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Effects of tolbutamide on ATP-sensitive K+ channels from human right atrial cardiac myocytes
B J Zünkler1, B Henning, T Ott
1Federal Institute for Drugs and Medical Devices, Berlin, Germany.
Abstract:
In order to gain further insight into possible deleterious effects on ischaemia-induced myocardial damage induced by sulfonylureas when administered to humans, the effects of tolbutamide on ATP-sensitive K+ (KATP) channels from human right atrial myocytes were studied. Single myocytes were enzymatically isolated from human right atrium. The cell-attached and inside-out configuration of the patch-clamp technique were employed at room temperature (both the pipette and the bath solution contained high [K+]). KATP channels in inside-out patches showed slight inward rectification, had a slope conductance of 75.1 +/- 2.4 pS (mean +/- S.E.M.; n = 5) at negative membrane potentials and these channels were blocked by ATP (half-maximal block (EC50) at 39 microM; Hill coefficient = 1.65). In cell-attached recordings, cromakalim (300 microM) opened KATP channels (with a slope conductance of 73.3 +/- 1.8 pS (n = 16) at negative membrane potentials) in previously silent patches. Cromakalim-induced openings of KATP channels were not markedly affected by 100 or 300 microM tolbutamide but were blocked by tolbutamide at millimolar concentrations (1-3 mM). The concentration-response relationship for tolbutamide-induced block of KATP channels in the presence of 300 microM cromakalim in cell-attached patches was calculated to values for the EC50 of 1.325 mM and for the Hill coefficient of 1.0, respectively. 1 mM tolbutamide-induced block of cromakalim-induced KATP channel openings was not different at room temperature when compared to 37 degrees. It is concluded that KATP channels from human right atrial myocytes have a low sensitivity towards tolbutamide-induced block.
Insights
Sulfonylureas like tolbutamide have low sensitivity for blocking ATP-sensitive potassium (KATP) channels in human heart cells. This suggests minimal risk of ischemia-induced myocardial damage from these drugs in humans.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Pharmacology
Background:
- Sulfonylureas are commonly prescribed medications.
- Potential deleterious effects on myocardial damage during ischemia are a concern.
- ATP-sensitive potassium (KATP) channels play a crucial role in cardiac function and protection.
Purpose of the Study:
- To investigate the effects of tolbutamide on ATP-sensitive potassium (KATP) channels in human atrial myocytes.
- To assess the potential for tolbutamide to induce myocardial damage via KATP channel interaction.
Main Methods:
- Human right atrial myocytes were enzymatically isolated.
- Patch-clamp techniques (cell-attached and inside-out configurations) were used.
- The effects of tolbutamide and cromakalim on KATP channel activity were measured.
Main Results:
- KATP channels exhibited inward rectification and were blocked by ATP.
- Cromakalim activated KATP channels.
- Tolbutamide showed low sensitivity for blocking KATP channels, requiring millimolar concentrations for significant block.
Conclusions:
- Human atrial KATP channels have a low sensitivity to tolbutamide-induced block.
- This suggests a limited direct detrimental effect of tolbutamide on these channels in the context of ischemia-induced damage.