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https://hdl.handle.net/2440/53425
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Type: | Journal article |
Title: | Heterogeneity of L- and T-channels in the vasculature: Rationale for the efficacy of combined L- and T-blockade |
Author: | Smith, C. Wilson, D. Turner, S. Saint, D. Beltrame, J. |
Citation: | Hypertension, 2009; 53(4):654-660 |
Publisher: | Lippincott Williams & Wilkins |
Issue Date: | 2009 |
ISSN: | 0194-911X 1524-4563 |
Statement of Responsibility: | Christine J. Ball, David P. Wilson, Stuart P. Turner, David A. Saint and John F. Beltrame |
Abstract: | Clinical studies suggest that T-type Ca(2+) channel blockade may have incremental benefits over conventional L-channel blockade, particularly in microvascular disorders. This study examined functional vasomotor differences in L- and T-channel blockade between large and small vessels and compared the abundance of the L- and T-type channels in these vessels. The inhibition of endothelin-1 and potassium-induced vascular contractile responses by L-channel blockers (verapamil and nifedipine) was compared with combined L- and T-channel blockers (mibefradil and efonidipine) in large (rat aorta) and small (rat mesenteric and human subcutaneous) vessels using wire myography. All 4 of the Ca(2+) channel blockers inhibited contractile responses to a similar extent in large rat vessels; however, in rat microvessels, the combined L- and T-channel blockers produced significantly greater inhibition of contraction than L-channel blockers alone. The significance of this differential T-channel effect in microvessels was further supported by the following: (1) a greater abundance of T-channels compared with L-channels in microvessels but not in large vessels; (2) demonstration of divergent Ca(2+) channel blocker responses in human microvessels; (3) incremental inhibition of constrictor responses with combined L- and T-Ca(2+) channel blockers despite maximal L-channel blockade; (4) the use of structurally diverse Ca(2+) channel blockers with varied affinity for L- and T-channels; (5) the use of pharmacodynamically and therapeutically appropriate Ca(2+) channel blocker concentrations; (6) confirmation of contractile agonist independent responses; and (7) exclusion of an endothelium-dependent mechanism. We propose that T-type channels play an important role in regulating contractile responses in the microvasculature and, therefore, are a potential therapeutic target. |
Keywords: | calcium calcium channel blockers vessels vasoconstriction vasculature |
Description: | Copyright © 2009 American Heart Association, Inc. |
DOI: | 10.1161/HYPERTENSIONAHA.108.125831 |
Published version: | http://dx.doi.org/10.1161/hypertensionaha.108.125831 |
Appears in Collections: | Aurora harvest Molecular and Biomedical Science publications |
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