Natriuretic peptides (NPs) are a family of three structurally related hormone/paracrine factors with natriuretic/diuretic and vasorelaxant properties. NPs consist of Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). These peptides are widely regulating blood pressure, cardiac growth, and neural and skeletal development.
NPR-A is the main natriuretic peptide receptor (NPR) located cell surface. It mediates diverse function via membrane-associated guanylyl cyclases (GC) activation, as well as the classical second messenger cyclic guanosine monophosphate (cGMP) production. NPR-A binds to ANP and BNP, leading to beneficial recompilation and anti-inflammatory effects. Thus it is important for NPR-A to improve human lung diseases. Significantly research has demonstrated that NPR-A results in the relaxation of airway smooth muscle (ASM), and the attenuation of airway inflammation and hyperresponsiveness. Here, we will introduce a potent NPR-A agonist, PL-3994.
PL-3994, an NPR-A agonist, has great potential to serve as a bronchodilator.
Specifically, PL-3994 dose-dependently induces cGMP generation in HEK293 cells, expressing recombinant human, dog, and rat NPR-As (EC50s=2nM, 3 nM, and 14 nM, respectively). The diverse efficacy is due to different affinities for NPR-As. PL-3994 (0.1 nM-100 mM; 5-20 min) also elicits a potent but small relaxation of pre-contracted human precision-cut lung slices (hPCLS). Interestingly, PL-3994 (50 μM, 2 h) is resistant to metabolism by neutral endopeptidase (NEP) with stability.
Besides, about in vivo potency, PL-3994 (10, 100 and 1000 mg/kg; i.t.; single dose) leads to a dose-dependent inhibition of the bronchoconstrictor response to aerosolized methacholine in guinea pigs. But PL-3994 lacks a significant effect in falling mean arterial blood pressure and heart rate.
All in all, PL-3994 is a full NPR-A agonist, relative to ANP, inducing cGMP production and has relatively natriuretic and hemodynamic effects. Meanwhile, PL-3994 is resistant to NEP and is capable of bronchodilator.