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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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Effects of iptakalim on the KATP currents of microvascular endothelial cells (MVECs). The effects of iptakalim (Ipt) on the KATP currents of MVECs were tested using whole-cell recordings with a membrane potential of −100 mV. Cells were incubated with 1.0–100 μmol/L Ipt, and 1000 μmol/L of a nucleotide (ATP, ADP, or UDP) was given by internal perfusion. The whole-cell currents increased significantly with 10 or 100 μmol/L Ipt in the presence of 1000 μmol/L ATP (A), ADP (B), or UDP (C). The effect was reversed with 1.0 μmol/L glibenclamide (Gli). bP<0.05, cP<0.01 vs ATP, ADP, or UDP group. fP<0.01 vs 100 μmol/L Ipt group (n=8). (D) Typical recordings showed the activation of KATP channels by Ipt.
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fig1: Effects of iptakalim on the KATP currents of microvascular endothelial cells (MVECs). The effects of iptakalim (Ipt) on the KATP currents of MVECs were tested using whole-cell recordings with a membrane potential of −100 mV. Cells were incubated with 1.0–100 μmol/L Ipt, and 1000 μmol/L of a nucleotide (ATP, ADP, or UDP) was given by internal perfusion. The whole-cell currents increased significantly with 10 or 100 μmol/L Ipt in the presence of 1000 μmol/L ATP (A), ADP (B), or UDP (C). The effect was reversed with 1.0 μmol/L glibenclamide (Gli). bP<0.05, cP<0.01 vs ATP, ADP, or UDP group. fP<0.01 vs 100 μmol/L Ipt group (n=8). (D) Typical recordings showed the activation of KATP channels by Ipt.

Mentions: The KATP currents of MVECs were recorded by whole-cell patch clamp with a membrane potential of −100 mV (Figure 1). Whole-cell currents were suppressed by application of 1000 μmol/L intracellular ATP. These currents were enhanced with 1000 μmol/L intracellular ADP or UDP. This result indicates that the toggled channels were in fact KATP channels. In the presence of 1 mmol/L of ATP, ADP, or UDP, 1.0−100 μmol/L iptakalim increases the whole-cell currents. This can be prevented by application of 1.0 μmol/L glibenclamide, a specific KATP blocker. The currents of the control groups, in the presence of only 1000 μmol/L of ATP, ADP, or UDP, also decreased with application of 1.0 μmol/L glibenclamide. The currents decreased by a similar amount to that in groups treated with 100 μmol/L iptakalim, which suggests that the iptakalim-induced currents were completely blocked by 1.0 μmol/L glibenclamide.


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)

Effects of iptakalim on the KATP currents of microvascular endothelial cells (MVECs). The effects of iptakalim (Ipt) on the KATP currents of MVECs were tested using whole-cell recordings with a membrane potential of −100 mV. Cells were incubated with 1.0–100 μmol/L Ipt, and 1000 μmol/L of a nucleotide (ATP, ADP, or UDP) was given by internal perfusion. The whole-cell currents increased significantly with 10 or 100 μmol/L Ipt in the presence of 1000 μmol/L ATP (A), ADP (B), or UDP (C). The effect was reversed with 1.0 μmol/L glibenclamide (Gli). bP<0.05, cP<0.01 vs ATP, ADP, or UDP group. fP<0.01 vs 100 μmol/L Ipt group (n=8). (D) Typical recordings showed the activation of KATP channels by Ipt.
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Related In: Results  -  Collection

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fig1: Effects of iptakalim on the KATP currents of microvascular endothelial cells (MVECs). The effects of iptakalim (Ipt) on the KATP currents of MVECs were tested using whole-cell recordings with a membrane potential of −100 mV. Cells were incubated with 1.0–100 μmol/L Ipt, and 1000 μmol/L of a nucleotide (ATP, ADP, or UDP) was given by internal perfusion. The whole-cell currents increased significantly with 10 or 100 μmol/L Ipt in the presence of 1000 μmol/L ATP (A), ADP (B), or UDP (C). The effect was reversed with 1.0 μmol/L glibenclamide (Gli). bP<0.05, cP<0.01 vs ATP, ADP, or UDP group. fP<0.01 vs 100 μmol/L Ipt group (n=8). (D) Typical recordings showed the activation of KATP channels by Ipt.
Mentions: The KATP currents of MVECs were recorded by whole-cell patch clamp with a membrane potential of −100 mV (Figure 1). Whole-cell currents were suppressed by application of 1000 μmol/L intracellular ATP. These currents were enhanced with 1000 μmol/L intracellular ADP or UDP. This result indicates that the toggled channels were in fact KATP channels. In the presence of 1 mmol/L of ATP, ADP, or UDP, 1.0−100 μmol/L iptakalim increases the whole-cell currents. This can be prevented by application of 1.0 μmol/L glibenclamide, a specific KATP blocker. The currents of the control groups, in the presence of only 1000 μmol/L of ATP, ADP, or UDP, also decreased with application of 1.0 μmol/L glibenclamide. The currents decreased by a similar amount to that in groups treated with 100 μmol/L iptakalim, which suggests that the iptakalim-induced currents were completely blocked by 1.0 μmol/L glibenclamide.

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