title: High affinity complexes of pannexin channels and L-type calcium channel splice-variants in human lung: Possible role in clevidipine-induced dyspnea relief in acute heart failure.
abstract: Clevidipine, a dihydropyridine (DHP) analogue, lowers blood pressure (BP) by inhibiting l-type calcium channels (CaV1.2; gene CACNA1C) predominantly located in vascular smooth muscle (VSM). However, clinical observations suggest that clevidipine acts by a more complex mechanism. Clevidipine more potently reduces pulmonary vascular resistance (PVR) than systemic vascular resistance and its spectrum of effects on PVR are not shared by other DHPs. Clevidipine has potent spasmolytic effects in peripheral arteries at doses that are sub-clinical for BP lowering and, in hypertensive acute heart failure, clevidipine, but not other DHPs, provides dyspnea relief, partially independent of BP reduction. These observations suggest that a molecular variation in CaV1.2 may exist which confers unique pharmacology to different DHPs. We sequenced CACNA1C transcripts from human lungs and measured their affinity for clevidipine. Human lung tissue contains CACNA1C mRNA with many different splice variations. CaV1.2 channels with a specific combination of variable exons showed higher affinity for clevidipine, well below the concentration associated with BP reduction. Co-expression with pannexin 1 further increased the clevidipine affinity for this CaV1.2 splice variant. A high-affinity splice variant of CaV1.2 in combination with pannexin 1 could underlie the selective effects of clevidipine on pulmonary arterial pressure and on dyspnea.
  
  
  BACKGROUND
  Clevidipine lowers blood pressure by inhibiting calcium channels in vascular smooth muscle. In patients with acute heart failure, clevidipine was shown to relieve breathing problems. This was only partially related to the blood pressure lowering actions of clevidipine and not conferred by another calcium channel inhibitor. We here found calcium channel variants in human lung that are more selectively inhibited by clevidipine, especially when associated with pannexin channels. This study gives a possible mechanism for clevidipine's relief of breathing problems and supports future clinical trials testing the role of clevidipine in the treatment of acute heart failure.
authors.affiliation: Department of Physiology and Biophysics, University of Miami, Miller School of Medicine, Miami, Florida, United States.
authors.forename: Gerhard P
authors.initials: GP
authors.lastname: Dahl
authors.affiliation: Department of Cell Biology, University of Miami, Miller School of Medicine, Miami Florida, United States.
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Conner
authors.affiliation: Department of Physiology and Biophysics, University of Miami, Miller School of Medicine, Miami, Florida, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Qiu
authors.affiliation: Department of Physiology and Biophysics, University of Miami, Miller School of Medicine, Miami, Florida, United States.
authors.forename: Junjie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Surgery and Perioperative Care, The Medicines Company, Parsippany, NJ, United States.
authors.forename: Edward
authors.initials: E
authors.lastname: Spindler
authors.affiliation: Surgery and Perioperative Care, The Medicines Company, Parsippany, NJ, United States.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Campagna
authors.affiliation: Department of Physiology and Biophysics, University of Miami, Miller School of Medicine, Miami, Florida, United States. Electronic address: plarsson@med.miami.edu.
authors.forename: H Peter
authors.initials: HP
authors.lastname: Larsson
mesh_terms: D000208:Acute Disease; D017398:Alternative Splicing; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000235:genetics* / Q000378:metabolism; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D004417:Dyspnea / Q000188:drug therapy / Q000209:etiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D017630:Connexins; D011725:Pyridines; C118563:clevidipine
keywords: CaV1.2; Clevidipine; Dyspnea; Hypertensive heart failure; Pannexin; Voltage-gated calcium channels