Transient Receptor Potential Channels, Natriuretic Peptides, and Angiotensin Receptor-Neprilysin Inhibitors in Patients With Heart Failure

Figures

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  FIGURE 1. Architecture of TRP channels. TRP can be activated by various physical and chemical stimuli and consist of six transmembrane helices (TM1-6), cytoplasmic N- and C-termini, and a pore area between TM5 and TM6. Ankyrin repeats are found in the amino termini of TRPC and TRPV channels. Currently, the functions and activation mechanisms of TRP family proteins are unclear.

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  FIGURE 2. Mechanisms of action of novel therapeutics for heart failure. The ARNi LCZ696 is split into the ARB valsartan and the neprilysin-inhibitor sacubitril. Valsartan abrogates signaling via the AT1 receptor, inhibiting deleterious effects mediated by Ang-II such as vasoconstriction, hypertrophy, and fibrosis in major cardiovascular organs. Sacubitril prevents breakdown of endogenous natriuretic peptides (ANP, BNP, and CNP), thereby augmenting their beneficial actions in cardiovascular disease. The overall effects of ARNi are vasodilatation, natriuresis, and diuresis, as well as inhibition of fibrosis and hypertrophy. Ularitide selectively targets NPR-A, whereas cenderitide activates both NPR-A and NPR-B. Both peptides increase intracellular cGMP, which in turn leads to inhibition of the renin-angiotensin-aldosterone system and attenuation of fibrosis, hypertrophy, and vasoconstriction. Our proposed model shows that TRPV1 interacting with NPR-A, activation of the NPR1 and ANP pathway leads to cGMP-dependent stimulation ofTRPV1 phosphorylation. PDE3 antagonists (enoximone, milrinone), calcium sensitizers (levosimendan), and a direct activator of cardiac myosin (omecamtiv mecarbil). ACE,…