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

Gerhard P Dahl,Gregory E Conner,Feng Qiu,Junjie Wang,Edward Spindler,Jason A Campagna,H Peter Larsson

doi:10.1016/j.ebiom.2016.06.027

Gerhard P Dahl, Gregory E Conner + Show 5 more

Open Access

https://doi.org/10.1016/j.ebiom.2016.06.027

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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. Research in ContextClevidipine 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.

Highlights

Clevidipine is a 3rd generation dihydropyridine (DHP) that lowers blood pressure via selective antagonism of peripheral vascular smooth muscle (VSM) voltage-gated L-type calcium channels (CaV1.2) (Fig. 1A)
Clevidipine is a potent pulmonary vasodilator with most of the pulmonary vascular resistance (PVR) reduction occurring at doses that are lower than those needed to cause the majority of the reduction of systemic blood pressure (Cleviprex package insert and (Kieler-Jensen et al, 2000)) (Fig. 1A)
Because clevidipine has greater potency for reducing PVR, it is possible that, in human lungs, there is expressed a unique combination of CaV1.2 splice variants with a higher affinity for clevidipine that CaV1.2 expressed in other tissues

Summary

Introduction

Clevidipine is a 3rd generation dihydropyridine (DHP) that lowers blood pressure via selective antagonism of peripheral vascular smooth muscle (VSM) voltage-gated L-type calcium channels (CaV1.2) (Fig. 1A). Clinical observations suggest that the mechanisms of clevidipine action are more complex than simple antagonism of peripheral VSM CaV1.2. When compared to standard of care, dyspnea relief in patients receiving clevidipine was more robust and faster, and this benefit was only partially related to the blood pressure lowering actions of clevidipine. This benefit was not conferred by nicardipine, another L-type blocking DHP agent. Clevidipine is a potent pulmonary vasodilator with most of the PVR reduction occurring at doses that are lower than those needed to cause the majority of the reduction of systemic blood pressure (Cleviprex package insert and (Kieler-Jensen et al, 2000)) (Fig. 1A)

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