ARTICLE: PDE1 Inhibition Modulates Ca v 1.2 Channel to Stimulate Cardiomyocyte Contraction

AUTHORS: Grace K MullerJoy SongVivek JaniYuejin WuTing LiuWilliam P D JeffreysBrian O'RourkeMark E AndersonDavid A Kass

JOURNAL: Circ Res. 2021 Oct 15;129(9):872-886. doi: 10.1161/CIRCRESAHA.121.319828. Epub 2021 Sep 15.


Rationale: cAMP activation of PKA (protein kinase A) stimulates excitation-contraction (EC) coupling, increasing cardiac contractility. This is clinically achieved by β-ARs (β-adrenergic receptor) stimulation or PDE3i (inhibition of phosphodiesterase type-3), although both approaches are limited by arrhythmia and chronic myocardial toxicity. PDE1i (Phosphodiesterase type-1 inhibition) also augments cAMP and enhances contractility in intact dogs and rabbits. Unlike β-ARs or PDE3i, PDE1i-stimulated inotropy is unaltered by β-AR blockade and induces little whole-cell Ca2+ (intracellular Ca2+ concentration; [Ca2+]i) increase. Positive inotropy from PDE1i was recently reported in human heart failure. However, mechanisms for this effect remain unknown.

Objective: Define the mechanism(s) whereby PDE1i increases myocyte contractility.

Methods and Results: We studied primary guinea pig myocytes that express the PDE1C isoform found in larger mammals and humans. In quiescent cells, the potent, selective PDE1i (ITI-214) did not alter cell shortening or [Ca2+]i, whereas β-ARs or PDE3i increased both. When combined with low-dose adenylate cyclase stimulation, PDE1i enhanced shortening in a PKA-dependent manner but unlike PDE3i, induced little [Ca2+]i rise nor augmented β-ARs. β-ARs or PDE3i reduced myofilament Ca2+ sensitivity and increased sarcoplasmic reticulum Ca2+ content and phosphorylation of PKA-targeted serines on TnI (troponin I), MYBP-C (myosin binding protein C), and PLN (phospholamban). PDE1i did not significantly alter any of these. However, PDE1i increased Cav1.2 channel conductance similarly as PDE3i (both PKA dependent), without altering Na+-Ca2+ exchanger current density. Cell shortening and [Ca2+]i augmented by PDE1i were more sensitive to Cav1.2 blockade and to premature or irregular cell contractions and [Ca2+]i transients compared to PDE3i. 

Conclusions: PDE1i enhances contractility by a PKA-dependent increase in Cav1.2 conductance with less total [Ca2+]i increase, and no significant changes in sarcoplasmic reticulum [Ca2+], myofilament Ca2+-sensitivity, or phosphorylation of critical EC-coupling proteins as observed with β-ARs and PDE3i. PDE1i could provide a novel positive inotropic therapy for heart failure without the toxicities of β-ARs and PDE3i.

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Research From Bench to Bedside

The story behind this paper began back in 2018, when the the laboratory of Dr. David Kass, professor in the Division of Cardiology, published a paper in Circulation titled “Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition.” They found that in conscious dogs and intact rabbits, the PDE1 inhibitor ITI-214 increased contractility and caused arterial dilation – called an inodilator – working by a cAMP mechanism. Importantly, it did so quite differently from what a beta-adrenergic agonist or PDE3 inhibitor achieves. The new paper, just published in Circulation Research and authored by Dr. Grace Muller, instructor in the Division of Cardiology, reveals the cellular mechanisms underlying these differences. The same inhibitor was also tested in  human heart failure patients in a joint Johns Hopkins and Duke University study reported earlier in 2021 in Circulation: Heart Failure titled “Acute Hemodynamic Effects and Tolerability of Phosphodiesterase-1 Inhibition With ITI-214 in Human Systolic Heart Failure.” In this proof of concept study, patients received a single dose at different concentrations, and the results showed similar cardiovascular changes as what Dr. Kass’ lab had first reported in the canine and rabbit models.  All together, these studies represent a rather fast bench-to-bedside progression in about 4 years time.

The next steps in the process is to find a path forward for future human trials. The same drug was also been recently studied in humans with Parkinson’s disease, as PDE1 is in the brain. Cardiac disease indications remain to be further explored as well. The research from the Hopkins teams also provides a prime example of how mice and rats are not always the right animal model. In the case of PDE1, both small rodents express the PDE1A isoform of the enzyme which primarily regulates cGMP, whereas larger mammals and humans express more PDE1C that regulates cAMP as well.  In both the larger animal and human hearts, and in heart muscle cells, cAMP appears to be the primary effector, albeit in a novel manner.




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