Inhibition of L-Type and Cyclic Nucleotide-Gated Calcium Channels Demonstrates Synergistic Mechanisms for Prolonging Vascular Contractions Induced by a Mimetic of Thromboxane A2




Kellum, Joseph

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Previous experiments have demonstrated that the rates of relaxation of blood vessels treated with the thromboxane-A2 mimetic, U-46619, are significantly lower when compared to vessels treated with other vasoactive agents (e.g. α-adrenergic agonists). As a means of investigating the molecular mechanisms responsible for this prolonged contraction, we examined the roles of two types of calcium channels. L-type Ca2+ channels have long been associated with the U-46619 contraction, while cyclic nucleotide-gated (CNG) Ca2+ channels have only recently been shown to be involved. We tested the hypothesis that functioning of both channels is necessary to prolong the U-46619 contraction. An isolated organ bath preparation was used to measure the rates of relaxation (g/min) in aortic vessel segments obtained from euthanized rabbits. Isolated vessels contracted with U-46619 were treated with either L-type channel inhibitor (nifedipine, 200 μM) or CNG channel inhibitor (L-cis-dilitiazem, 140 μM), or both inhibitors simultaneously. Mean rates of relaxation were obtained for the four treatment groups: nifedipine only (7.95 x 10-2 ± 0.562 x 10-2 g/min, n = 10), L-cis-diltiazem only (6.36 x 10-2 ± 0.603 x 10-2 g/min, n = 10), both inhibitors simultaneously (6.93 x 10-2 ± 0.875 x 10-2 g/min, n = 12), and a control with vehicle only (3.94 x 10-2 ± 0.494 x 10-2 g/min, n = 15). Statistical analysis of the data indicated that the mean relaxation rate for the vehicle-treated group differed significantly from the relaxation rates of the experimental groups (P < 0.001), which were deemed statistically synonymous (P = 0.324). These data indicate that inhibition of either calcium channel alone or both channels simultaneously leads to equivalent increases in the rate of relaxation. This demonstrates that optimal functioning of both channels is necessary for the prolonged contraction, characteristic of U-46619-treated vessels. These results may have implications for reversing the contractions in vessels during myocardial infarction or stroke.

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The 52nd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, February 4, 2014, 3-6 p.m., D1.502)

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Kellum, J., Monnet, P. L., Hinman, M. R., & Orr, J. A. (2014, February 4) Inhibition of L-type and cyclic nucleotide-gated calcium channels demonstrates synergistic mechanisms for prolonging vascular contractions induced by a mimetic of thromboxane A2 Poster session presented at the 52nd Annual Medical Students Research Forum, Dallas, TX. Retrieved from

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