title: Regulation of vascular tone in animals overexpressing the sarcolemmal calcium pump.
abstract: 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.
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry, Versbacher Strasse 5, 97078 Wuerzburg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Schuh
authors.forename: Thomas
authors.initials: T
authors.lastname: Quaschning
authors.forename: Sebastian
authors.initials: S
authors.lastname: Knauer
authors.forename: Kai
authors.initials: K
authors.lastname: Hu
authors.forename: Serkan
authors.initials: S
authors.lastname: Kocak
authors.forename: Nicola
authors.initials: N
authors.lastname: Roethlein
authors.forename: Ludwig
authors.initials: L
authors.lastname: Neyses
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D027682:Cation Transport Proteins; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D009130:Muscle, Smooth / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D053499:Plasma Membrane Calcium-Transporting ATPases; D011189:Potassium Chloride / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012508:Sarcolemma / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution; D019076:Transgenes; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D002147:Calmodulin; D027682:Cation Transport Proteins; D012333:RNA, Messenger; D014665:Vasodilator Agents; D009599:Nitroprusside; D011189:Potassium Chloride; D019001:Nitric Oxide Synthase; D053499:Plasma Membrane Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D000109:Acetylcholine; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester