isolated from cerebrovascular smooth muscle cells. Indomethacin dose-dependently inhibited [3H]iloprost receptor binding (ID50 = 10-4 M; maximal inhibition, 70{\%}). The present data suggest that combination of highly effective inhibition of prostaglandin H synthase and receptor binding resulting in inhibition of dilator prostanoid-mediated cAMP formation in target cells may contribute to the increased efficacy of indomethacin compared with other prostaglandin H synthase inhibitors in blocking certain vasodilator responses associated with prostanoids.",
author = "Elena Parfenova and P. Hsu and Charles Leffler",
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T1 - Dilator prostanoid-induced cyclic AMP formation and release by cerebral microvascular smooth muscle cells

T2 - Inhibition by indomethacin

AU - Parfenova, Elena

AU - Hsu, P.

AU - Leffler, Charles

PY - 1995/1/1

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N2 - The effect of indomethacin on dilator prostanoid receptor-mediated cAMP formation was investigated using primary cultures of vascular smooth muscle cells from the newborn pig cerebral microvessels. Cerebral microvascular smooth muscle cells responded to dilator prostanoids (iloprost > PGE2) by increasing cAMP formation and release in to the media (EC50 = 2 x 10-8 M and 2 x 10-7 M for iloprost and PGE2, respectively). Indomethacin inhibited iloprost- and PGE2-evoked increases in cAMP formation (IC50 = 10-4 M) and release (IC50 = 10-6 M) by microvascular smooth muscle cells (maximal inhibition 80-90%), whereas isoproterenol-induced cAMP formation was only slightly attenuated at the highest concentration of indomethacin used (10-3 M). Aspirin was much less effective in inhibiting dilator prostanoid-induced cAMP formation and release by the cells. Direct analysis of prostacyclin receptor sites using [3H]iloprost as the ligand revealed saturable, high affinity (ED50 = 2 x 10-8 M) and reversible binding to the membranes isolated from cerebrovascular smooth muscle cells. Indomethacin dose-dependently inhibited [3H]iloprost receptor binding (ID50 = 10-4 M; maximal inhibition, 70%). The present data suggest that combination of highly effective inhibition of prostaglandin H synthase and receptor binding resulting in inhibition of dilator prostanoid-mediated cAMP formation in target cells may contribute to the increased efficacy of indomethacin compared with other prostaglandin H synthase inhibitors in blocking certain vasodilator responses associated with prostanoids.

AB - The effect of indomethacin on dilator prostanoid receptor-mediated cAMP formation was investigated using primary cultures of vascular smooth muscle cells from the newborn pig cerebral microvessels. Cerebral microvascular smooth muscle cells responded to dilator prostanoids (iloprost > PGE2) by increasing cAMP formation and release in to the media (EC50 = 2 x 10-8 M and 2 x 10-7 M for iloprost and PGE2, respectively). Indomethacin inhibited iloprost- and PGE2-evoked increases in cAMP formation (IC50 = 10-4 M) and release (IC50 = 10-6 M) by microvascular smooth muscle cells (maximal inhibition 80-90%), whereas isoproterenol-induced cAMP formation was only slightly attenuated at the highest concentration of indomethacin used (10-3 M). Aspirin was much less effective in inhibiting dilator prostanoid-induced cAMP formation and release by the cells. Direct analysis of prostacyclin receptor sites using [3H]iloprost as the ligand revealed saturable, high affinity (ED50 = 2 x 10-8 M) and reversible binding to the membranes isolated from cerebrovascular smooth muscle cells. Indomethacin dose-dependently inhibited [3H]iloprost receptor binding (ID50 = 10-4 M; maximal inhibition, 70%). The present data suggest that combination of highly effective inhibition of prostaglandin H synthase and receptor binding resulting in inhibition of dilator prostanoid-mediated cAMP formation in target cells may contribute to the increased efficacy of indomethacin compared with other prostaglandin H synthase inhibitors in blocking certain vasodilator responses associated with prostanoids.

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