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Acta Physiologica 2012; Volume 206, Supplement 693
Joint FEPS and Spanish Physiological Society Scientific Congress 2012
9/8/2012-9/11/2012
Santiago de Compostela, Spain
VASODILATION OF MICROVESSELS BY THE AMP-ACTIVATED PROTEIN KINASE (AMPK) INVOLVES REDUCTION OF SMOOTH MUSCLE CALCIUM SENSITIVITY AND ACTIVATION OF BKCA CHANNELS
Abstract number: O480
Schubert1 KM, Wiedenmann1 M, Mederos y Schnitzler2 M, Gudermann2 T, Pohl3 U
1Ludwig-Maximilians-University of Munich, Walter-Brendel-Centre for Experimental Medicine,
2Ludwig-Maximilians University of Munich, Walther-Straub-Institute of Pharmacology and Toxicology,
3Ludwig-Maximilians University of Munich, Walter-Brendel-Centre for Experimental Medicine
Objectives:
Adequate organ function requires the continuous matching of blood supply with metabolism. The energy-sensing heterotrimeric enzyme AMPK plays a key role in regulating energy metabolism and may therefore be also a potential regulator of resistance vessel tone. Thus we studied a potential vasomotor function of AMPK in microvessels.
Materials:
Studies were conducted in microvessels (hamster and mouse) using cannulated segments, as well as in freshly isolated smooth muscle cells. In the vessels, pre-treated with the COX-inhibitor indomethacin and the NOS-inhibitor L-NAME, we measured simultaneously smooth muscle intracellular calcium levels [Ca2+]i (FURA2-AM) and vascular diameters. Conventional perforated patch-clamp recordings were carried out in the isolated cells.
Results:
In vessels pre-constricted with norepinephrine the AMPK-stimulators A76 (A769662) and PT-1 induced a dose-dependent vasodilation which was endothelium-independent. While PT-1 dilations were not associated with significant decreases of [Ca2+]i, dilations induced by higher concentrations (10mM-100M) of A76 went along with calcium-decreases.
In vessels pre-constricted by high extracellular potassium the vasodilations were diminished and the A76 induced [Ca2+]i-decrease abolished. Patch-clamp studies and pre-treatment of vessels with selective BKCa-inhibitors (paxilline, iberiotoxin) revealed activation of BKchannels by A76 and PT-1.
Further experiments to investigate the role of PT-1 and A76 on calcium-sensitivity showed a desensitisation of the contractile apparatus to [Ca2+]i. Incubation of microvessels with the myosin-light-chain-phosphatase inhibitor CalyculinA completely blocked the dilator effect of A76.
Conclusions:
AMPK activation reduces calcium sensitivity of the contractile machinery and augments BKchannel currents in smooth muscle. Both mechanisms play a role in microvascular vasodilation. Their relative contribution may vary dependent on AMPK subunit stimulation or different subunit composition of the heterorimeric AMPK.
To cite this abstract, please use the following information:
Acta Physiologica 2012; Volume 206, Supplement 693 :O480