Article (Scientific journals)
Regulation of vascular tone in animals overexpressing the sarcolemmal calcium pump.
Schuh, Kai; Quaschning, Thomas; Knauer, Sebastian et al.
2003In The Journal of biological chemistry, 278 (42), p. 41246-52
Peer reviewed
 

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Keywords :
Acetylcholine/pharmacology; Animals; Aorta/drug effects; Blood Pressure; Calcium/metabolism; Calcium-Transporting ATPases/metabolism; Calmodulin/metabolism; Cation Transport Proteins; Cytosol/metabolism; Dose-Response Relationship, Drug; Hemodynamics; Humans; Mice; Mice, Knockout; Mice, Transgenic; Models, Genetic; Muscle, Smooth/metabolism; NG-Nitroarginine Methyl Ester/pharmacology; Nitric Oxide Synthase/antagonists & inhibitors; Nitroprusside/pharmacology; Plasma Membrane Calcium-Transporting ATPases; Potassium Chloride/pharmacology; Promoter Regions, Genetic; RNA, Messenger/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Sarcolemma/metabolism; Time Factors; Tissue Distribution; Transgenes; Vasodilator Agents/pharmacology
Abstract :
[en] The mechanisms governing vascular smooth muscle tone are incompletely understood. In particular, the role of the sarcolemmal calcium pump PMCA (plasma membrane calmodulin-dependent calcium ATPase), which extrudes Ca2+ from the cytosol, and its importance compared with the sodium/calcium exchanger remain speculative. To test whether the PMCA is a regulator of vascular tone, we generated transgenic mice overexpressing the human PMCA4b under control of the arterial smooth muscle-specific SM22alpha promoter. This resulted in an elevated systolic blood pressure compared with littermate controls. In PMCA-overexpressing mice, endothelium-dependent relaxation of norepinephrine-preconstricted aortic rings to acetylcholine did not differ from wild type controls (76 +/- 8% versus 79 +/- 8% of maximum relaxation; n = 12, n.s.). De-endothelialized aortas of transgenic mice exhibited stronger maximum contraction to KCl (100 mmol/liter) compared with controls (86 +/- 6% versus 68 +/- 7% of reference KCl contraction at the beginning of the experiment; p <0.05). Preincubation of de-endothelialized vessels with the nitric oxide synthase (NOS) inhibitor l-NAME (l-N(G)-nitroarginine methyl ester) (10-5 mol/liter) resulted in a stronger contraction to KCl (p <0.05 versus without l-NAME), thus unmasking vasodilatory effects of inherent NO production. Maximum contraction to KCl after preincubation with l-NAME did not differ between PMCA mice and controls. In analogy to the results in PMCA-overexpressing mice, contractions of de-endothelialized aortas of neuronal NOS-deficient mice to KCl were significantly increased compared with controls (151 +/- 5% versus 131 +/- 6% of reference KCl contraction; p <0.05). In conclusion, our data suggest a model in which the sarcolemmal Ca2+ pump down-regulates activity of the vascular smooth muscle Ca2+/calmodulin-dependent neuronal NOS by a functionally relevant interaction. Therefore, the PMCA represents a novel regulator of vascular tone.
Disciplines :
Cardiovascular & respiratory systems
Author, co-author :
Schuh, Kai
Quaschning, Thomas
Knauer, Sebastian
Hu, Kai
Kocak, Serkan
Roethlein, Nicola
Neyses, Ludwig ;  University of Luxembourg > Research Office
Language :
English
Title :
Regulation of vascular tone in animals overexpressing the sarcolemmal calcium pump.
Publication date :
2003
Journal title :
The Journal of biological chemistry
ISSN :
0021-9258
Volume :
278
Issue :
42
Pages :
41246-52
Peer reviewed :
Peer reviewed
Available on ORBilu :
since 16 October 2014

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