Knockout of Na+/Ca2+ exchanger in smooth muscle attenuates vasoconstriction and L-type Ca2+ channel current and lowers blood pressure

Jin Zhang, Chongyu Ren, Ling Chen, Manuel F Navedo, Laura K. Antos, Stephen P. Kinsey, Takahiro Iwamoto, Kenneth D. Philipson, Michael I. Kotlikoff, Luis Fernando Santana, W. Gil Wier, Donald R. Matteson, Mordecai P. Blaustein

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Mice with smooth muscle (SM)-specific knockout of Na+/Ca 2+ exchanger type-1 (NCX1SM-/-) 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 NCX1SM-/- mice than in wild-type (WT) controls. Vasoconstriction was studied in isolated, pressurized mesenteric small arteries from WT and NCX1SM-/- mice and in heterozygotes with a global null mutation (NCX1Fx/-). 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 ∼15% in NCX1SM-/- arteries and, to a similar extent, by SEA0400 in WT arteries. MT was normal in arteries from NCX1Fx/- mice, which had normal BP. Vasoconstrictions to phenylephrine and elevated extracellular K+ concentration were significantly reduced in NCX1SM-/- arteries. Because a high extracellular K+ concentration-induced vasoconstriction involves the activation of L-type voltage-gated Ca2+ channels (LVGCs), we measured LVGC-mediated currents and Ca2+ sparklets in isolated mesenteric artery myocytes. Both the currents and the sparklets were significantly reduced in NCX1 SM-/- (vs. WT or NCX1Fx/-) 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 Ca2+ sparklets between NCX1SM-/- and control myocytes, suggesting that LVGC expression was normal in NCX1SM-/- myocytes. Bay K 8644 did not, however, eliminate the difference in myogenic constriction between WT and NCX1SM-/- arteries. We conclude that, under physiological conditions, NCX1-mediated Ca2+ entry contributes significantly to the maintenance of MT. In NCX1SM-/- mouse artery myocytes, the reduced Ca2+ entry via NCX1 may lower cytosolic Ca2+ concentration and thereby reduce MT and BP. The reduced LVGC activity may be the consequence of a low cytosolic Ca2+ concentration.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume298
Issue number5
DOIs
StatePublished - May 2010
Externally publishedYes

Keywords

  • Bay K 8644
  • Calcium sparklets
  • Mesenteric arteries
  • Myogenic tone
  • Patch clamp

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Fingerprint Dive into the research topics of 'Knockout of Na<sup>+</sup>/Ca<sup>2+</sup> exchanger in smooth muscle attenuates vasoconstriction and L-type Ca<sup>2+</sup> channel current and lowers blood pressure'. Together they form a unique fingerprint.

  • Cite this