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Published on: September 14, 2012
TRPM4 inhibitor 9-phenanthrol activates endothelial cell intermediate conductance calcium-activated potassium
C J Garland1, S V Smirnov, P Bagher
1Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, UK.
Background And Purpose:
Smooth muscle transient receptor potential melastatin 4 (TRPM4) channels play a fundamental role in the development of the myogenic arterial constriction that is necessary for blood flow autoregulation. As TRPM4 channels are present throughout the vasculature, we investigated their potential role in non-myogenic resistance arteries using the TRPM4 inhibitor 9-phenanthrol.
Experimental Approach:
Pressure and wire myography were used to assess the reactivity of rat arteries, the latter in combination with measurements of smooth muscle membrane potential. Immunohistochemistry (IHC) and endothelial cell (EC) calcium changes were assessed in pressurized vessels and patch clamp measurements made in isolated ECs.
Key Results:
The TRPM4 inhibitor 9-phenanthrol reversibly hyperpolarized mesenteric arteries to circa EK and blocked α1 -adrenoceptor-mediated vasoconstriction. Hyperpolarization was abolished and vasoconstriction re-established by damaging the endothelium. In mesenteric and cerebral artery smooth muscle, 9-phenanthrol hyperpolarization was effectively blocked by the KCa 3.1 inhibitor TRAM-34. 9-Phenanthrol did not increase mesenteric EC [Ca(2+)]i , and Na(+) substitution with N-methyl-D-glucamine only increased the muscle resting potential by 10 mV. Immunolabelling for TRPM4 was restricted to the endothelium and perivascular tissue.
Conclusions And Implications:
These data reveal a previously unrecognized action of the TRPM4 inhibitor 9-phenanthrol - the ability to act as an activator of EC KCa 3.1 channels. They do not indicate a functionally important role for TRPM4 channels in the reactivity of non-myogenic mesenteric arteries.
Insights
The TRPM4 inhibitor 9-phenanthrol activates endothelial KCa 3.1 channels, not TRPM4 channels, in mesenteric arteries. This study reveals a new role for 9-phenanthrol in vascular reactivity.
Area of Science:
- Vascular physiology
- Ion channel function
- Smooth muscle biology
Background:
- Transient receptor potential melastatin 4 (TRPM4) channels are crucial for myogenic arterial constriction and blood flow autoregulation.
- TRPM4 channels are expressed throughout the vasculature, suggesting potential roles in various artery types.
Purpose of the Study:
- To investigate the role of TRPM4 channels in non-myogenic resistance arteries using the TRPM4 inhibitor 9-phenanthrol.
- To elucidate the mechanism of action of 9-phenanthrol in vascular smooth muscle and endothelial cells.
Main Methods:
- Utilized pressure and wire myography to assess rat artery reactivity and smooth muscle membrane potential.
- Employed immunohistochemistry (IHC), endothelial cell (EC) calcium imaging, and patch clamp electrophysiology.
- Investigated the effects of 9-phenanthrol and KCa 3.1 inhibitor TRAM-34.
Main Results:
- 9-Phenanthrol hyperpolarized mesenteric arteries and blocked α1-adrenoceptor-mediated vasoconstriction, effects abolished by endothelial damage.
- Endothelial KCa 3.1 channels, not TRPM4, mediated the hyperpolarization effect of 9-phenanthrol.
- TRPM4 immunolabeling was localized to the endothelium and perivascular tissue, not smooth muscle.
Conclusions:
- The TRPM4 inhibitor 9-phenanthrol activates endothelial KCa 3.1 channels, a previously unrecognized action.
- TRPM4 channels do not appear to play a functionally significant role in the reactivity of non-myogenic mesenteric arteries.
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