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Novel PPARgamma agonists GI 262570, GW 7845, GW 1929, and pioglitazone decrease calcium channel function and myogenic
Thomas J Heppner1, Adrian D Bonev, Delrae M Eckman
1Department of Pharmacology, University of Vermont College of Medicine, Burlington, VT 05406-0068, USA.
Pharmacology
|September 29, 2004
Summary
Novel PPAR gamma agonists, including GSK compounds and pioglitazone, effectively inhibit voltage-dependent calcium channels (VDCC) and relax mesenteric arteries. This suggests calcium channel inhibition contributes to vasodilation in resistance arteries.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Molecular Biology
Background:
- Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are investigated for therapeutic potential.
- PPARγ agonists, including thiazolidinediones and novel tyrosine-derived compounds, modulate various cellular functions.
- Voltage-dependent calcium channels (VDCC) play a critical role in vascular smooth muscle contraction and blood pressure regulation.
Purpose of the Study:
- To investigate the effects of novel non-thiazolidinedione, tyrosine-derived PPARγ agonists (GI 262570, GW 7845, GW 1929) and pioglitazone on L-type VDCC.
- To determine the impact of these PPARγ agonists on the diameter of pressurized mesenteric arteries in vitro.
- To elucidate the potential mechanism of vasodilation induced by these compounds.
Main Methods:
- Electrophysiological recordings were used to measure currents through L-type VDCC in isolated smooth muscle cells from mesenteric arteries, using Ba2+ as the charge carrier.
- Pressurized mesenteric artery preparations were used to assess the effects of compounds on arterial diameter in vitro.
- Half-maximal inhibitory concentrations (IC50) were determined for each compound's effect on VDCC currents and arterial relaxation.
Main Results:
- Novel PPARγ agonists GI 262570, GW 7845, GW 1929, and pioglitazone demonstrated inhibitory effects on L-type VDCC.
- The IC50 values for VDCC inhibition were 2.0, 3.0, 5.0, and 10.0 µmol/l, respectively.
- These compounds also caused relaxation of pressurized mesenteric arteries with corresponding IC50 values of 2.4, 4.1, 6.3, and 13.9 µmol/l, indicating dose-dependent effects.
Conclusions:
- The studied GlaxoSmithKline (GSK) compounds and pioglitazone effectively inhibit VDCC in vascular smooth muscle cells.
- These PPARγ agonists induce vasodilation in resistance arteries, as evidenced by the relaxation of pressurized mesenteric arteries.
- The findings suggest that inhibition of calcium entry through VDCC is a key mechanism underlying the vasodilatory effects of these novel PPARγ agonists.