T-type calcium channels are involved in hypoxic pulmonary hypertension. (11th July 2014)

• Record Type: Journal Article
• Authors: Chevalier, Marc; Gilbert, Guillaume; Roux, Etienne; Lory, Philipe; Marthan, Roger; Savineau, Jean-Pierre; Quignard, Jean-François
• Is Part Of: Cardiovascular research. Volume 103:Number 4(2014)
• Page Start: 597
• Page End: 606
• Publication Date: 2014-07-11
• Subjects: Arterial reactivity -- Calcium channel blockers -- Pulmonary circulation -- Patch-clamp -- T-type calcium currents; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvu166
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: Pulmonary hypertension (PH) is the main disease of pulmonary circulation. Alteration in calcium homeostasis in pulmonary artery smooth muscle cells (PASMCs) is recognized as a key feature in PH. The present study was undertaken to investigate the involvement of T-type voltage-gated calcium channels (T-VGCCs) in the control of the pulmonary vascular tone and thereby in the development of PH. Methods and results: Experiments were conducted in animals (rats and mice) kept 3–4 weeks in either normal (normoxic) or hypoxic environment (hypobaric chamber) to induce chronic hypoxia (CH) PH. In vivo, chronic treatment of CH rats with the T-VGCC blocker, TTA-A2, prevented PH and the associated vascular hyperreactivity, pulmonary arterial remodelling, and right cardiac hypertrophy. Deletion of the Cav 3.1 gene (a T-VGCC isoform) protected mice from CH-PH. In vitro, patch-clamp and PCR experiments revealed the presence of T-VGCCs (mainly Cav 3.1 and Cav 3.2) in PASMCs. Mibefradil, NNC550396, and TTA-A2 inhibited, in a concentration-dependent manner, T-VGCC current, KCl-induced contraction, and PASMC proliferation. Conclusion: The present study demonstrates that T-VGCCs contribute to intrapulmonary vascular reactivity and is implicated in the development of hypoxic PH. Specific blockers of T-VGCCs may thus prove useful for the therapeutic management of PH.