Regulation of vascular tone in animals overexpressing the sarcolemmal calcium pump.
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.
Schuh
Kai
K
Institute of Clinical Biochemistry and Pathobiochemistry, Versbacher Strasse 5, 97078 Wuerzburg, Germany.
Quaschning
Thomas
T
Knauer
Sebastian
S
Hu
Kai
K
Kocak
Serkan
S
Roethlein
Nicola
N
Neyses
Ludwig
L
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
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