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The new antihypertensive drug iptakalim activates ATP-sensitive potassium channels in the endothelium of resistance blood vessels.

Wang SY, Cui WY, Wang H - Acta Pharmacol. Sin. (2015)

Bottom Line: Application of iptakalim (10 and 100 μmol/L) significantly increased the whole-cell K(ATP) currents, which were prevented by the specific K(ATP) blocker glibenclamide (1.0 μmol/L).The opening of K(ATP) channels by iptakalim depended upon the intracellular concentrations of ATP or NDPs: iptakalim activated K(ATP) channels when the intracellular ATP or NDPs were at 100 or 1000 μmol/L, and was ineffective when the non-hydrolysable ATP analogue ATPγS (1000 μmol/L) was infused into the cells.Iptakalim activates K(ATP) channels in the endothelial cells of resistance blood vessels with a low metabolic status, and this activation is dependent on both ATP hydrolysis and ATP ligands.

View Article: PubMed Central - PubMed

Affiliation: Department of Environment and Pharmacy, Tianjin Institute of Health and Environmental Medicine, Beijing 100850, China.

ABSTRACT

Aim: To investigate the mechanisms underlying the activation of ATP-sensitive potassium channels (K(ATP)) by iptakalim in cultured rat mesenteric microvascular endothelial cells (MVECs).

Methods: Whole-cell KATP currents were recorded in MVECs using automated patch clamp devices. Nucleotides (ATP, ADP and UDP) were added to the internal perfusion system, whereas other drugs were added to the cell suspension on NPC-1 borosilicate glass chips.

Results: Application of iptakalim (10 and 100 μmol/L) significantly increased the whole-cell K(ATP) currents, which were prevented by the specific K(ATP) blocker glibenclamide (1.0 μmol/L). The opening of K(ATP) channels by iptakalim depended upon the intracellular concentrations of ATP or NDPs: iptakalim activated K(ATP) channels when the intracellular ATP or NDPs were at 100 or 1000 μmol/L, and was ineffective when the non-hydrolysable ATP analogue ATPγS (1000 μmol/L) was infused into the cells. In contrast, the K(ATP) opener pinacidil activated K(ATP) channels when the intracellular concentrations of ATP or NDPs ranged from 10 to 5000 μmol/L, and even ATPγS (1000 μmol/L) was infused into the cells.

Conclusion: Iptakalim activates K(ATP) channels in the endothelial cells of resistance blood vessels with a low metabolic status, and this activation is dependent on both ATP hydrolysis and ATP ligands.

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Related in: MedlinePlus

Modulation of the KATP opening effects of iptakalim and pinacidil in microvascular endothelial cells (MVECs) by nucleotides. The KATP currents were recorded in MVECs with a membrane potential of −100 mV. Cells were incubated with 100 μmol/L iptakalim (Ipt) or pinacidil (Pin) and nucleotides (ATP, ADP or UDP) at concentrations ranging from 10 to 3000 or 5000 μmol/L. n=8. cP<0.01 vs control.
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fig2: Modulation of the KATP opening effects of iptakalim and pinacidil in microvascular endothelial cells (MVECs) by nucleotides. The KATP currents were recorded in MVECs with a membrane potential of −100 mV. Cells were incubated with 100 μmol/L iptakalim (Ipt) or pinacidil (Pin) and nucleotides (ATP, ADP or UDP) at concentrations ranging from 10 to 3000 or 5000 μmol/L. n=8. cP<0.01 vs control.

Mentions: The modulatory effects of intracellular ATP on the channel-opening ability of 100 μmol/L iptakalim or 100 μmol/L pinacidil were investigated. Intracellular ATP was added at 10, 100, 1000, 3000, or 5000 μmol/L, and the resultant current amplitudes were 92.42%±1.48%, 100.67%±3.87%, 83.1%±0.55%, 74.08%±2.69% and 67.3%±2.02% of the control amplitude, respectively. These results suggest that MVEC whole-cell currents can be regulated by intracellular ATP. The channel-opening effects of iptakalim were observed in the presence of 100 or 1000 μmol/L ATP (P<0.01). However, iptakalim was not shown to activate KATP channels in the presence of 10, 3000 or 5000 μmol/L intracellular ATP (Figure 2A). Under the same experimental conditions, the opening effects of pinacidil were observed in the presence of 10 to 5000 μmol/L ATP (Figure 2B, P<0.01).


The new antihypertensive drug iptakalim activates ATP-sensitive potassium channels in the endothelium of resistance blood vessels.

Wang SY, Cui WY, Wang H - Acta Pharmacol. Sin. (2015)

Modulation of the KATP opening effects of iptakalim and pinacidil in microvascular endothelial cells (MVECs) by nucleotides. The KATP currents were recorded in MVECs with a membrane potential of −100 mV. Cells were incubated with 100 μmol/L iptakalim (Ipt) or pinacidil (Pin) and nucleotides (ATP, ADP or UDP) at concentrations ranging from 10 to 3000 or 5000 μmol/L. n=8. cP<0.01 vs control.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4816240&req=5

fig2: Modulation of the KATP opening effects of iptakalim and pinacidil in microvascular endothelial cells (MVECs) by nucleotides. The KATP currents were recorded in MVECs with a membrane potential of −100 mV. Cells were incubated with 100 μmol/L iptakalim (Ipt) or pinacidil (Pin) and nucleotides (ATP, ADP or UDP) at concentrations ranging from 10 to 3000 or 5000 μmol/L. n=8. cP<0.01 vs control.
Mentions: The modulatory effects of intracellular ATP on the channel-opening ability of 100 μmol/L iptakalim or 100 μmol/L pinacidil were investigated. Intracellular ATP was added at 10, 100, 1000, 3000, or 5000 μmol/L, and the resultant current amplitudes were 92.42%±1.48%, 100.67%±3.87%, 83.1%±0.55%, 74.08%±2.69% and 67.3%±2.02% of the control amplitude, respectively. These results suggest that MVEC whole-cell currents can be regulated by intracellular ATP. The channel-opening effects of iptakalim were observed in the presence of 100 or 1000 μmol/L ATP (P<0.01). However, iptakalim was not shown to activate KATP channels in the presence of 10, 3000 or 5000 μmol/L intracellular ATP (Figure 2A). Under the same experimental conditions, the opening effects of pinacidil were observed in the presence of 10 to 5000 μmol/L ATP (Figure 2B, P<0.01).

Bottom Line: Application of iptakalim (10 and 100 μmol/L) significantly increased the whole-cell K(ATP) currents, which were prevented by the specific K(ATP) blocker glibenclamide (1.0 μmol/L).The opening of K(ATP) channels by iptakalim depended upon the intracellular concentrations of ATP or NDPs: iptakalim activated K(ATP) channels when the intracellular ATP or NDPs were at 100 or 1000 μmol/L, and was ineffective when the non-hydrolysable ATP analogue ATPγS (1000 μmol/L) was infused into the cells.Iptakalim activates K(ATP) channels in the endothelial cells of resistance blood vessels with a low metabolic status, and this activation is dependent on both ATP hydrolysis and ATP ligands.

View Article: PubMed Central - PubMed

Affiliation: Department of Environment and Pharmacy, Tianjin Institute of Health and Environmental Medicine, Beijing 100850, China.

ABSTRACT

Aim: To investigate the mechanisms underlying the activation of ATP-sensitive potassium channels (K(ATP)) by iptakalim in cultured rat mesenteric microvascular endothelial cells (MVECs).

Methods: Whole-cell KATP currents were recorded in MVECs using automated patch clamp devices. Nucleotides (ATP, ADP and UDP) were added to the internal perfusion system, whereas other drugs were added to the cell suspension on NPC-1 borosilicate glass chips.

Results: Application of iptakalim (10 and 100 μmol/L) significantly increased the whole-cell K(ATP) currents, which were prevented by the specific K(ATP) blocker glibenclamide (1.0 μmol/L). The opening of K(ATP) channels by iptakalim depended upon the intracellular concentrations of ATP or NDPs: iptakalim activated K(ATP) channels when the intracellular ATP or NDPs were at 100 or 1000 μmol/L, and was ineffective when the non-hydrolysable ATP analogue ATPγS (1000 μmol/L) was infused into the cells. In contrast, the K(ATP) opener pinacidil activated K(ATP) channels when the intracellular concentrations of ATP or NDPs ranged from 10 to 5000 μmol/L, and even ATPγS (1000 μmol/L) was infused into the cells.

Conclusion: Iptakalim activates K(ATP) channels in the endothelial cells of resistance blood vessels with a low metabolic status, and this activation is dependent on both ATP hydrolysis and ATP ligands.

Show MeSH
Related in: MedlinePlus