Knockout of Na+/Ca2+ exchanger in smooth muscle attenuates vasoconstriction and L-type Ca2+ channel current and lowers blood pressure.
Enviado por Manuel F Navedo el
Título | Knockout of Na+/Ca2+ exchanger in smooth muscle attenuates vasoconstriction and L-type Ca2+ channel current and lowers blood pressure. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Autores | Zhang, J, Ren, C, Chen, L, Navedo, MF, Antos, LK, Kinsey, SP, Iwamoto, T, Philipson, KD, Kotlikoff, MI, Santana, LF, W Wier, G, Matteson, DR, Blaustein, MP |
Journal | Am J Physiol Heart Circ Physiol |
Volume | 298 |
Issue | 5 |
Pagination | H1472-83 |
Date Published | 2010 May |
ISSN | 1522-1539 |
Palabras clave | 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester, Aniline Compounds, Animals, Arteries, Blood Pressure, Blotting, Western, Calcium Channel Agonists, Calcium Channels, L-Type, Calcium Signaling, Electrophysiology, Green Fluorescent Proteins, Indicators and Reagents, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle Tonus, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Patch-Clamp Techniques, Phenyl Ethers, Sodium-Calcium Exchanger, Telemetry, Vasoconstriction |
Abstract | Mice with smooth muscle (SM)-specific knockout of Na(+)/Ca(2+) exchanger type-1 (NCX1(SM-/-)) and the NCX inhibitor, SEA0400, were used to study the physiological role of NCX1 in mouse mesenteric arteries. NCX1 protein expression was greatly reduced in arteries from NCX1(SM-/-) mice generated with Cre recombinase. Mean blood pressure (BP) was 6-10 mmHg lower in NCX1(SM-/-) mice than in wild-type (WT) controls. Vasoconstriction was studied in isolated, pressurized mesenteric small arteries from WT and NCX1(SM-/-) mice and in heterozygotes with a global null mutation (NCX1(Fx/-)). Reduced NCX1 activity was manifested by a marked attenuation of responses to low extracellular Na(+) concentration, nanomolar ouabain, and SEA0400. Myogenic tone (MT, 70 mmHg) was reduced by approximately 15% in NCX1(SM-/-) arteries and, to a similar extent, by SEA0400 in WT arteries. MT was normal in arteries from NCX1(Fx/-) mice, which had normal BP. Vasoconstrictions to phenylephrine and elevated extracellular K(+) concentration were significantly reduced in NCX1(SM-/-) arteries. Because a high extracellular K(+) concentration-induced vasoconstriction involves the activation of L-type voltage-gated Ca(2+) channels (LVGCs), we measured LVGC-mediated currents and Ca(2+) sparklets in isolated mesenteric artery myocytes. Both the currents and the sparklets were significantly reduced in NCX1(SM-/-) (vs. WT or NCX1(Fx/-)) myocytes, but the voltage-dependent inactivation of LVGCs was not augmented. An acute application of SEA0400 in WT myocytes had no effect on LVGC current. The LVGC agonist, Bay K 8644, eliminated the differences in LVGC currents and Ca(2+) sparklets between NCX1(SM-/-) and control myocytes, suggesting that LVGC expression was normal in NCX1(SM-/-) myocytes. Bay K 8644 did not, however, eliminate the difference in myogenic constriction between WT and NCX1(SM-/-) arteries. We conclude that, under physiological conditions, NCX1-mediated Ca(2+) entry contributes significantly to the maintenance of MT. In NCX1(SM-/-) mouse artery myocytes, the reduced Ca(2+) entry via NCX1 may lower cytosolic Ca(2+) concentration and thereby reduce MT and BP. The reduced LVGC activity may be the consequence of a low cytosolic Ca(2+) concentration. |
DOI | 10.1152/ajpheart.00964.2009 |
Alternate Journal | Am. J. Physiol. Heart Circ. Physiol. |
PubMed ID | 20173044 |
PubMed Central ID | PMC2867439 |