# The Late L-type Ca Current as the Target for a New Class of Antiarrhythmics

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $563,220

## Abstract

PROJECT SUMMARY:
The motivation for these studies is the pressing need for a new class of effective and safe antiarrhythmics to
prevent VT/VF without compromising EC coupling. CaV channel blockers (Class IV antiarrhythmic agents, such
as Diltiazem and Verapamil) have limited therapeutic value because of their negative inotropic effect. These
investigators have recently discovered that arrhythmogenic EADs are potently suppressed by the minimal
modification of the L-type Ca channel biophysical parameters. Crucially, what these maneuvers have in
common is that they all reduce the late component of the L-type Ca current (late ICa,L). The selective reduction
of late ICa,L has the benefit of leaving peak ICa,L largely intact, preserving contractility. Regrettably, while the
relevance of the ICa,L window current to EAD formation was hypothesized 30 years ago, no therapy based on
this idea has emerged yet. The antiarrhythmic strategies that emerged from the investigators’ recent studies in
animal models of VT/VF are now ready to be pharmacologically implemented: Aim 1 proposes "to evaluate
LTCC gating modifiers selectively reducing the late component of ICa,L as prototype members of a new
class of antiarrhythmics that do not block peak ICa,L". Specifically, Aim 1A will "validate the antiarrhythmic
potential of pedestal ICa,L reduction using LTCC gating modifiers" and determine the efficacy of pilot
compounds that selectively decrease late ICa,L: roscovitine enantiomers, known to reduce ICa,L pedestal current.
Aim 1B will “validate the antiarrhythmic potential of ICa,L window current reduction using LTCC gating
modifiers”. Gabapentinoids, found in preliminary studies to reduce ICa,L window current by shifting LTCC
voltage-dependent activation to depolarized potentials, will be used as pilot compounds. Based on the success
of preliminary studies in single cells and full hearts, the ability of these drugs to prevent or suppress VT/VF will
be assessed in whole rabbit and rat hearts under EAD-favoring conditions (oxidative stress, hypokalemia).
Establishing the VT/VF-preventing efficacy of late ICa,L reduction in two small animal models will justify
translation to larger mammalian models and eventually humans. Aim 2, is designed “to identify the
molecular mechanisms underlying late ICa,L reduction by roscovitine and gabapentinoids, prototype
members of a potential new class of antiarrhythmic action”. The investigators will take advantage of their
recent breakthrough in optically tracking molecular transitions of the human CaV1.2 channel using Voltage
Clamp Fluorometry to determine the mechanism by which pilot compounds modify the LTCC to reduce late
ICa,L. Specifically, Aim 2A will “identify the molecular mechanisms underlying pedestal ICa,L reduction by
roscovitine” and Aim 2B will “identify the molecular mechanisms underlying window ICa,L reduction by
gabapentinoids”. This information will reveal how next-generation antiarrhythmics should act on the LTCC.
T...

## Key facts

- **NIH application ID:** 9915944
- **Project number:** 5R01HL134346-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Riccardo Olcese
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $563,220
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9915944

## Citation

> US National Institutes of Health, RePORTER application 9915944, The Late L-type Ca Current as the Target for a New Class of Antiarrhythmics (5R01HL134346-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9915944. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*