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Contribution of Cav1.2 Channels to Coronary Microvascular Dysfunction in Metabolic Syndrome
Author(s) -
Berwick Zachary C,
Dick Gregory M,
Bender Shawn B,
Moberly Steven P,
Kohr Meredith C,
Goodwill Adam G,
Obukhov Alexander G,
Tune Johnathan D
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.860.16
Subject(s) - medicine , nifedipine , blood flow , cardiology , reactive hyperemia , endocrinology , blockade , coronary circulation , coronary flow reserve , calcium , receptor
Previous investigations by our group indicate that diminished functional expression of K V channels impairs control of coronary blood flow in obesity/metabolic syndrome (MetS). The goal of this investigation was to test the hypothesis that coronary microvascular dysfunction in MetS is also related to subsequent increases in Ca V 1.2 channel activity. Initial studies revealed that inhibition of K V channels with 4‐aminopyridine (4AP, 0.3 mM) increased intracellular [Ca 2+ ], contracted isolated coronary arterioles, and decreased coronary reactive hyperemia, and that these effects were reversed by blockade of Ca V 1.2 channels. Further studies in chronically instrumented Ossabaw swine showed that inhibition of Ca V 1.2 channels with nifedipine (10 μg/kg, iv) had no effect on coronary blood flow at rest or during exercise in lean swine. However, blockade of Ca V 1.2 channels significantly elevated coronary blood flow, conductance, and the balance between flow and metabolism in swine with the MetS ( P < 0.05). These changes were associated with a ~50% increase in inward Ca V 1.2 current and elevations in α 1 c and α 2 δ 1 channel subunit expression in coronary smooth muscle cells from MetS swine. Taken together, these data indicate that increased functional expression of coronary Ca V 1.2 channels contributes to coronary microvascular dysfunction in the MetS.